benzofurans and Chemical-and-Drug-Induced-Liver-Injury

Increasing prevalence of herbal and dietary supplement-induced hepatotoxicity has been reported worldwide. Usnic acid (UA) is a well-known hepatotoxin derived from lichens. Since 2000, more than 20 incident reports have been received by the US Food and Drug Administration after intake of UA containing dietary supplement resulting in severe complications. Scientists and clinicians have been studying the cause, prevention and treatment of UA-induced hepatotoxicity. It is now known that UA decouples oxidative phosphorylation, induces adenosine triphosphate (ATP) depletion, decreases glutathione (GSH), and induces oxidative stress markedly leading to lipid peroxidation and organelle stress. In addition, experimental rat liver tissues have shown massive vacuolization associated with cellular swellings. Additionally, various signaling pathways, such as c-JNK N-terminal kinase (JNK), store-operated calcium entry, nuclear erythroid 2-related factor 2 (Nrf2), and protein kinase B/mammalian target of rapamycin (Akt/mTOR) pathways are stimulated by UA causing beneficial or harmful effects. Nevertheless, there are controversial issues, such as UA-induced inflammatory or anti-inflammatory responses, cytochrome P450 detoxifying UA into non-toxic or transforming UA into reactive metabolites, and unknown mechanism of the formation of vacuolization and membrane pore. This article focused on the previous and latest comprehensive putative mechanistic findings of UA-induced hepatotoxicity and cell death. New insights on controversial issues and future perspectives are also discussed and summarized.

Topics: Animals; Autophagy; Benzofurans; Cell Death; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Humans; Inflammation; Liver; Mitochondria; Oxidative Phosphorylation; Oxidative Stress

Topics: Amiodarone; Benzofurans; Chemical and Drug Induced Liver Injury; Eye Diseases; Humans; Hyperthyroidism; Lung Diseases; Peripheral Nervous System Diseases; Pigmentation Disorders; Thyroid Hormones

During January 10-11, 1978 in Lyon, France, a joint National Institute of Environmental Health Sciences/International Agency for Research on Cancer ad hoc Working Group considered and discussed the feasibility of coordinating epidemiological studies on the long-term hazards associated with the chlorinated dibenzo-p-dioxins and chlorinated dibenzofurans (PCDDs and and PCDFs). Nineteen invited scientists from eight countries presented introductory working papers summarizing the most up-to-date and relevant information available from their individual programs. This report represents the collective views and scientific opinions of the Working Group. The greater part of this document comprises epidemiological studies related to episodes of human exposures. The review begins with a brief section concerning possible routes of human exposure, an overview of the pertinent chemical characteristics, and the salient toxicological properties of the structurally similar PCDDs/PCDFs. The Working Group report ends with recommendations for future activities.

Topics: Abnormalities, Drug-Induced; Accidents, Occupational; Acne Vulgaris; Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Chickens; Dioxins; Female; Guinea Pigs; Haplorhini; Humans; Male; Mice; Occupational Diseases; Polychlorinated Dibenzodioxins; Rats; Structure-Activity Relationship

Topics: Abnormalities, Drug-Induced; Animal Diseases; Animals; Benzofurans; Biphenyl Compounds; Cattle; Cattle Diseases; Chemical and Drug Induced Liver Injury; Chickens; Dermatitis, Occupational; Dioxins; Edema; Environmental Exposure; Herbicides; Humans; Hydrocarbons, Halogenated; Poultry Diseases

Fasiglifam (TAK-875) is a G protein-coupled receptor 40 agonist that was being investigated for treatment of type 2 diabetes mellitus (T2DM). A development program was terminated late in phase III clinical trials due to liver safety concerns.. The liver safety of fasiglifam was assessed from data based on six phase II and nine phase III double-blind studies and two open-label studies with emphasis on pooled data from 15 double-blind studies from both global and Japanese development programs. Taking into consideration different daily doses of fasiglifam administered in clinical studies, the primary comparisons were between all patients exposed to fasiglifam (any dose) versus placebo, and, where applicable, versus the two active comparators, sitagliptin or glimepiride. A Liver Safety Evaluation Committee consisting of hepatologists blinded to treatment assignments evaluated hepatic adverse events (AEs) and serious AEs (SAEs) for causal relationship to study drug.. The analysis included data from 9139 patients with T2DM in 15 double-blind controlled studies who received either fasiglifam (n = 5359, fasiglifam group), fasiglifam and sitagliptin (n = 123), or a comparator agent (n = 3657, non-exposed group consisting of placebo and other antidiabetic agents). Exposure to treatment for more than 1 year ranged from 249 patients in the placebo arm, to 370 patients in the glimepiride arm and 617 patients in the fasiglifam 50 mg arm. The primary focus of the analysis was on the hepatic safety of fasiglifam. The overall safety profile based on treatment-emergent AEs (TEAEs), SAEs, deaths, and withdrawal due to AEs was similar between fasiglifam and placebo (excluding liver test abnormalities). However, there was an increased incidence rate of serum alanine aminotransferase (ALT) elevations > 3 × upper limit of normal (ULN), 5 × ULN, and 10 × ULN in fasiglifam-treated patients compared with those treated with placebo or active comparators. ALT elevations > 3 × ULN for fasiglifam were 2.7% compared with 0.8 and 0.5% for the active comparators and placebo. There did not appear to be a clear dose response in incidence of ALT elevations between patients receiving 25 or 50 mg daily. The cumulative incidence of elevations in serum ALT > 3 × ULN was higher in the first 6 months of treatment with fasiglifam compared with both placebo and the active comparators, but the rate of new ALT elevations appeared to be similar across all treatment groups thereafter. No demographic or baseline patient characteristics were identified to predict elevations exceeding ALT > 3 × ULN in fasiglifam-treated patients. The pattern of liver injury with fasiglifam was hepatocellular, and there were no reports of liver-related deaths, liver failure or life-threatening liver injury. Most fasiglifam-associated ALT elevations were asymptomatic and resolved promptly upon discontinuing treatment, but in two patients the recovery was prolonged. Importantly, three important serious liver injury cases were identified among fasiglifam-treated patients; one case was adjudicated to be a clear Hy's Law case and the two remaining cases were considered to closely approximate Hy's Law cases.. Although the incidence of overall AEs, SAEs, and deaths was similar between fasiglifam and placebo, a liver signal was identified based primarily on the difference in liver chemistry values in the fasiglifam group compared with the placebo and active comparator groups. Three serious liver injuries were attributed to fasiglifam treatment. Clinical development of fasiglifam was halted due to these liver safety concerns.

Topics: Adult; Aged; Alanine Transaminase; Benzofurans; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Liver; Male; Middle Aged; Sitagliptin Phosphate; Sulfones; Sulfonylurea Compounds

To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes.. A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina.. The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ≥3-5 × upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ≥3 × ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%,. Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration-mandated CV outcomes trial supported the termination of the fasiglifam clinical program.

Topics: Aged; Benzofurans; Cardiovascular Diseases; Cardiovascular System; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Sulfones; Treatment Outcome

To investigate the effect of fasiglifam on glycaemic control in people with type 2 diabetes mellitus (T2DM).. In total, 421 people with T2DM and glycated haemoglobin (HbA1c) ≥7.0% and ≤10.5% who had received only diet and exercise treatment for ≥12 weeks prior to screening were randomized to receive fasiglifam 25 or 50 mg or placebo. The primary efficacy endpoint was change from baseline in HbA1c at week 24.. The mean participant age was 53.5 years, mean baseline body mass index 32.3 kg/m. The data indicate that fasiglifam effectively reduced HbA1c from baseline for 24 weeks in participants with T2DM. The incidence of TEAEs was higher in the fasiglifam groups; however, the incidence of serious AEs was low overall and similar between groups. ALT elevations were observed only in the fasiglifam groups, which contributed to the decision to terminate the fasiglifam programme after completion of the present study.

Topics: Benzofurans; Body Mass Index; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Dose-Response Relationship, Drug; Double-Blind Method; Exercise; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Liver; Lost to Follow-Up; Male; Middle Aged; Obesity; Patient Dropouts; Receptors, G-Protein-Coupled; Sulfones

Fraxinellone (FRA), a major active component from Cortex Dictamni, produces hepatotoxicity via the metabolization of furan rings by CYP450. However, the mechanism underlying the hepatotoxicity of FRA remains unclear. Therefore, zebrafish larvae at 72 h post fertilization were used to evaluate the metabolic hepatotoxicity of FRA and to explore the underlying molecular mechanisms. The results showed that FRA (10-30 μM) induced liver injury and obvious alterations in the metabolomics of zebrafish larvae. FRA induces apoptosis by increasing the level of ROS and activating the JNK/P53 pathway. In addition, FRA can induce cholestasis by down-regulating bile acid transporters P-gp, Bsep, and Ntcp. The addition of the CYP3A inhibitor ketoconazole (1 μM) significantly reduced the hepatotoxicity of FRA (30 μM), which indicated that FRA induced hepatotoxicity through CYP3A metabolism. Targeted metabolomics analysis indicates the changes in amino acid levels can be combined with molecular biology to clarify the mechanism of hepatotoxicity induced by FRA, and amino acid metabolism monitoring may provide a new method for the prevention and treatment of DILI from FRA.

Topics: Amino Acids; Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Larva; Liver; Oxidative Stress; Zebrafish

Topics: Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Ischemia; Ischemic Stroke; Magnetic Resonance Spectroscopy; Neuroprotective Agents; Rats; Stroke

Salvianolic acid B(Sal B), tanshinone Ⅱ_A(TSN Ⅱ_A), and glycyrrhetinic acid(GA) lipid emulsion(GTS-LE) was prepared by the high-speed dispersion method combined with ultrasonic emulsification.The preparation process of the emulsion was optimized by single-factor method and D-optimal method with appearance, centrifugal stability, and particle size of the emulsion as evalua-tion indexes, followed by verification.In vitro release of Sal B, TSN Ⅱ_A, and GA in GTS-LE was performed by reverse dialysis.In vivo pharmacokinetic evaluation was carried out in mice.The acute liver injury model was induced by acetaminophen.The effect of oral GTS-LE on the acute liver injury was investigated by serum liver function indexes and pathological changes in liver tissues of mice.The results showed that under the optimal preparation process, the average particle size of GTS-LE was(145.4±9.25) nm and the Zeta potential was(-33.6±1.45) mV.The drug-loading efficiencies of Sal B, TSN Ⅱ_A, and GA in GTS-LE were above 95%, and the drug release in vitro conformed to the Higuchi equation.The pharmacokinetic results showed that the C_(max) of Sal B, TSN Ⅱ_A, and GA in GTS-LE was 3.128, 2.7, and 2.85 times that of the GTS-S group, and AUC_(0-t) of Sal B, TSN Ⅱ_A, and GA in GTS-LE was 3.09, 2.23, and 1.9 times that of the GTS-S group.After intragastric administration of GTS-LE, the activities of alanine aminotransferase and aspartate aminotransferase were significantly inhibited, the content of malondialdehyde was reduced, and the structure of hepatocytes recovered to normal.In conclusion, GTS-LE can delay the release of Sal B and promote the release of TSN Ⅱ_A and GA.The encapsulation of three drug components in the emulsion can improve the oral bioavailability to varying degrees and can effectively prevent the acute liver injury caused by acetaminophen.

Topics: Abietanes; Acetaminophen; Alanine Transaminase; Animals; Antipyretics; Aspartate Aminotransferases; Benzofurans; Chemical and Drug Induced Liver Injury; Depsides; Emulsions; Glycyrrhetinic Acid; Liver; Malondialdehyde; Mice

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially fatal disease that is unpredictable and independent of the dose of the drug. Increasing evidence suggests that the majority of IDILI cases are immune-mediated, and the aberrant activation of inflammasome plays a vital role in progression. Psoraleae Fructus (PF), a tonic Chinese medicine, has been able to cause IDILI, but the precise mechanism of hepatotoxicity remains unclear. In this study, eight bioactive compounds involved in PF-induced inflammasome activation were investigated. The results demonstrated that psoralidin activated the inflammasomes followed by secreting caspase-1 and interleukin 1β (IL-1β) in a dose-dependent manner. Interestingly, MCC950, a potent inhibitor of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, could not entirely suppress the psoralidin-induced inflammasome activation. Moreover, psoralidin significantly induced IL-1β maturation and caspase-1 activation in NLRP3-knockout bone marrow-derived macrophages (BMDMs), suggesting that psoralidin not only activates the NLRP3 inflammasome but also activates other types of inflammasomes. The results also demonstrated that psoralidin activated the inflammasomes by promoting the C-terminal caspase recruitment domain (ASC) oligomerization, and the production of mitochondrial reactive oxygen species (mtROS) is a decisive factor in psoralidin-induced inflammasome activation. Importantly, in vivo data revealed that psoralidin induced hepatic inflammation, increased aminotransferase activity and increased the production of IL-1β and tumor necrosis factor(TNF-α) in a susceptible mouse model of lipopolysaccharide (LPS)-mediated IDILI. In summary, these results confirmed that psoralidin causes IDILI by inducing inflammasome activation. The study suggests that psoralidin is a possible risk factor and is responsible for PF-induced IDILI.

Topics: Animals; Benzofurans; Cells, Cultured; Chemical and Drug Induced Liver Injury; Coumarins; Disease Models, Animal; Female; Inflammasomes; Lipopolysaccharides; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Phytochemicals; Psoralea

Usnic acid (UA) is one of the well-known lichen metabolites that induces liver injury. It is mainly extracted from Usnea longissima and U. diffracta in China or from other lichens in other countries. U. longissima has been used as traditional Chinese medicine for treatment of cough, pain, indigestion, wound healing and infection. More than 20 incidences with hepatitis and liver failure have been reported by the US Food and Drug Administration since 2000. UA is an uncoupler of oxidative phosphorylation causing glutathione and ATP depletion. Previous histological studies observed extensive cell and organelle swellings accompanied with hydrotropic vacuolization of hepatocytes.. This study was to investigate the mechanism of UA-induced liver toxicity in normal human L02 liver cells and ICR mice using various techniques, such as immunoblotting and siRNA transfection.. Assays were performed to evaluate the oxidative stress and levels of GSH, MDA and SOD. Double flouresencence staining was used for the detection of apoptotic cell death. The protein expressions, such as glutathione S transferase, glutathione reductase, glutathione peroxidase 4, catalase, c-Jun N-terminal protein kinase, caspases, gastamin-D and porimin were detected by Western blotting. Comparisons between transfected and non-transfected cells were applied for the elucidation of the role of porimin in UA-induced hepatotoxicity. Histopathological examination of mice liver tissue, serum total bilirubin and hepatic enzymes of alanine aminotransferase and aspatate aminotransferase were also studied.. The protein expressions of glutathione reductase, glutathione S transferase and glutathione peroxidase-4 were increased significantly in normal human L02 liver cells. Catalase expression was diminished in dose-dependent manner. Moreover, (+)-UA did not induce the activation of caspase-3, caspase-1 or gasdermin-D. No evidence showed the occurrence of pyroptosis. However, the porimin expressions were increased significantly. In addition, (+)-UA caused no cytotoxicity in the porimin silencing L02 cells.. In conclusion, (+)-UA induces oncotic L02 cell death via increasing protein porimin and the formation of irreversible membrane pores. This may be the potential research area for future investigation in different aspects especially bioactivity and toxicology.

Topics: Animals; Anti-Infective Agents; Benzofurans; Caspase Inhibitors; Caspases; Cell Death; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Gene Knockdown Techniques; Glutathione; Hepatocytes; Humans; Intracellular Signaling Peptides and Proteins; Ischemia; JNK Mitogen-Activated Protein Kinases; Liver; Mice, Inbred ICR; Necrosis; Oxidative Stress; Phosphate-Binding Proteins; Receptors, Cell Surface

Development of TAK-875 was discontinued when a small number of serious drug-induced liver injury (DILI) cases were observed in Phase 3 clinical trials. Subsequent studies have identified hepatocellular oxidative stress, mitochondrial dysfunction, altered bile acid homeostasis, and immune response as mechanisms of TAK-875 DILI and the contribution of genetic risk factors in oxidative response and mitochondrial pathways to the toxicity susceptibility observed in patients. We tested the hypothesis that a novel preclinical approach based on gene pathway analysis in the livers of Collaborative Cross mice could be used to identify human-relevant mechanisms of toxicity and genetic risk factors at the level of the hepatocyte as reported in a human genome-wide association study. Eight (8) male mice (4 matched pairs) from each of 45 Collaborative Cross lines were treated with a single oral (gavage) dose of either vehicle or 600 mg/kg TAK-875. As expected, liver injury was not detected histologically and few changes in plasma biomarkers of hepatotoxicity were observed. However, gene expression profiling in the liver identified hundreds of transcripts responsive to TAK-875 treatment across all strains reflecting alterations in immune response and bile acid homeostasis and the interaction of treatment and strain reflecting oxidative stress and mitochondrial dysfunction. Fold-change expression values were then used to develop pathway-based phenotypes for genetic mapping which identified candidate risk factor genes for TAK-875 toxicity susceptibility at the level of the hepatocyte. Taken together, these findings support our hypothesis that a gene pathway-based approach using Collaborative Cross mice could inform sensitive strains, human-relevant mechanisms of toxicity, and genetic risk factors for TAK-875 DILI. This novel preclinical approach may be helpful in understanding, predicting, and ultimately preventing clinical DILI for other drugs.

Topics: Animals; Benzofurans; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Collaborative Cross Mice; Gene Expression Profiling; Genetic Predisposition to Disease; Genome-Wide Association Study; Hepatocytes; Humans; Male; Mice; Oxidative Stress; Risk Factors; Sulfones

New phenylethylamine derivatives are among the most commonly abused new psychoactive substances. They are synthesized and marketed in lieu of classical amphetaminic stimulants, with no previous safety testing. Our study aimed to determine the in vitro hepatotoxicity of two benzofurans [6-(2-aminopropyl)benzofuran (6-APB) and 5-(2-aminopropyl)benzofuran (5-APB)] that have been misused as 'legal highs'. Cellular viability was assessed through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay, following 24-h drug exposure of human hepatoma HepaRG cells (EC

Topics: Animals; Autophagy; Benzofurans; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Designer Drugs; Hep G2 Cells; Hepatocytes; Humans; Isomerism; Male; Membrane Potential, Mitochondrial; Oxidative Stress; Propylamines; Rats, Wistar; Reactive Oxygen Species

Fraxinellone, a furanoid, is one of the bioactive and potentially hepatotoxic constituents from

Topics: Activation, Metabolic; Administration, Oral; Alanine Transaminase; Animals; Aspartate Aminotransferases; Benzofurans; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Dictamnus; Female; Liver; Male; Mice, Inbred ICR; Recombinant Proteins

Topics: Animals; Benzofurans; Blood Glucose; Chemical and Drug Induced Liver Injury; Gene Expression Regulation; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Lipids; Liver; Liver Cirrhosis, Experimental; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones

Drug-induced liver injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market; this is partially due to the inability to identify patients who are at risk

Topics: Alleles; Benzofurans; Case-Control Studies; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cohort Studies; Datasets as Topic; Gene Expression Profiling; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Hepatocytes; Humans; Microarray Analysis; Multifactorial Inheritance; Polymorphism, Single Nucleotide; Sulfones

TAK-875 (fasiglifam), a GPR40 agonist in development for the treatment of type 2 diabetes (T2D), was voluntarily terminated in Phase III trials due to adverse liver effects. The potential mechanisms of TAK-875 toxicity were explored by combining in vitro experiments with quantitative systems toxicology (QST) using DILIsym, a mathematical representation of drug-induced liver injury. In vitro assays revealed that bile acid transporters were inhibited by both TAK-875 and its metabolite, TAK-875-Glu. Experimental data indicated that human bile salt export pump (BSEP) inhibition by TAK-875 was mixed whereas sodium taurocholate co-transporting polypeptide (NTCP) inhibition by TAK-875 was competitive. Furthermore, experimental data demonstrated that both TAK-875 and TAK-875-Glu inhibit mitochondrial electron transport chain (ETC) enzymes. These mechanistic data were combined with a physiologically based pharmacokinetic (PBPK) model constructed within DILIsym to estimate liver exposure of TAK-875 and TAK-875-Glu. In a simulated population (SimPops) constructed to reflect T2D patients, 16/245 (6.5%) simulated individuals developed alanine aminotransferase (ALT) elevations, an incidence similar to that observed with 200 mg daily dosing in clinical trials. Determining the mode of bile acid transporter inhibition (Ki) was critical to accurate predictions. In addition, simulations conducted on a sensitive subset of individuals (SimCohorts) revealed that when either BSEP or ETC inhibition was inactive, ALT elevations were not predicted to occur, suggesting that the two mechanisms operate synergistically to produce the observed clinical response. These results demonstrate how utilizing QST methods to interpret in vitro experimental results can lead to an improved understanding of the clinically relevant mechanisms underlying drug-induced toxicity.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 11; Benzofurans; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Computer Simulation; Humans; Liver; Mitochondria; Models, Biological; Sulfones

Different approaches to safety event collection influence the determination of liver toxicity within drug development programs. Herein, a description of how fasiglifam-induced liver injury was detected is provided.. This eight-trial drug development program was intended to evaluate fasiglifam (25 mg, 50 mg) against placebo or active comparators (glimepiride, sitagliptin) in approximately 11,000 suboptimally controlled patients with type 2 diabetes (terminated Dec 2013 due to liver toxicity). Liver safety had been pre-identified as a concern, and within the phase 3 trials, was measured through (1) adverse event reporting, (2) central predefined liver monitoring schedule with various thresholds for potential drug-induced liver injury, and (3) blinded adjudication of serious liver toxicity by a panel of experts in drug-induced liver injury. A single data monitoring committee provided safety oversight across all trials within the program.. Prior to program termination, 7595 of 7602 (99.9%) randomized participants across the eight trials received at least one dose of the study drug (fasiglifam, placebo, or active control). No concerning trends were noted in adverse or serious adverse event frequency, suspected unexpected serious adverse reaction, alanine or aspartate transaminase elevations, or hepatobiliary or gastrointestinal adverse events as reported by local site investigators. However, the predefined central liver safety measurements revealed a greater frequency of possible Hy's Law cases (5 vs 2) and a 3- to 7-fold greater relative risk in alanine or aspartate transaminase elevation (with respect to upper limit of normal) within fasiglifam recipients compared with placebo/active control: alanine or aspartate transaminase > 3×: relative risk 3.34 (95% confidence interval 2.29-4.90), alanine or aspartate transaminase > 5×: relative risk 6.60 (95% confidence interval 3.03-14.38), alanine or aspartate transaminase > 8×: relative risk 6.14 (95% confidence interval 2.18-17.27), and alanine or aspartate transaminase > 10×: relative risk 6.74 (95% confidence interval 2.05, 22.14). All elevations resolved on study drug discontinuation. Drug-induced liver injury was adjudicated as highly likely or probably related in 0.64% of fasiglifam-treated versus 0.06% placebo or active control-treated patients.. In spite of clear liver toxicity detected with a systematic surveillance program, liver safety signals were not identified from investigator adverse event reporting alone. By integrating key safety monitoring processes within the randomized design of adequately sized clinical trials, the rare but serious liver toxicity signal became clear, leading to timely program termination.

Topics: Benzofurans; Chemical and Drug Induced Liver Injury; Clinical Trials Data Monitoring Committees; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Humans; Liver Function Tests; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Sulfones

The purpose of this study was to investigate the pharmacological effects of salvianolic acid B (SA-B) on α-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury with the focus on bile acid homeostasis and anti-inflammatory pathways. Rats were randomly assigned into four groups. The control group was given normal saline (i.p.) for 7 consecutive days and on the 5th day was given the vehicle (i.g.). Model group was treated with normal saline (i.p.) for 7 days and administrated with ANIT (75 mg/kg, i.g.) on the 5th day. The SA-B groups were treated with SA-B (15 mg/kg and 30 mg/kg, i.p.) for 7 consecutive days as well as ANIT (75 mg/kg, i.g.) on the 5th day. We found that the serum levels of ALT, γ-GT, TBA, and other liver function indexes were found to be lower in the SA-B treatment groups than in the model group. SA-B also upregulated the transporters and enzymes involved in bile acid homeostasis such as Bsep, Oatp2, and Cyp3a2 in rats and BSEP, CYP3A4, and OATP2 in human cell lines. Moreover, SA-B suppressed NF-κB translocation into the nucleus, inhibited phosphorylation of p38 and JNK, and inhibited inflammation markers including IL-1β, IL-6, TGF-β, TNF-α, and COX-2 to extenuate cholestatic liver injury both in vivo and vitro. Taken together, our findings suggest that anti-cholestatic effects of SA-B may be associated with its ability to regulate NF-κB/IκB and MAPK inflammatory signaling pathways to inhibit inflammation and regulate transporters and enzymes to maintain bile acid homeostasis.

Topics: 1-Naphthylisothiocyanate; Animals; Benzofurans; Carrier Proteins; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Cholestasis; Cytokines; Humans; JNK Mitogen-Activated Protein Kinases; Liver; Male; Membrane Glycoproteins; NF-kappa B; NF-KappaB Inhibitor alpha; p38 Mitogen-Activated Protein Kinases; Protective Agents; Rats, Sprague-Dawley; Signal Transduction

An 81-year-old woman developed liver dysfunction after two months' treatment with direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection. She was positive for serum anti-nuclear antibody, with an elevated immunoglobulin G level. A liver biopsy revealed high-grade interface hepatitis and infiltrate of lymphocytes and plasma cells. DAA-associated drug-induced autoimmune hepatitis (DI-AIH) was considered. Her liver dysfunction improved after discontinuing DAA therapy and starting prednisolone treatment. The differential diagnosis for AIH should include liver injury during DAA therapy for chronic HCV infection.

Topics: Aged, 80 and over; Antibodies, Antinuclear; Antiviral Agents; Benzofurans; Biopsy; Chemical and Drug Induced Liver Injury; Drug Combinations; Female; Hepatitis C, Chronic; Hepatitis, Autoimmune; Humans; Imidazoles; Liver; Quinoxalines

Fasiglifam (TAK-875), a G protein-coupled receptor 40 (GPR40) agonist, was a drug candidate for type 2 diabetes. However, its development was terminated in phase 3 trials due to liver safety concerns. Although TAK-875 was reported to inhibit hepatobiliary transporters and disturb bile acid disposition, pathogenic mechanisms of TAK-875-induced liver injury are not fully understood. In this study, we sought to identify the mechanisms with a hepatic genome-wide transcriptomic analysis in a murine model. We demonstrated that, among the three GPR40 agonists, TAK-875, AMG-837, and TUG-770, only TAK-875 induced acute liver injury in mice. Transcriptome profiles of TAK-875-exposed liver was compared with those of non-hepatotoxic analogues AMG-837 and TUG-770 as negative controls and those of classical hepatotoxicants concanavalin A and carbon tetrachloride as positive controls. The comparative hepatic transcriptome analyses revealed the enrichment of genes involved in inflammation, endoplasmic reticulum (ER) stress, apoptosis, and hepatic lipid accumulation, suggesting that these events play pathophysiologic roles in the development of TAK-875-induced liver injury. These results were validated by quantitative PCR with significant changes in chemokines, danger signals, ER stress mediators, proapoptotic factors, and hepatic steatosis markers only in TAK-875-exposed liver. Pretreatment of TAK-875-administered mice with an ER stress inhibitor 4-phenylbutyric acid (4-PBA) alleviated the liver injury. Consistent with the in vivo study, pretreatment of HepG2 cells with 4-PBA significantly improved the decrease of cell viability induced by TAK-875. In conclusion, by a comprehensive transcriptomic analysis, we found multiple possible processes that contribute to TAK-875-induced acute liver injury in mice.

Topics: Animals; Benzofurans; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Concanavalin A; Female; Liver; Liver Failure, Acute; Mice; Mice, Inbred ICR; Molecular Structure; Sulfones; Transcriptome

Cortex Dictamni is a commonly-used traditional Chinese herbal medicine for the treatment of skin inflammation, tinea, and eczema. Recently, some studies reported that Cortex Dictamni might induce liver injury, suggesting more attention to its safety. The current study was designed to investigate subchronic toxicity of Cortex Dictamni aqueous extract (CDAE) and ethanol extract (CDEE) in mice and the potential hepatotoxicity mechanisms in vitro. Firstly, CDAE or CDEE groups were administrated with varying dosages (2.3, 4.6, or 9.2 g/kg/day, p.o.) in mice for 28 days in subchronic toxicity studies. General clinical signs and biochemical parameters were examined, and morphological analyses were conducted. Secondly, we identified the different constituents of CDAE and CDEE using HPLC-MS/MS and chose major components for further study. In order to determine the toxic components, we investigated the cytotoxicity of extracts and chosen components using CCK-8 assay in HepG2 cells. Furthermore, we explored the possible hepatotoxicity mechanisms of Cortex Dictamni using a high content analysis (HCA). The results showed that no significant differences of general clinical signs were observed in mice. Aspartate alanine aminotransferase (ALT) and aminotransferase (AST) were significantly increased in the high-dose CDAE and CDEE groups compared to the control group. Meanwhile, the absolute and relative liver weights and liver/brain ratio were significantly elevated, and histological examination of liver demonstrated cellular enlargement or nuclear shrinkage. In UPLC analysis, we compared the chemical constituents between CDAE and CDEE, and chose dictamnine, obakunone, and fraxinellone for hepatotoxicity evaluation in the in vitro studies. In the CCK-8 assay, CDAE, CDEE, dictamnine, obakunone, and fraxinellone decreased the cell viability in a dose-dependent manner after treatment for 48 h. Furthermore, the cell number decreased, while the nuclear intensity, cell membrane permeability, and concentration of reactive oxygen species were shown to increase, meanwhile, mitochondrial membrane potential was also changed in HepG2 cells following 48 h of compounds treatment using HCA. Our studies suggested that CDAE and CDEE have potential hepatotoxicity, and that the alcohol extraction process could increase toxicity. Dictamnine, obakunone, and fraxinellone may be the possible toxic components in Cortex Dictamni with dictamnine as the most potentially hepatotoxic component, whose

Topics: Animals; Apoptosis; Benzofurans; Benzoxepins; Cell Count; Cell Survival; Chemical and Drug Induced Liver Injury; Dictamnus; Drugs, Chinese Herbal; Ethanol; Female; Hep G2 Cells; Humans; Limonins; Liver; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred ICR; Quinolines; Toxicity Tests, Subchronic; Water

TAK-875, a GPR40 agonist, was withdrawn from Phase III clinical trials due to drug-induced liver injury (DILI). Mechanistic studies were conducted to identify potential DILI hazards (covalent binding burden (CVB), hepatic transporter inhibition, mitochondrial toxicity, and liver toxicity in rats) associated with TAK-875. Treatment of hepatocytes with radiolabeled TAK-875 resulted in a CVB of 2.0 mg/day, which is above the threshold of 1 mg/day considered to be a risk for DILI. Covalent binding to hepatocytes was due to formation of a reactive acyl glucuronide (AG) and, possibly, an acyl-CoA thioester intermediate. Formation of TAK-875AG in hepatocytes and/or in vivo was in the order of non-rodents > human (in vitro only) > rat. These data suggest that non-rodents, and presumably humans, form TAK-875AG more efficiently than rats, and that AG-mediated toxicities in rats may only occur at high doses. TAK-875 (1000 mg/kg/day) formed significant amounts of AG metabolite (≤32.7 μM) in rat liver that was associated with increases in ALT (×4), bilirubin (×9), and bile acids (×3.4), and microscopic findings of hepatocellular hypertrophy and single cell necrosis. TAK-875 and TAK-875AG had similar potencies (within 3-fold) for human multi-drug resistant associated protein 2/4 (MRP2/4) and bile salt export pump, but TAK-875AG was exceptionally potent against MRP3 (0.21 μM). Inhibition of MRPs may contribute to liver accumulation of TAK-875AG. TAK-875 also inhibited mitochondrial respiration in HepG2 cells, and mitochondrial Complex 1 and 2 activities in isolated rat mitochondria. In summary, formation of TAK-875AG, and possibly TAK-875CoA in hepatocytes, coupled with inhibition of hepatic transporters and mitochondrial respiration may be key contributors to TAK-875-mediated DILI.

Topics: Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Dogs; Dose-Response Relationship, Drug; Gene Expression; Hep G2 Cells; Hepatocytes; Humans; Macaca fascicularis; Mitochondria, Liver; Multidrug Resistance-Associated Proteins; Organic Anion Transporters; Oxygen Consumption; Protein Binding; Rats; Species Specificity; Sulfones

This study deals with the levels of toxic polychlorinated dibenzo-p-dioxin and furan congeners (PCDD/Fs) in the livers of piglets affected by infectious diseases using isotope dilution high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). Seventeen toxic congeners in the liver samples infected with bacterial and viral diseases were compared. For porcine reproductive and respiratory syndrome virus (PRRSV) samples, the North American- and European-type PRRS diseases were observed. This study shows that there are significantly different levels of PCDD/Fs, present, which vary according to the types of diseases as evidenced by our analysis of the piglet liver samples.

Topics: Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Liver; Mass Spectrometry; Polychlorinated Dibenzodioxins; Swine

Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs.

Topics: Administration, Oral; Animals; Benzofurans; Bile Acids and Salts; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dogs; Dose-Response Relationship, Drug; Homeostasis; Humans; Male; Rats; Rats, Sprague-Dawley; Sulfones

Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer's disease. Most hybrids exhibited good inhibitory activities on cholinesterases and β-amyloid self-aggregation. Selected compounds displayed significant inhibition of human β-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both β-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 μM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Behavior, Animal; Benzofurans; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Cholinesterase Inhibitors; Crystallography, X-Ray; Drug Design; Humans; Male; Mice; Mice, Inbred ICR; Models, Molecular; Nootropic Agents; Structure-Activity Relationship; Tacrine; Torpedo

We have recently demonstrated that concanavalin A (Con A)-induced hepatitis is associated with the release of endogenous 1-methylnicotinamide (MNA). Here we study the mechanism by which exogenous MNA alleviates Con A-induced liver inflammation and injury in vivo. The involvement of prostacyclin (PGI2) in hepatoprotective action of MNA (30-100 mg kg(-1); i.v.) was studied by the use of IP receptor antagonist RO3244794 (10 mg kg(-1); p.o.) given prior to Con A (5-20 mg kg(-1); i.v.). Liver damage was assessed by measurements of: liver specific transaminases in plasma (alanine aminotransferase; aspartate aminotransferase); cytokines release (IL-4, IFN-γ and TNF-α); liver histopathology; and 24h survival rates. Additionally, the effect of a stable analog of prostacyclin (carbaprostacyclin) on IL-4, IFN-γ and TNF-α production by isolated spleen lymphocytes in response to Con A was analyzed. MNA diminished Con A-induced rise in liver specific transaminases, alleviated histopathological injury and improved 24h survival rates, the latter effect in a degree comparable with the pretreatment of animals with dexamethasone (0.5 mg kg(-1); i.p.). MNA inhibited also a rise in IL-4 and TNF-α concentration in plasma measured 2 h after Con A administration, while IFN-γ was less affected. The effects of MNA were reversed by pretreatment with IP antagonist RO3244794. In isolated spleen lymphocytes, carbaprostacyclin profoundly decreased production of IL-4, the effect on TNF-α was modest with no effect on IFN-γ production. In conclusion, MNA attenuated Con A-induced hepatitis by a prostacyclin-dependent mechanism involving the inhibition of lymphocytes-derived IL-4 and the inhibition of Kuppfer-cells derived TNF-α.

Topics: Animals; Benzofurans; Cells, Cultured; Chemical and Drug Induced Liver Injury; Concanavalin A; Dexamethasone; Epoprostenol; Interleukin-4; Liver; Mice; Mice, Inbred BALB C; Niacinamide; Propionates; Receptors, Epoprostenol; Tumor Necrosis Factor-alpha

Investigation of the pharmacological potential of Tetrahydrofurano/pyrano quinoline and Benzo [b]furoindolyl derivatives in acute inflammation, pain and oxidative stress.. Tetrahydrofurano/ pyrano quinoline and Benzo[b]furoindolyl were evaluated for anti-inflammatory activity by carrageenan-induced hind paw edema in rats. Analgesic activity in mice was assessed by both peripheral and central analgesic models. The free radical scavenging activity of the synthetic compound was analyzed by the in vivo antioxidant assays, by measuring the antioxidant enzymes such as Superoxide dismutase (SOD), Catalase and Peroxidase from the liver homogenate and the in vitro antioxidant activity was evaluated by DPPH photometric assay, Hydroxyl radical scavenging and Lipid Peroxidation assay.. The compounds had substantially inhibited the inflammation induced by subcutaneous carrageenan injection. The same compounds had demonstrated remarkable central and peripheral analgesic activity with potent free radical scavenging activity as evident from both in vitro and in vivo antioxidant assays.. Tetrahydrofurano/pyrano quinoline and Benzo[b]furoindolyl derivatives exhibit varied pharmacological activities that include anti-inflammatory, analgesic and antioxidant activity.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antioxidants; Benzofurans; Carbon Tetrachloride; Carrageenan; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Design; Edema; Furans; Indoles; Lipid Peroxidation; Liver; Mice; Oxidative Stress; Pain; Quinolines; Rats

Acetaminophen (APAP) is used drugs worldwide for treating pain and fever. However, APAP overdose is the principal cause of acute liver failure in Western countries. Salvianolic acid B (SalB), a major water-soluble compound extracted from Radix Salvia miltiorrhiza, has well-known antioxidant and anti-inflammatory actions. We aimed to evaluate the ability of SalB to protect against APAP-induced acute hepatotoxicity by inducing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. SalB pretreatment ameliorated acute liver injury caused by APAP, as indicated by blood aspartate transaminase levels and histological findings. Moreover, SalB pretreatment increased the expression of Nrf2, Heme oxygenase-1 (HO-1) and glutamate-l-cysteine ligase catalytic subunit (GCLC). Furthermore, the HO-1 inhibitor zinc protoporphyrin and the GCLC inhibitor buthionine sulfoximine reversed the protective effect of SalB. Additionally, siRNA-mediated depletion of Nrf2 reduced the induction of HO-1 and GCLC by SalB, and SalB pretreatment activated the phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) signaling pathways. Both inhibitors (PI3K and PKC) blocked the protective effect of SalB against APAP-induced cell death, abolishing the SalB-induced Nrf2 activation and decreasing HO-1 and GCLC expression. These results indicated that SalB induces Nrf2, HO-1 and GCLC expression via activation of the PI3K and PKC pathways, thereby protecting against APAP-induced liver injury.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents; Antioxidants; Benzofurans; Cell Death; Chemical and Drug Induced Liver Injury; Gene Expression; Glutamate-Cysteine Ligase; Heme Oxygenase-1; Hep G2 Cells; Humans; Male; Metabolic Detoxication, Phase II; Mice, Inbred Strains; NF-E2-Related Factor 2; Phosphatidylinositol 3-Kinases; Protein Kinase C; Salvia miltiorrhiza; Signal Transduction; Up-Regulation

Novel hepatoprotectives are needed to address the increasing cases of liver problems worldwide. Pterocarpus erinaceus Poir (Fabaceae) ethanol stem bark extract (PE) and its constituent flavonoid, homopterocarpin (HP), were investigated for their protective property in acetaminophen-induced oxidative stress and liver damage.. Adult male albino rats were divided into nine groups. Seven groups were pretreated with PE (50-, 100-, and 150 mg/kg), HP (25-, 50-, and 75 mg/kg) or silymarin (25 mg/kg), respectively, once daily for 5 consecutive days and then administered acetaminophen (2 g/kg) on the 5th day. The control and acetaminophen-intoxicated groups received normal saline throughout the experimental period, with the latter group additionally receiving 2 g/kg acetaminophen on the 5th day. Administrations were performed po.. In the acetaminophen-intoxicated group, there were significant increases (p<0.05) in serum activities of alanine aminotransferase (31.72±3.3 vs. 22.1±1.2 U/I), aspartate aminotransferase (185.1±10.1 vs. 103.83±13.3 U/I), bilirubin level and hepatic malondialdehyde (2.32±0.3 vs. 1.42±0.1 units/mg protein), accompanied with significant decreases (p<0.05) in hepatic reduced glutathione level (0.10±0.01 vs. 0.23±0.03 units/mg protein) and glutathione peroxidase activity (2.51±0.2 vs. 3.25±0.2 μmol H2O2 consumed/min/mg protein) compared with the control.. PE and HP ameliorated most of the observed biochemical alterations with HP appearing to show more potency. The results suggest that the flavonoid, homopterocarpin contributes to the hepatoprotective and antioxidant potentials of P. erinaceus extract.

Topics: Acetaminophen; Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Benzofurans; Benzopyrans; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Male; Malondialdehyde; Oxidative Stress; Plant Extracts; Pterocarpus; Rats; Rats, Wistar

Fasiglifam (TAK-875), a selective G-protein-coupled receptor 40 agonist, was developed for the treatment of type 2 diabetes mellitus; however, its development was terminated in phase III clinical trials because of liver safety concerns. Our preliminary study indicated that intravenous administration of 100 mg/kg of TAK-875 increased the serum total bile acid concentration by 3 to 4 times and total bilirubin levels by 1.5 to 2.6 times in rats. In the present study, we examined the inhibitory effects of TAK-875 on hepatobiliary transporters to explore the mechanisms underlying its hepatotoxicity. TAK-875 decreased the biliary excretion index and the in vitro biliary clearance of d₈-taurocholic acid in sandwich-cultured rat hepatocytes, suggesting that TAK-875 impaired biliary excretion of bile acids, possibly by inhibiting bile salt export pump (Bsep). TAK-875 inhibited the efflux transporter multidrug resistance-associated protein 2 (Mrp2) in rat hepatocytes using 5 (and 6)-carboxy-2',7'-dichlorofluorescein as a substrate. Inhibition of MRP2 was further confirmed by reduced transport of vinblastine in Madin-Darby canine kidney cells overexpressing MRP2 with IC₅₀ values of 2.41 μM. TAK-875 also inhibited the major bile acid uptake transporter Na(+)/taurocholate cotransporting polypeptide (Ntcp), which transports d₈-taurocholic acid into rat hepatocytes, with an IC₅₀ value of 10.9 μM. TAK-875 significantly inhibited atorvastatin uptake in organic anion transporter protein (OATP) 1B1 and OATP1B3 cells with IC₅₀ values of 2.28 and 3.98 μM, respectively. These results indicate that TAK-875 inhibited the efflux transporter MRP2/Mrp2 and uptake transporters Ntcp and OATP/Oatp, which may affect bile acid and bilirubin homeostasis, resulting in hyperbilirubinemia and cholestatic hepatotoxicity.

Topics: Animals; Benzofurans; Biliary Tract; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dogs; Dose-Response Relationship, Drug; HEK293 Cells; Hepatocytes; Humans; Madin Darby Canine Kidney Cells; Male; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Organic Anion Transporters; Organic Anion Transporters, Sodium-Dependent; Rats; Rats, Sprague-Dawley; Sulfones; Symporters

The aims of this study were to demonstrate the hepatoprotective activity of herpetin (HPT) and the enhanced hepatoprotective efficiency of liposomal herpetin against carbon tetrachloride-induced liver injury in mice.. Herpetin was isolated from Herpetospermum seed and identified by ESI-MS and NMR. To enhance liver targeting and improve solubility of HPT, liposomal HPT was prepared with optimal formulation. The intravenous injection safety of the liposomes was then evaluated. Further, the hepatoprotective effects of liposomal HPT on model mice were investigated by the comparison of different liver marker enzymes and histopathological examination.. The prepared HPT liposome showed spherical or ellipsoidal vesicles with the entrapment efficiency of 94.50 ± 2.15% and particle size of 119.2 ± 10.7 nm. After 4 days intravenous administration of liposomal herpetin, no obvious damage could be observed at the injection site of each group. The liposomal HPT has no destructive effect on erythrocytes and little influence on whole blood clotting time. Free HPT exhibited only a weak protective function to model mice, whereas an enhanced hepatoprotective activity was observed using liposomal herpetin for treatment.. The hepatoprotective efficiency of herpetin is able to be promoted through pharmaceutical application of liposome and liposomal herpetin is a promising new medicine for hepatoprotection.

Topics: Animals; Benzofurans; Blood Circulation Time; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cucurbitaceae; Erythrocytes; Injections, Intravenous; Liposomes; Liver Function Tests; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred ICR; Particle Size; Protective Agents; Seeds; Spectrometry, Mass, Electrospray Ionization

(+)-Usnic acid (UA) is consumed as a dietary supplement to promote weight loss; however, dietary supplements containing UA have been associated with clinical cases of severe liver injury. UA has been shown to be hepatotoxic in rats and is extensively metabolized by hepatic cytochrome P450s (CYPs); therefore, we examined if UA metabolism results in the formation of cytotoxic metabolites or if metabolism is a detoxification process in primary rat hepatocytes. When CYP activity was suppressed by the non-isoenzyme-selective inhibitor SKF-525A (20 μM), or the CYP1A inhibitor alpha-naphthoflavone (10 μM), or the CYP3A inhibitor ketoconazole (25 μM), the cytotoxicity of UA at 3~6 μM after 3~20 h of exposure was significantly increased as measured by lactate dehydrogenase (LDH) leakage. At 2 h after UA exposure, an earlier time point prior to LDH release, these CYP inhibitors potentiated UA-induced inhibition of cellular respiration as determined by the Clark type oxygen electrode. Cellular adenosine triphosphate (ATP) depletion by UA was also exacerbated by these CYP inhibitors. The CYP2B/2C inhibitor, ticlopidine at 20 μM, showed no effects in parallel experiments. These data demonstrate that UA is bio-transformed to less toxic metabolites in rat primary hepatocytes, probably mainly by CYP1A and 3A, but not 2B/2C. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Topics: Animals; Benzoflavones; Benzofurans; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dietary Supplements; Enzyme Inhibitors; Hepatocytes; Ketoconazole; Liver; Male; Mitochondria; Proadifen; Rats; Rats, Sprague-Dawley; Ticlopidine

Salvianolic acid A (Sal A) was considered to be the compound with highest activity in Salvia miltiorrhiza (danshen). Due to its low content in raw materials, many studies reported its preparation from salvianolic acid B (Sal B). However, the process of this transformation is still unknown. Our objective was to find the chemical change of the transformation from Sal B to Sal A. The results showed that Sal B was hydrolyzed to lithospermic acid (LA) first, and the latter was transformed into Sal A in thermal aqueous solution. The radical scavenging ability of Sal A, Sal B, and LA was tested through DPPH, and Sal A showed higher radical elimination ability compared to Sal B and LA. In vitro liver damage was induced by CCl4 in human hepatic WRL68 cell line. Sal A, Sal B, and LA showed liver protective ability in a dose-dependent manner, while Sal A possessed a much higher ability compared to Sal B and LA.

Topics: Antioxidants; Benzofurans; Biphenyl Compounds; Caffeic Acids; Carbon Tetrachloride; Cell Line; Chemical and Drug Induced Liver Injury; Depsides; Drugs, Chinese Herbal; Hot Temperature; Humans; In Vitro Techniques; Lactates; Liver; Phytotherapy; Picrates; Salvia miltiorrhiza; Water

Salvianolic acid B (SalB) is isolated from the traditional Chinese medical herb salvia miltiorrhiza. It has many biological and pharmaceutical activities. This study aimed to investigate the effect of SalB on acute ethanol-induced hepatic injury in rats and to explore the role of SIRT1 in this process. The results showed that pretreatment with SalB significantly reduced ethanol-induced elevation in aminotransferase activities, decreased hepatotoxic cytokine levels such as Interleukin-6 (IL-6), and increased the antioxidant enzyme activity. Moreover, SalB pretreatment reversed the increase in NF-κB, cleaved caspase-3 and decrease in B-cell lymphoma-extra large (Bcl-xL) caused by ethanol exposure. Importantly, SalB pretreatment significantly increased the expression of SIRT1, a NAD(+)-dependent deacetylase, whereas the increase in SIRT1 was accompanied by decreased acetyl-p53 expression. In HepG2 cells, SalB pretreatment increased SIRT1 expression in a time and dose-dependent manner and such an increase was abrogated by siRNA knockdown of SIRT1. Additionally, inhibition of SIRT1 significantly increased the acetylation of p53, and blocked SalB-induced acetylation of p53 down-regulation. Collectively, this study indicated that SalB can alleviate acute ethanol-induced hepatocyte apoptosis through SIRT1-mediated deacetylation of p53 pathway.

Topics: Acetylation; Alanine Transaminase; Animals; Antioxidants; Aspartate Aminotransferases; Benzofurans; Blotting, Western; Cell Survival; Central Nervous System Depressants; Chemical and Drug Induced Liver Injury; Cytokines; Ethanol; Glutathione; Immunoprecipitation; Liver; Male; Malondialdehyde; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA, Small Interfering; Sirtuin 1; Tumor Suppressor Protein p53

In this study, the hepatoprotective effect of dieckol on carbon tetrachloride (CCl4) induced hepatic damages in ICR mice liver was investigated. Mice were randomly divided into 4 groups such as saline treated (negative control), CCl4 treated (positive control), CCl4+dieckol (5mg/kg mouse) and CCl4+dieckol (25mg/kg mouse), respectively. The body weights and survival rates of mice, followed by dieckol treatments were significantly increased compared to the positive control. The level of GOT, GPT and MDA in the serum of the dieckol treated groups were reduced dose dependently than the control, significantly. The antioxidant enzymes including CAT, and GSH-px levels were increased significantly compared to the positive control. However, no significant differences were observed on hepatic histophathological analysis in dieckol treated groups dose dependently. Down-regulation of Bax and up-regulation of Bcl-xl protein expressions were observed in liver tissues of the dieckol administered groups. These results suggested that, dieckol can be developed as a therapeutic agent for liver disease by oxidative stress.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; bcl-2-Associated X Protein; bcl-X Protein; Benzofurans; Carbon Tetrachloride; Catalase; Chemical and Drug Induced Liver Injury; Glutathione Peroxidase; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Phaeophyceae; Phytotherapy; Plant Extracts; Polyphenols; Protective Agents; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Usnic acid, a lichen metabolite, is used as a dietary supplement for weight loss. However, clinical studies have shown that usnic acid causes hepatotoxicity. The present study aims to investigate the mechanism of usnic acid hepatotoxicity in vivo. Two-dimensional gel electrophoresis coupled with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to analyze the expression profiles of differentially regulated and expressed proteins in rat liver after usnic acid administration. The results reveal the differential expression of 10 proteins in usnic-acid-treated rats compared to the normal controls. These proteins are associated with oxidative stress, lipid metabolism, and several other molecular pathways. The endoplasmic reticulum and mitochondria may be the primary targets of usnic-acid-induced hepatotoxicity.

Topics: Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Electrophoresis, Gel, Two-Dimensional; Endoplasmic Reticulum; Hepatocytes; Liver Diseases; Male; Mitochondria, Liver; Oxidative Stress; Proteins; Proteomics; Rats; Rats, Wistar; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Transcriptome

Three doses of (+)-usnic acid (100, 200, and 240 mg/kg per d) were administered orally to Wistar rats for 8 days, and metabonomic characterization of (+)-usnic acid-induced liver injury based on gas chromatography-mass spectrometry metabolic profiles was evaluated. Serum biochemical analysis and histopathological examinations were simultaneously performed. The liver/body weight ratio was significantly increased in (+)-usnic acid-treated groups, whereas serum alanine aminotransferase and total bilirubin were significantly elevated. In liver sections of 200 and 240 mg/kg dosage groups, widespread hydropic degeneration of hepatocytes was observed. Clusters in partial least squares discriminant analysis score plots showed control and (+)-usnic acid-treated groups had an obvious separation. (+)-Usnic acid exposure can lead to disturbances in energy metabolism, amino acid metabolism, lipid metabolism, and nucleotide metabolism, which may be attributable to (+)-usnic acid toxicological effects on the liver through oxidative stress. The significant changes in 22 metabolites in liver might be adopted as potential biomarkers.

Topics: Administration, Oral; Animals; Benzofurans; Biomarkers; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Energy Metabolism; Gas Chromatography-Mass Spectrometry; Hepatocytes; Lipid Metabolism; Liver; Male; Metabolome; Metabolomics; Oxidative Stress; Plasma; Rats; Rats, Wistar; Reproducibility of Results

To describe the mechanisms of severe hepatocellular injury with apoptosis in 2 patients receiving hepatitis C virus (HCV)-796.. HCV-796 is a hepatitis C polymerase inhibitor approved by the US Food and Drug Administration for a phase 2 study of the treatment of hepatitis C in combination with PEG-Interferon and ribavirin.. The injury occurred after more than 12 weeks of treatment, with a >20-fold increase in serum alanine aminotransferase and aspartate aminotransferase, and a marked increase in total (and direct) bilirubin in the absence of cholestasis. There was no evidence of autoimmune or viral hepatitis. Involvement of the mitochondrial apoptotic pathway was demonstrated by (1) release of cytochrome C into the cytosol; (2) association of cytochrome C with apoptotic protease activating factor-1 in the cytosol; (3) activation of initiator caspase 9; (4) activation of effector caspase 3; (5) increased serum caspase-3 cleaved cytokeratin-18 peptide; (6) nuclear fragmentation; (7) mitochondrial structural abnormalities; (8) expression of light chain 3 B, an indicator of autophagy; (9) probable autophagy of mitochondria by autophagosomes; and (10) probable phagocytosis of apoptotic hepatocytes by activated macrophages. Immunoglobulin G immune complexes were identified in the hepatocytes and localized to the endoplasmic reticulum and Golgi of these patients after the drug-induced liver disease, reflecting a primary or secondary target. Hepatitis C treatment was discontinued at weeks 15 and 19 in patients 1 and 2, respectively. After more than 6 months off the medication, both patients normalized the serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin with undetectable HCV RNA.. HCV-796 may cause severe hepatocellular injury and apoptosis, with a marked immune reaction in susceptible patients.

Topics: Antiviral Agents; Apoptosis; Benzofurans; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Interferons; Liver; Liver Diseases; Male; Middle Aged; Polyethylene Glycols; Ribavirin; Sulfonamides

Usnic acid is a component of nutritional supplements promoted for weight loss that have been associated with liver-related adverse events including mild hepatic toxicity, chemical hepatitis, and liver failure requiring transplant. To determine if metabolism factors might have had a role in defining individual susceptibility to hepatotoxicity, in vitro metabolism studies were undertaken using human plasma, hepatocytes, and liver subcellular fractions. Usnic acid was metabolized to form three monohydroxylated metabolites and two regio-isomeric glucuronide conjugates of the parent drug. Oxidative metabolism was mainly by cytochrome P450 (CYP) 1A2 and glucuronidation was carried out by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT1A3. In human hepatocytes, usnic acid at 20 microM was not an inducer of CYP1A2, CYP2B6, or CYP3A4 relative to positive controls omeprazole, phenobarbital, and rifampicin, respectively. Usnic acid was a relatively weak inhibitor of CYP2D6 and a potent inhibitor of CYP2C19 (the concentration eliciting 50% inhibition (IC(50)) = 9 nM) and CYP2C9 (IC(50) = 94 nM), with less potent inhibition of CYP2C8 (IC(50) = 1.9 microM) and CYP2C18 (IC(50) = 6.3 microM). Pre-incubation of microsomes with usnic acid did not afford any evidence of time-dependent inhibition of CYP2C19, although evidence of slight time-dependent inhibition of CYP2C9 (K(I) = 2.79 microM and K(inact) = 0.022 min(-1)) was obtained. In vitro data were used with SimCYP(R)to model potential drug interactions. Based on usnic acid doses in case reports of 450 mg to >1 g day(-1), these in vitro data indicate that usnic acid has significant potential to interact with other medications. Individual characteristics such as CYP1A induction status, co-administration of CYP1A2 inhibitors, UGT1A1 polymorphisms, and related hyperbilirubinaemias, or co-administration of low therapeutic index CYP2C substrates could work alone or in consort with other idiosyncrasy risk factors to increase the risk of adverse events and/or hepatotoxicity. Thus, usnic acid in nutritional supplements might be involved as both victim and/or perpetrator in clinically significant drug-drug interactions.

Topics: Benzofurans; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dietary Supplements; Drug Interactions; Enzyme Induction; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Kinetics; Liver Diseases; Microsomes, Liver; Models, Molecular; Protein Binding; Risk Factors; Substrate Specificity

Despite the recognised antiproliferative and antitumour properties of usnic acid, its therapeutic application has yet to be introduced. In fact, the high hepatotoxicity and low water solubility of usnic acid have somewhat restricted its practical use in anticancer therapy. The aim of this study was therefore to investigate the antitumour activity of usnic acid encapsulated into nanocapsules prepared with lactic co-glycolic acid polymer. Usnic acid-loaded nanocapsules were obtained using the interfacial deposition of a preformed polymer. The antitumour activity was confirmed on an ascitic tumour (Sarcoma-180) implanted in Swiss mice and estimated by means of the tumour inhibition. The results of antitumour activity confirmed that the encapsulation of usnic acid into PLGA-nanocapsules produced a 26.4% increase in tumour inhibition as compared with the standard free usnic acid treatment. Vacuolization of hepatocytes and a mild lymphocytic infiltration in portal spaces were observed in animals treated with free usnic acid. However, this hepatotoxicity was substantially reduced when animals were treated with usnic acid-loaded nanocapsules. No histological changes were noticed in the kidneys or spleen of animals treated either with usnic acid or usnic acid-loaded nanocapsules. These results suggest that nanoencapsulation may be a way of enabling usnic acid to be used in chemotherapy.

Topics: Animals; Benzofurans; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Disease Progression; Drug Compounding; Injections, Intraperitoneal; Lactic Acid; Liver; Male; Mice; Nanostructures; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Sarcoma 180; Survival Analysis

Topics: Acute Disease; Adult; Anti-Infective Agents; Benzofurans; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Female; Humans; Plants, Medicinal; Weight Loss

Topics: Adult; Benzofurans; Chemical and Drug Induced Liver Injury; Diet, Reducing; Dietary Supplements; Drugs, Chinese Herbal; Ephedra sinica; Female; Humans; Male; Middle Aged; Obesity; Plant Preparations

The use of potentially hepatotoxic herbal and dietary supplements is highly prevalent in the fulminant hepatic failure (FHF) patient population at our institution, and this subgroup of patients has a worse prognosis.. Retrospective case series. Settings An adult tertiary care university hospital and a Veterans Affairs hospital in Oregon.. All patients referred to the liver transplantation service for FHF from January 2001 through October 2002 (N = 20). We defined FHF as onset of encephalopathy within 8 weeks of onset of jaundice in the absence of preexisting liver disease. All patients underwent investigation for potential causes of liver injury. Potentially hepatotoxic supplements were defined as those with previously published reports of hepatic injury related to their use.. Ten patients (50%) were recent or active users of potentially hepatotoxic supplements or herbs; 10 had no history of supplement use. In the supplement group, 7 patients (35%) had no other identified cause for hepatic failure. Six patients in the supplement group and 2 patients in the nonsupplement group underwent orthotopic liver transplantation. Five patients in each group died. There were no significant differences in transplantation rate (P =.07) or survival (P>.99) between groups. Supplement use alone accounted for the most cases of FHF during this period, exceeding acetaminophen toxicity and viral hepatitis.. Herbal and dietary supplements were potential hepatotoxins in a high proportion of patients with FHF at our institution. Enhanced public awareness of the potential hepatotoxicity of these commonly used agents and increased regulatory oversight of their use is strongly urged.

Topics: Adult; Benzofurans; Benzopyrans; Caffeine; Chemical and Drug Induced Liver Injury; Dietary Supplements; Diiodothyronines; Drug Combinations; Ephedra sinica; Female; Humans; Kava; Larrea; Liver Failure; Liver Transplantation; Male; Middle Aged; Phenylpropanolamine; Plant Preparations; Prevalence; Retrospective Studies; Yohimbine

LipoKinetix (Syntrax, Cape Girardeau, Missouri) is a dietary supplement marketed for weight loss.. To describe a possible causal association between LipoKinetix and hepatotoxicity.. Case series.. Outpatient clinic, tertiary care hospital, and U.S. Food and Drug Administration databases.. Routine medical and supportive care.. Clinical and laboratory evaluation.. All patients developed acute hepatotoxicity within 3 months of starting LipoKinetix. At presentation, symptoms and results of laboratory tests were characteristic of acute hepatitis. All patients recovered spontaneously after LipoKinetix use was discontinued. Three of the seven patients, including one who developed fulminant hepatic failure complicated by cerebral edema, were taking LipoKinetix alone at the time of presentation. Of the four patients who were taking multiple supplements, two resumed taking supplements other than LipoKinetix without incident.. The use of LipoKinetix may be associated with hepatotoxicity. Despite extensive evaluations, no other cause for hepatotoxicity could be identified in the seven patients studied.

Topics: Acute Kidney Injury; Adult; Adverse Drug Reaction Reporting Systems; Benzofurans; Benzopyrans; Caffeine; Chemical and Drug Induced Liver Injury; Dietary Supplements; Diiodothyronines; Drug Approval; Drug Combinations; Female; Humans; Male; Phenylpropanolamine; United States; United States Food and Drug Administration; Yohimbine

Topics: Benzofurans; Benzopyrans; Caffeine; Chemical and Drug Induced Liver Injury; Dietary Supplements; Diiodothyronines; Drug Approval; Drug Combinations; Humans; Legislation, Drug; Phenylpropanolamine; Safety; United States; United States Food and Drug Administration; Yohimbine

Topics: Acute Kidney Injury; Adult; Adverse Drug Reaction Reporting Systems; Benzofurans; Benzopyrans; Caffeine; Chemical and Drug Induced Liver Injury; Dietary Supplements; Diiodothyronines; Drug Approval; Drug Combinations; Female; Humans; Male; Phenylpropanolamine; United States; United States Food and Drug Administration; Yohimbine

In 1979, a mass poisoning involving some 2,000 persons occurred in central Taiwan from cooking oil contaminated by polychlorinated biphenyls (PCBs) and their heat-degraded byproducts, including polychlorinated dibenzofurans (PCDFs). The responsible health department registered cases for clinical purposes between 1979 and 1983. The exposed persons are referred to as the "yucheng" (oil disease) cohort. PCBs and PCDFs are toxic chemicals widely dispersed in the environment and in human tissue, which persist long after exposure. The consequences of exposure to these agents are not well understood. We traced the cohort through December 31, 1991, and compared overall and cause-specific mortality of 1,837 "yucheng" subjects with age, gender, and calendar time-specific mortality rates for the Taiwan general population. Eighty-three deaths were identified from 23,404 observed person-years. Even though the overall standardized mortality ratio (SMR) was 0.8 (95% confidence interval (CI) 0.7-1.0), there was a substantial elevation in the mortality rate for chronic liver disease and cirrhosis (10 deaths, SMR = 2.7, 95% CI = 1.3-4.9). Mortality from malignant neoplasms and other causes was not significantly different from that of the Taiwan population. PCB/PCDF exposure appears to promote the development of severe liver disease, perhaps in combination with known risk factors such as infection with hepatitis B virus. Further follow-up of this young cohort is necessary to see if the consequences include hepatic cancer.

Topics: Adolescent; Benzofurans; Cause of Death; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Chronic Disease; Confidence Intervals; Female; Follow-Up Studies; Food Contamination; Humans; Infant; Infant, Newborn; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Oryza; Plant Oils; Polychlorinated Biphenyls

The methanol extract of the Oriental medicinal plant Vitis coignetiae (Vitaceae) showed hepatoprotective activity in the in vitro assay method using primary cultured rat hepatocytes. Activity-guided fractionation of the extract afforded epsilon-viniferin as an active principle. The protective effect of epsilon-viniferin against mice carbon tetrachloride-induced hepatic injury in mice was shown by serum enzyme assay as well as by pathological examination. In addition to epsilon-viniferin, plant oligostilbenes, ampelopsins A, C, F and the mixture of vitisin A and cis-vitisin A were also present in the extract. Among them, ampelopsin C and the mixture of vitisin A and cis-vitisin A were found to be powerful hepatotoxins.

Topics: Animals; Benzofurans; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Liver Diseases; Male; Mice; Molecular Structure; Plants, Medicinal; Stilbenes

Six groups of C57BL/6J mice received single oral doses of 1.5-10.6 nmol/kg 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PnCDD), 1,2,3,6,7,8-hexachlorodibenzo-p-dioxin (HxCDD) or 2,3,4,7,8-pentachlorodibenzofuran (PnCDF) as single compounds or in combination with 300 mumol/kg 2,2',4,4',5,5'-hexachlorobiphenyl (HxCB). Two other groups of mice received a mixture of the first three compounds, either with or without HxCB. The hepatic deposition and elimination of the compounds and their CYP1a dependent 7-ethoxyresorufin-O-deethylation (EROD) activity were studied until day 175. Interactive effects on the hepatic deposition of PnCDD were observed in most of the mixed dose groups. For HxCDD and PnCDF interactive effects were either very small or absent. No interactive effects were observed on hepatic elimination rates of PnCDD, HxCDD or PnCDF. No evidence was found for the influence of HxCB cotreatment on the hepatic concentration-response curves of the three compounds or their mixture. Based on the results from the present study it is concluded that PCDDs, PCDFs and PCBs may influence each other's, toxicokinetics when administered in mixtures.

Topics: Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Drug Interactions; Hydrocarbons, Chlorinated; Liver; Mice; Mice, Inbred C57BL; Oxidoreductases; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polymers

1. R-(+)-Pulegone was administered orally to rats and the urinary metabolites were investigated. Six metabolites were isolated and purified using column and thin layer chromatographic techniques. Metabolites were identified by i.r., n.m.r. and mass spectral analyses. 2. The neutral metabolites isolated from urine of rats treated with pulegone (I) were: pulegone (II), 2-hydroxy-2(1'-hydroxy-1'-methylethyl)-5-methylcyclohexanone (III), 3,6-dimethyl-7a-hydroxy-5,6,7,7a-tetrahydro-2(4H)-benzofuranone (V) and menthofuran (VII). Metabolites II and III were also excreted in conjugated form. 3. Acidic metabolites isolated from urine of rats treated with pulegone (I) were: 5-methyl-2(1'-methyl-1'-carboxyethylidene)cyclohexanone (IV) and 5-methyl-5-hydroxy-2(1'hydroxy-1'-carboxyethyl)cyclohexanone (VI).

Topics: Administration, Oral; Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Chromatography, Thin Layer; Cyclohexane Monoterpenes; Cyclohexanones; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Menthol; Monoterpenes; Rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) (233 nmol/kg) causes a significant increase of hepatic uroporphyrin, heptacarboxyporphyrin, and total porphyrins in female C57BL/6 mice, ovariectomized C57BL/6 mice, male C57BL/10 mice, and male C57BL/6 mice 3 weeks after treatment. In contrast, 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) was inactive at a dose of 750 mumol/kg. Cotreatment of the mice with TCDD (233 mol/kg) plus MCDF (750 mumol/kg) resulted in partial antagonism of TCDD-induced hepatic porphyrin accumulation only in the female mice. Parallel studies in female C57BL/6 mice showed that the TCDD-induced porphyria was accompanied by the induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) activities and the depression of uroporphyrinogen decarboxylase (UROD). MCDF (750 mumol/kg) did not significantly affect these enzymes. In the cotreatment studies (MCDF plus TCDD), MCDF partially antagonized TCDD-induced hepatic porphyrin accumulation but did not affect the levels of hepatic AHH, EROD, or UROD. These results indicate that other factors, in addition to the induction of cytochrome P450-dependent monooxygenases and depressed UROD activity, are important in TCDD-induced porphyria in C57BL/6 female mice.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benzofurans; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; Dioxins; Drug Antagonism; Female; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Ovariectomy; Oxidoreductases; Polychlorinated Dibenzodioxins; Porphyrias; Porphyrins; Uroporphyrinogen Decarboxylase

A patient with acute changes suggesting acute hepatitis after parenteral amiodarone administration is described. A 77-year-old man with previous myocardial infarction was admitted with chronic left heart failure and atrial tachycardia. Initial hepatic function tests were strictly normal. After therapy with parenteral amiodarone (2300 mg in 3 days) and other measures, signs of congestive heart failure disappeared; subsequently the patient developed jaundice, marked increase in serum transaminase levels and fall in prothrombin time, and histologic changes of severe centrilobular necrosis were observed in hepatic biopsy. Clinical, laboratory (absence of others markers of hepatic disease), and histological findings seem to rule out common causes of hepatic disease. Therefore, parenteral amiodarone was implicated as the cause of acute hepatitis in this patient. In addition, there were findings suggesting a possibly immunologically mediated mechanism.

Topics: Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Biopsy; Chemical and Drug Induced Liver Injury; Coronary Disease; Dose-Response Relationship, Drug; Humans; Infusions, Parenteral; Liver; Liver Function Tests; Male

Five patients had amiodarone hepatotoxicity detected on routine biochemical monitoring. Symptoms attributable to hepatotoxicity were minimal or absent; reversible hepatomegaly was seen in two patients, whereas three patients had signs of nonhepatic amiodarone toxicity before or with hepatotoxicity. Serum aminotransferase levels were elevated in all patients and alkaline phosphatase levels in four; no patient had hyperbilirubinemia or prolongation of the prothrombin time. Light microscopy showed steatosis, cellular degeneration, and cellular necrosis in the biopsy samples of four patients, whereas the fifth patient's sample had a granulomatous injury pattern. Electron microscopic study of liver tissue done in two patients showed phospholipid-laden lysosomal lamellar bodies. These findings suggest that both toxic and hypersensitivity liver injury can occur in response to amiodarone. The presence of phospholipid-laden lysosomal lamellar bodies may help differentiate amiodarone hepatotoxicity from alcoholic liver disease or other causes of hepatic steatosis.

Topics: Aged; Alanine Transaminase; Alkaline Phosphatase; Amiodarone; Aspartate Aminotransferases; Benzofurans; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Hepatomegaly; Humans; Liver; Liver Diseases; Male; Middle Aged

Amiodarone is a cardiac antiarrhythmic agent now undergoing clinical trials in the United States. Its most important side effect is pulmonary toxicity, which may present radiographically in two forms. One is similar to eosinophilic pneumonia with peripheral alveolar opacities but without any of the laboratory or pathologic findings. A second presentation is as a bilateral interstitial pattern resembling interstitial pulmonary edema. This is often mistaken for heart failure in the clinical and radiographic setting. Amiodarone also causes a phospholipidosis of the liver, which is usually asymptomatic but on occasion may present as hepatitis. On abdominal CT the liver will have an abnormally high attenuation (80-140 HU), which appears to be due to accumulation of an amiodarone metabolite in hepatocytes. This appearance is usually distinguishable from the other causes of increased hepatic attenuation by virtue of other CT criteria and clinical history. However, from a radiographic standpoint alone, the combination of acute congestive heart failure and an abnormally dense liver may result in at least an initial misdiagnosis of advanced primary hemochromatosis.

Topics: Aged; Amiodarone; Benzofurans; Chemical and Drug Induced Liver Injury; Female; Heart Failure; Humans; Liver; Liver Diseases; Lung; Pulmonary Fibrosis; Radiography

Muscle weakness, neuropathy, and transient rises in hepatic enzyme activity have been reported with the use of the antiarrhythmic agent amiodarone. A 68 year old teetotaller with normal liver function was given amiodarone for resistant supraventricular arrhythmias. He presented 19 months later with vomiting, muscle weakness and wasting, sensory neuropathy, and hepatomegaly. Liver biopsy showed fibrosis and the presence of hyaline. The amiodarone was withdrawn. Three months later he developed ascites. Oesophageal varices were found and he later died. The liver showed micronodular cirrhosis. The large volume of distribution and long half life of amiodarone may explain the persistence of toxicity, which may have been aggravated by simultaneously administered doxepin in this case. Amiodarone should be withdrawn if abnormal liver function or neuropathy develops.

Topics: Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Chemical and Drug Induced Liver Injury; Humans; Liver Cirrhosis; Male; Peripheral Nervous System Diseases

The rice oil ingested by the patients with yusho and their blood, liver, and adipose tissue were analyzed for individual congeners of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans ( PCDFs ). The individual congeners identified were examined for accumulation in the liver of monkeys and rats, inducing activities of benzo[a]pyrene 3-hydroxylase, benzphetamine demethylase, and DT-diaphorase in rats, and gravimetric changes of the thymus and liver in rats. Among the six PCB congeners detected in yusho patients, 2,3,4,5,3',4'-hexa-CB seems to be the compound most related to yusho judging from its strong enzyme-inducing activities in the liver and the thymus atrophy and liver hypertrophy caused by feeding it to rats. PCDF congeners identified in the patients' tissues showed a stronger toxicity in rats than these PCBs, exhibiting stronger enzyme induction activities and gravimetric changes of the tissues. These PCDF congeners, especially 2,3,4,7,8-penta-CDF, were also very accumulative in the liver. Therefore, they are considered as the most important etiologic agents for the current symptoms and signs of yusho patients.

Topics: Adipose Tissue; Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Dibenzofurans, Polychlorinated; Food Contamination; Haplorhini; Humans; Liver; Male; Oils; Oryza; Polychlorinated Biphenyls; Rats; Rats, Inbred Strains; Spleen; Thymus Gland

The hepatic morphological findings in 3 patients treated with amiodarone, a potent and effective antiarrhythmic drug, are reported. An enlarged liver and mild elevation of hepatic enzymes were the most important clinical findings. Fibrosis, cholangitis, mixed inflammatory infiltrate, and cytoplasmic granularity of the hepatocytes were the main histologic changes common to all cases. In 2 of the cases the presence of Mallory bodies was confirmed by electron microscopy. In 1 of these 2 cases, Mallory bodies were also confirmed by immunostaining. Ultrastructurally, numerous cytoplasmic inclusions with a membranous or lamellar structure identical to those described in phospholipidosis were the most striking features seen in hepatocytes, biliary epithelial cells, Kupffer cells, and endothelial cells.

Topics: Amiodarone; Benzofurans; Biopsy; Chemical and Drug Induced Liver Injury; Cholangitis; Female; Humans; Liver; Liver Diseases; Male; Middle Aged; Phospholipids

Topics: Adult; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Humans; Liver; Liver Diseases; Liver Diseases, Alcoholic; Male; Transaminases

We evaluated the electrophysiologic effects of amiodarone and its ability to control ventricular arrhythmia in a selected group of 51 patients with refractory sustained ventricular arrhythmia. Amiodarone in doses of 400 to 800 mg/day prolonged refractoriness in the atria, atrioventricular (AV) node, and ventricle as well as conduction through the AV node and His-Purkinje system. Although it had no effect on measurements of sinus nodal function (sinus nodal recovery time and sinoatrial conduction time), it prolonged the sinus cycle length and 2 patients required a permanent pacemaker for symptomatic sinus bradycardia. Amiodarone did not alter the ease of inducibility in any consistent manner, and only 5 of 43 patients (12%) who had inducible ventricular tachycardia before amiodarone therapy had none induced during amiodarone treatment. The clinical effectiveness of amiodarone could be evaluated in 46 patients followed up for 8.6 +/- 6 months (range 0.5 to 22). It provided effective therapy in 23 patients (50%), partly effective therapy in 13 (28%), and was ineffective in 10 (22%). Adverse effects were noted in 28 of 51 patients (55%), and in 11 of these (22%) the drug had to be discontinued because of adverse effects. We conclude that amiodarone is a useful agent for the treatment of refractory sustained ventricular arrhythmia. Its use should be reserved for patients with life-threatening sustained arrhythmia because of the significant incidence of adverse effects. Furthermore, good clinical response can be observed in patients receiving amiodarone in spite of continued inducibility.

Topics: Adolescent; Adult; Aged; Amiodarone; Benzofurans; Cardiac Pacing, Artificial; Chemical and Drug Induced Liver Injury; Corneal Diseases; Electrophysiology; Female; Heart Conduction System; Heart Failure; Humans; Male; Middle Aged; Myocardial Contraction; Peripheral Nervous System Diseases; Photosensitivity Disorders; Pulmonary Fibrosis; Stroke Volume; Tachycardia; Ventricular Fibrillation

A chronic oral toxicity study of citalopram in rats revealed dose dependent hepatic fatty infiltrations in male rats while female rats were unaffected. Subsequent studies demonstrated markedly reduced availability due to first-pass hepatic metabolism in male rats and roughly complete availability in females. Pretreatment of male rats with phenobarbital for 2 weeks caused increased metabolism and simultaneous administration of phenobarbital and citalopram gave more pronounced fatty infiltrations than citalopram alone. A connection is suggested between the first-pass metabolism in male rats and the hepatotoxicity, which is possibly mediated through a metabolite or intermediate formed in toxic amount during the first passage of the liver.

Topics: Administration, Oral; Animals; Benzofurans; Chemical and Drug Induced Liver Injury; Female; Injections, Intravenous; Male; Phenobarbital; Propylamines; Rats; Sex Factors

Topics: Benzofurans; Chemical and Drug Induced Liver Injury; Furans; Hepatitis; Jaundice; Toxicology; Vasodilator Agents