diosbulbin-b and Chemical-and-Drug-Induced-Liver-Injury

The rhizome of

Topics: Activation, Metabolic; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Dioscorea; Diterpenes; Drugs, Chinese Herbal; Heterocyclic Compounds, 4 or More Rings; Humans; Liver

Exposure to diosbulbin B (DBB), the primary component of the herbal medicine Dioscorea bulbifera L. (DB), can cause liver injury in humans and experimental animals. A previous study found DBB-induced hepatotoxicity was initiated by CYP3A4-mediated metabolic activation and subsequent formation of adducts with cellular proteins. The herbal medicine licorice (Glycyrrhiza glabra L.) is frequently combined with DB used in numerous Chinese medicinal formulas in an effort to protect against DB-elicited hepatotoxicity. Importantly, glycyrrhetinic acid (GA), the major bioactive ingredient in licorice, inhibits CYP3A4 activity. The study aimed to investigate the protection of GA against DBB-induced hepatotoxicity and the underlying mechanism. Biochemical and histopathological analysis showed GA alleviated DBB-induced liver injury in a dose-dependent manner. In vitro metabolism assay with mouse liver microsomes (MLMs) indicated that GA decreased the generation of metabolic activation-derived pyrrole-glutathione (GSH) conjugates from DBB. Toxicokinetic studies demonstrated that GA increased maximal serum concentration (C

Topics: Activation, Metabolic; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP3A; Glycyrrhetinic Acid; Heterocyclic Compounds, 4 or More Rings; Humans; Liver; Mice; Plant Extracts; Plants, Medicinal

Diosbulbin B (DIOB) has been reported to cause serious liver injury. However, in traditional medicine, DIOB-containing herbs are highly safe in combination with ferulic acid (FA)-containing herbs, suggesting potential neutralizing effect of FA on the toxicity of DIOB. DIOB can be metabolized to generate reactive metabolites (RMs), which can covalently bind to proteins and lead to hepatoxicity. In the present study, the quantitative method was firstly established for investigating the correlation between DIOB RM-protein adducts (DRPAs) and hepatotoxicity. Then, we estimated the detoxication effect of FA in combination with DIOB and revealed the underlying mechanism. Our data indicated that the content of DRPAs positively correlate with the severity of hepatotoxicity. Meanwhile, FA is able to reduce the metabolic rate of DIOB in vitro. Moreover, FA suppressed the production of DRPAs and decreased the serum alanine/aspartate aminotransferase (ALT/AST) levels elevated by DIOB in vivo. Thus, FA can ameliorate DIOB-induced liver injury through reducing the production of DRPAs.

Topics: Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Proteins

Dioscorea bulbifera L. (DBL) is an herbal medicine used for the treatment of thyroid diseases and tumors in China. However, the hepatotoxicity of DBL limits its wide safe use. Diosbulbin B (DSB) is the most abundant diterpene lactone occurring in DBL. Numbers of studies showed that this furanoterpenoid plays an important role in DBL-induced liver injury and that DSB is metabolized to a cis-enedial intermediate which reacts with protein to form protein covalent binding and induces hepatotoxicity.. The present study aimed to define the association of DSB content in DBL with the severity of DBL hepatotoxicity to ensure the safe use of the herbal medicine in clinical practice and to determine the role of DSB in DBL-induced liver injury.. Chemical chromatographic fingerprints of DBL were established by UPLC-MS/MS. Their hepatotoxicity potencies were evaluated in vitro and in vivo. Metabolic activation of DSB was evaluated by liver microsomal incubation. Protein modification was assessed by mass spectrometry and immunostaining.. The contents of DSB in DBL herbs collected from 11 locations in China varied dramatically with as much as 47-fold difference. The hepatotoxicity potencies of DBL herbs were found to be proportional to the contents of DSB. Intensified protein adduction derived from the reactive metabolite of DSB was observed in mice administered DBL with high contents of DSB.. The findings not only demonstrated that contents of DSB can be quite different depending on harvest location and special attention needs to pay for quality control of DBL but also suggest DSB is a key contributor for DBL-induced hepatotoxicity.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chemical and Drug Induced Liver Injury, Chronic; Chromatography, Liquid; Dioscorea; Heterocyclic Compounds, 4 or More Rings; Mice; Plants, Medicinal; Tandem Mass Spectrometry

Diosbulbin B (DIOB) is an effective component of air potato yam with antitumor and anti-inflammatory activities, and it is the main toxic component leading to hepatotoxicity. However, the mechanism of its hepatotoxicity remains unclear. In this study, we aimed to systematically elucidate the molecular action of DIOB on liver metabolic function through systems toxicology approaches. C57BL/6 mice were orally treated with DIOB (10, 30, 60 mg/kg) for 28 days, and the liver metabonomics and histopathology, molecular docking, mRNA expression levels, and activities of enzymes were analyzed. The results illustrated that DIOB could affect fatty acid and glucose metabolism, block the TCA cycle, and DIOB also could disorder bile acid synthesis and transport and promote the occurrence of hyperbilirubinemia. In addition, DIOB increased Cyp3a11 expression in a dose-dependent manner. Thus, these results provide new insights into the mechanism of hepatotoxicity caused by DIOB.

Topics: Adenosine Triphosphatases; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP3A; Fatty Acids; Glucose; Heterocyclic Compounds, 4 or More Rings; Liver; Male; Membrane Proteins; Metabolomics; Mice, Inbred C57BL; Mice, Inbred ICR; Mitochondria, Liver; Molecular Docking Simulation; Systems Biology; Toxicology

Airpotato yam is a traditional Chinese medicine used for treating thyroid disease and cancer in China. Diosbulbin B (DB) is reported to be the main hepatotoxic compound isolated from Airpotato yam. A variety of reports have shown the acute liver injury induced by DB in vivo. However, whether long-term administration of DB will cause liver fibrosis in mice is unknown. This study aims to investigate the liver fibrosis induced by long-term DB treatment in mice. C57BL/6 mice were orally given with DB (25, 50 mg/kg) for 1 or 2 month, respectively. Liver hydroxyproline content, hepatic collagen deposition and immune cells infiltration were increased in mice treated with DB (50 mg/kg) for 2 months. Serum amounts of hyaluronic acid and laminin were increased in mice treated with DB for 1 or 2 months. DB (50 mg/kg) induced hepatic stellate cells (HSCs) activation when mice were treated with DB for 2 months. Liver mRNA expression of Col1a1, Col1a2, Col3a1, fibronectin (Fn1), vimentin (Vim) and fibroblast-specific protein 1 (FSP1) were all increased in DB-treated mice. Hepatic protein expression of Vim, FSP1 and collagen 1 (COL1) were increased in DB-treated mice. Additionally, DB induced nuclear factor κB (NFκB) activation and increased the expression of pro-inflammatory molecules including tumor necrosis factor (TNF)-α, interleukin (IL)-6, intercellular cell adhesion molecule-1 (ICAM-1) and inducible nitric oxide synthase (iNOS) in mice. In conclusion, long-term administration of DB induced liver fibrosis in mice. HSCs activation, epithelial-mesenchymal transition (EMT) and liver inflammation contributed to DB-induced liver fibrosis in mice.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Collagen; Epithelial-Mesenchymal Transition; Gene Expression Regulation; Hepatic Stellate Cells; Hepatitis; Heterocyclic Compounds, 4 or More Rings; Hyaluronic Acid; Hydroxyproline; Laminin; Liver; Liver Cirrhosis; Male; Mice, Inbred C57BL; Toxicity Tests, Chronic

Toosendan Fructus is traditionally used as an insecticide or digestive tract parasiticide for treating digestive parasites in China. It is recorded to have little toxicity in Chinese Pharmacopoeia and has been found to cause severe liver injury during clinical practice.. This study aims to identify candidate serum microRNAs (miRNAs) as potential toxicological biomarkers for reflecting the hepatotoxicity induced by toosendanin (TSN), which is the main toxic compound isolated from Toosendan Fructus METHODS: Alanine/aspartate aminotransferase (ALT/AST) activities detection and liver histological observation were performed to evaluate the liver injury induced by TSN or other hepatotoxicants in mice. miRNAs chip analysis and Real-time PCR assay were conducted to identify the altered miRNAs in serum from TSN-treated mice RESULTS: The results of serum ALT/AST and liver histological evaluation showed that TSN (10 mg/kg) induced hepatotoxicity in mice. The results of miRNAs chip showed that the expression of 81 serum miRNAs was obviously altered in mice treated with TSN for 12 h, and 22 of them have passed the further validation in serum from mice treated with TSN for both 6 h and 12 h. These 22 miRNAs were supposed to be the candidate toxicological biomarkers for TSN-induced hepatotoxicity with more sensitivity as compared to the alteration of AST or ALT activity. Moreover, the expression of miRNA-122-3p and mcmv-miRNA-m01-4-3p was not only increased in TSN-treated mice, but also increased in mice treated with other hepatotoxicants including acetaminophen (APAP), monocrotaline (MCT) and diosbuibin B (DB). Only the expression of serum miRNA-367-3p was increased in TSN-treated mice but not changed in the liver injury induced by APAP, MCT or DB CONCLUSION: miR-122-3p and mcmv-miRNA-m01-4-3p may be two commonly sensitive biomarkers for reflecting the hepatotoxicity induced by exogenous hepatotoxicants, and miR-367-3p may be a specific biomarker for reflecting the liver injury induced by TSN.

Topics: Acetaminophen; Alanine Transaminase; Animals; Aspartate Aminotransferases; Biomarkers; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Heterocyclic Compounds, 4 or More Rings; Liver; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred C57BL; MicroRNAs; Monocrotaline; Random Allocation; Specific Pathogen-Free Organisms

Topics: Activation, Metabolic; Animals; Chemical and Drug Induced Liver Injury; Cysteine; Dose-Response Relationship, Drug; Glutathione; Heterocyclic Compounds, 4 or More Rings; Ketoconazole; Liver; Lysine; Male; Mice; Microsomes, Liver; Proteins

Airpotato yam (the rhizome of Dioscorea bulbifera L.) is traditionally used to treat thyroid disease and various cancers in China. However, it was found to cause hepatotoxicity during clinical practice. This study aims to identify candidate serum microRNAs (miRNAs) as diagnostic biomarkers for the liver injury induced by Airpotato yam. The results of serum alanine/aspartate aminotransferase (ALT/AST) showed the remarkable hepatotoxicity induced by ethyl acetate fraction of Airpotato yam (EF) (450mg/kg) and diosbulbin B (DB) (300mg/kg) in mice. The results of miRNAs chip analysis showed that the expression of 28 and 37 serum miRNAs was obviously altered in EF- and DB-treated mice, respectively. Among these miRNAs, miRNA-122-3p, miR-194-3p and miR-5099 have passed the further validation in serum from both EF- and DB-treated mice. Moreover, the expression of miRNA-122-3p and miRNA-194-5p was significantly increased in EF (375mg/kg)-treated mice with no significant elevation of serum ALT/AST activity. Only the expression of serum miRNA-5099 was not altered in the liver injury induced by acetaminophen (APAP), monocrotaline (MCT) or toosendanin (TSN). In conclusion, this study demonstrated that miR-122-3p and miRNA-194-5p were two sensitive biomarkers, and miR-5099 might be a specific biomarker for reflecting the liver injury induced by Airpotato yam.

Topics: Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Dioscorea; Drugs, Chinese Herbal; Gene Expression Regulation; Heterocyclic Compounds, 4 or More Rings; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; MicroRNAs; Plant Extracts; Random Allocation; Transcriptome

Dioscorea bulbifera L. (DB) is a traditional Chinese herb used in thyroid disease and cancer. However, the clinical use of DB remains a challenge due to its hepatotoxicity, which is caused, in part, by the presence of Diosbulbin B (DIOB), a toxin commonly found in DB extracts. As abnormal expression of hepatobiliary transporters plays an important role in drug-induced liver injury, we assessed the hepatotoxicity induced by DB and DIOB, and explored their impacts on hepatobiliary transporter expression levels. Following liquid chromatography-tandem mass analysis of the DIOB content of DB extract, male ICR mice were randomly orally administered DB or DIOB for 14days. Liver injury was assessed by histopathological and biochemical analysis of liver fuction. The levels of transporter protein and mRNA were determined by western blotting and real-time PCR. Liver function and histopathological analysis indicated that both DB and DIOB could induce liver injury in mice, and that DIOB might be the primary toxic compound in DB. Moreover, down-regulation of Mrp2 blocked the excretion of bilirubin, glutathione disulfide, and bile acids, leading to the accumulation of toxic substrates in the liver and a redox imbalance. We identified down-regulated expression of Mrp2 as potential factors linked to increased serum bilirubin levels and decreased levels of glutathione in the liver and increased liver injury severity. In summary, our study indicates that down-regulation of Mrp2 represents the primary mechanism of DB- and DIOB-induced hepatotoxicity, and provides insight into novel therapies that could be used to prevent DB- and DIOB-mediated liver injury.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Chemical and Drug Induced Liver Injury; Dioscorea; Drugs, Chinese Herbal; Gene Expression; Heterocyclic Compounds, 4 or More Rings; Lipid Peroxidation; Liver; Male; Mice, Inbred ICR; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Organic Anion Transporters, Sodium-Dependent; Organic Cation Transport Proteins; Symporters

Diosbulbin B (DIOB), a furanoid, is a major constituent of herbal medicine Dioscorea bulbifera L. Exposure to DIOB caused liver injury in humans and experimental animals. The mechanisms of DIOB-induced hepatotoxicities remain unknown. The present study demonstrated that DIOB induced hepatotoxicities in a time- and dose-dependent manner in mice. H&E stained histopathologic image showed the occurrence of necrosis in the liver obtained from the mice treated with DIOB at dose of 200 mg/kg. Pretreatment with KTC protected the animals from hepatotoxicities and hepatic GSH depletion induced by DIOB, increased area under the concentration-time curve of blood DIOB, decreased urinary excretion of GSH conjugates derived from DIOB, and increased urinary excretion of parent drug. Pretreatment with BSO exacerbated DIOB-induced hepatotoxicities. In order to define the role of furan moiety in DIOB-induced liver toxicities, we replaced the furan of DIOB with a tetrahydrofuran group by chemical hydrogenation of the furan ring of DIOB. No liver injury was observed in the animals given the same doses of tetrahydro-DIOB. The furan moiety was essential for DIOB-induced hepatotoxicities. The results implicate the cis-enedial reactive metabolite of DIOB was responsible for the observed toxicities. The observed modest depletion of hepatic GSH in DIOB-treated animals suggests the actions of one or more reactive metabolites, and the hepatic injury observed could be due at least in part to reactions of these metabolites with crucial biomolecules. Cytochrome P450 3A enzymes are implicated in DIOB-induced hepatotoxicities by catalyzing the formation of the reactive metabolite of DIOB.

Topics: Activation, Metabolic; Animals; Buthionine Sulfoximine; Chemical and Drug Induced Liver Injury; Furans; Glutathione; Heterocyclic Compounds, 4 or More Rings; Ketoconazole; Liver; Male; Mice; Structure-Activity Relationship

The rhizome of Dioscorea bulbifera Linn, traditionally used to treat thyroid disease and cancer in China, is reported to induce serious liver injury during clinical practice. Diosbulbin B (DB), a diterpene lactone, has been found to be the main toxic compound in D. bulbifera. The present study aims to investigate the protection of ferulic acid (FA) against DB-induced acute liver injury and its engaged mechanism. Mice were orally administered FA (20, 40, 80 mg/kg) once daily for 6 consecutive days; and then orally given DB (250 mg/kg) on the last day. Daily FA (40, 80 mg/kg) decreased DB (250 mg/kg)-induced increase in serum levels of alanine/aspartate aminotransferase (ALT/AST) and alkaline phosphatase (ALP). Histological evaluation showed that FA (80 mg/kg) ameliorated DB-induced hepatocellular degeneration and lymphocyte infiltration. Results of terminal dUTP nick-end labeling (TUNEL) staining assay showed that FA (80 mg/kg) decreased the DB-increased number of apoptotic hepatocytes. FA (40, 80 mg/kg) reduced DB-increased liver malondialdehyde (MDA) amount. FA (40, 80 mg/kg) decreased DB-increased serum levels of tumor necrosis factor alpha (TNF-α) and interferon-γ (IFN-γ), and liver myeloperoxidase (MPO) activity. FA (80 mg/kg) reversed the DB-induced decrease in expression of inhibitor of kappa B (IκB) and the increase in nuclear translocation of the p65 subunit of nuclear factor kappa B (NFκBp65). Taken together, our results demonstrate that FA prevents DB-induced acute liver injury via inhibiting intrahepatic inflammation and liver apoptosis.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Coumaric Acids; Heterocyclic Compounds, 4 or More Rings; Interferon-gamma; Liver; Male; Mice; Mice, Inbred ICR; NF-kappa B

Diosbulbin B (DB) is the main hepatotoxic compound distributed in Dioscorea bulbifera L., which is widely used for the treatment of cancer and thyroid disorders in Asia. Scutellarin (SC) is the main compound in medicinal herb Scutellaria barbata D. Don, which is usually combined with Dioscorea bulbifera used for cancer therapy in clinic.. This study aims to investigate the protection of SC against the liver injury induced by DB and its engaged mechanism. In addition, the anti-tumor effect of DB and SC is further observed in vivo.. The protection of SC against DB-induced liver injury was evaluated by detecting serum alanine/aspartate aminotransferases (ALT/AST) and alkaline phosphatase (ALP) activities, and further liver histological observation. The inflammatory response was assessed by detecting liver myeloperoxidase (MPO) activity, and serum levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interferon-γ (IFN-γ). Western-blot analysis was used to detect the protein expression. The oxidative liver injury was evaluated by detecting liver malondialdehyde (MDA) and glutathione (GSH) contents, and glutathione peroxidase (GPx) enzymatic activity. In vivo anti-tumor activity was analyzed in S180 tumor-bearing mice.. SC significantly decreased the increased serum ALT/AST, and ALP activities induced by DB. Liver histological observation evidenced the protection of SC against DB-induced liver injury. SC obviously reduced the increased liver MPO activity and the number of MPO-positive staining cells induced by DB. SC also reversed the decreased expression of inhibitor of κB (IκB) and the translocation of nuclear factor κB (NF-κB) p65 from cytoplasm to nucleus induced by DB. In addition, SC significantly abrogated the increased serum levels of TNF-α, IL-6, and IFN-γ induced by DB. SC decreased the increased liver MDA content induced by DB significantly, and it also increased liver GSH level. The decreased GPx protein expression and its enzymatic activity induced by DB were both obviously reversed after SC treatment. The results in S180 tumor-bearing mice showed that SC combined with DB significantly inhibited tumor growth in vivo.. Our results demonstrate that SC prevents DB-induced liver injury by attenuating NF-κB-mediated hepatic inflammation and ameliorating liver oxidative stress injury. Meanwhile, DB plus SC has significant anti-tumor activity in vivo. This study indicates the potential combination of DB with SC for the treatment of cancer in clinic.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antineoplastic Agents; Apigenin; Aspartate Aminotransferases; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Cytokines; Glucuronates; Glutathione; Glutathione Peroxidase; Heterocyclic Compounds, 4 or More Rings; Lipid Peroxidation; Liver; Male; Mice, Inbred ICR; Neoplasms; NF-kappa B; Protective Agents; Tumor Burden

Dioscorea bulbifera L., a commonly used medicinal plant in China, is reported to induce hepatotoxicity. The present study is undertaken to investigate the hepatotoxicity induced by diosbulbin B (DB), a diterpene lactone isolated from D. bulbifera L., and to further explore its underlying mechanism. DB was administered to mice at the doses of 0, 16, 32, and 64 mg/kg once daily for 12 consecutive days. Liver injury induced by DB was evidenced by the increased activity of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). Liver histological evaluation showed that the mice treated with DB exhibited liver damage with the swelling of hepatocytes. Further results showed that the amount of malondialdehyde (MDA) in the liver was increased in mice treated with DB, while the glutathione amount and the enzymatic activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), copper/zinc-superoxide dismutase (CuZn-SOD), manganese-SOD (Mn-SOD), and catalase (CAT) were all decreased. DB also decreased the gene expression of CuZn-SOD and CAT. Taken together, our results indicate that oral administration of DB for 12 consecutive days can lead to the oxidative stress liver injury in mice.

Topics: Administration, Oral; Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Biomarkers; Chemical and Drug Induced Liver Injury; Drugs, Chinese Herbal; Gene Expression Regulation, Enzymologic; Glutathione; Heterocyclic Compounds, 4 or More Rings; Liver; Male; Malondialdehyde; Mice, Inbred ICR; Oxidative Stress; RNA, Messenger; Time Factors

The present study is designed to investigate the protection by ferulic acid against the hepatotoxicity induced by diosbulbin B and its possible mechanism, and further observe whether ferulic acid augments diosbulbin B-induced anti-tumor activity. The results show that ferulic acid decreases diosbulbin B-increased serum alanine transaminase/aspartate transaminase (ALT/AST) levels. Ferulic acid also decreases lipid peroxide (LPO) levels which are elevated in diosbulbin B-treated mice. Histological evaluation of the liver demonstrates hydropic degeneration in diosbulbin B-treated mice, while ferulic acid reverses this injury. Moreover, the activities of copper- and zinc-containing superoxide dismutase (CuZn-SOD) and catalase (CAT) are decreased in the livers of diosbulbin B-treated mice, while ferulic acid reverses these decreases. Further results demonstrate that the mRNA expressions of CuZn-SOD and CAT in diosbulbin B-treated mouse liver are significantly decreased, while ferulic acid prevents this decrease. In addition, ferulic acid also augments diosbulbin B-induced tumor growth inhibition compared with diosbulbin B alone. Taken together, the present study shows that ferulic acid prevents diosbulbin B-induced liver injury via ameliorating diosbulbin B-induced liver oxidative stress injury and augments diosbulbin B-induced anti-tumor activity.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Coumaric Acids; Dose-Response Relationship, Drug; Drug Synergism; Heterocyclic Compounds, 4 or More Rings; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Reactive Oxygen Species; Sarcoma; Treatment Outcome

Dioscorea bulbifera L., a traditionally used medicinal plant in China, is reported to induce hepatotoxicity. The present study is designed to investigate the protection of an ethanol extract of Angelica sinensis (Oliv) Diels (AE) against an ethyl acetate fraction of D. bulbifera (EF)-induced liver injury and its engaged mechanism. High performance liquid chromatography (HPLC) analysis showed that the amount of diosbulbin B in EF was 16.03% and ferulic acid in AE was 0.18%. EF (350 mg/kg) increased serum alanine/aspartate aminotransferase (ALT/AST), alkaline phosphatase (ALP) activities and total bilirubin (TB) amount, while AE inhibited such an increase. Liver histological evaluation showed that AE prevented development of severe hepatic lesions induced by EF. Further results showed that EF decreased the expression of Bcl-2 and induced the cleaved activation of caspase-9 and -3, and all those effects were reversed by AE. AE also reversed EF-induced decreased expression of the inhibitor of kappa B (IκB), superoxide dismutase (SOD), and glutathione peroxidase (GPx). Taken together, our results demonstrate that AE can prevent EF-induced hepatotoxicity via preventing apoptosis, meanwhile IκB, SOD, and GPx may be involved in such protection.

Topics: Angelica sinensis; Animals; Apoptosis; Biomarkers; Chemical and Drug Induced Liver Injury; Coumaric Acids; Dioscorea; Heterocyclic Compounds, 4 or More Rings; Liver; Male; Medicine, Traditional; Mice, Inbred ICR; Oxidative Stress; Plant Extracts; Protective Agents; Superoxide Dismutase

The present study was designed to observe the protection of Grateloupia filicina polysaccharide (GFP) against hepatotoxicity induced by Dioscorea bulbifera L in mice and its underlying mechanism. GFP was intragastrically (ig) given to mice at various doses. After 6 days, the mice were treated with ethyl acetate extract of Dioscorea bulbifera L (EF, ig). Serum levels of alanine/aspartate aminotransferase (ALT/AST), alkaline phosphatase (ALP), total bilirubin (TB) were measured, and liver histological evaluation was conducted. Furthermore, reductions of liver glutathione (GSH) amount and glutamate cysteine ligase (GCL) activity were tested. The expressions of GCL-c, GCL-m, and HO-1 (heme oxygenase-1) in liver were observed by Western-blot. The results showed that GFP (600 mg x kg(-1)) decreased EF-induced the increase of serum ALT, AST and TB, and GFP (400, 600 mg x kg(-1)) inhibited EF-induced the increase of serum ALP. Liver histological evaluation showed that the liver injury induced by EF was relieved after treated with GFP. GFP further increased liver GSH amount and reversed EF-induced the decrease of GCL activity. The Western-blot result showed that GFP augmented EF-induced the increase of HO-1, and reversed EF-induced the decrease of GCL-c. In conclusion, GFP can act against the oxidative stress liver injury induced by Dioscorea bulbifera L in mice.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Dioscorea; Glutamate-Cysteine Ligase; Glutathione; Heme Oxygenase-1; Heterocyclic Compounds, 4 or More Rings; Liver; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Plants, Medicinal; Polysaccharides; Random Allocation; Rhodophyta

The present study was undertaken to investigate the gender-related liver injury induced by Dioscorea bulbifera L. (DB), a traditional medicinal plant, in mice, and further explored its hepatotoxic chemical compound. Serum and liver tissue samples were collected at 0, 4, 8, 12 h, after mice were administrated orally with 640 mg/kg ethyl acetate extracts (EF) isolated from DB. After treatments, serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were both significantly elevated. Liver lipid peroxidation (LPO) level increased, while glutathione amounts, glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) activities all decreased in the time-dependent manner. Further analysis demonstrated that ALT and AST activities in female mice were significantly lower than those in male. Meanwhile, liver glutathione amounts and CAT activity in female mice after giving EF for 12 h were both higher than those in male. Further, comparing the liver injury induced by Diosbulbin B isolated from DB with that induced by EF on the basis of chemical analysis for the amounts of Diosbulbin B in EF of DB, we found that Diosbulbin B could be the main hepatotoxic chemical compound in DB. Taken together, our results show that DB can induce gender-related liver oxidative stress injury in mice, and its main hepatotoxic chemical compound is Diosbulbin B, for the first time.

Topics: Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Dioscorea; Drugs, Chinese Herbal; Female; Heterocyclic Compounds, 4 or More Rings; Lipid Peroxidation; Liver; Liver Function Tests; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Rhizome; Sex Factors

Metabolic profile of bile acids was used to evaluate hepatotoxicity of mice caused by ethanol extraction of Dioscorea bulbifera L. (ethanol extraction, ET) and diosbulbin B (DB), separately. Ultra-performance liquid chromatography coupled with quadrupole mass spectrometry (UPLC-MS) was applied to determine the contents of all kinds of endogenous bile acids including free bile acids, taurine conjugates and glycine conjugates. Obvious liver injuries could be observed in mice after administrated with ET and DB. Based on the analysis using principle components analysis (PCA), toxic groups could be distinguished from their control groups, which suggested that the variance of the contents of bile acids could evaluate hepatotoxicity caused by ET and DB. Meanwhile, ET and DB toxic groups were classified in the same trends comparing to control groups in the loading plot, and difference between the two toxic groups could also be observed. DB proved to be one of the toxic components in Dioscorea bulbifera L. Bile acids of tauroursodeoxycholic acid (TUDCA), taurochenodeoxycholic acid (TCDCA), taurocholic acid (TCA), taurodeoxycholic acid (TDCA), cholic acid (CA) and others proved to be important corresponds to ET and DB induced liver injury according to analysis of partial least square-discriminant analysis (PLS-DA) and the statistical analysis showed that there were significant differences between the control groups and toxic groups (P < 0.01). Furthermore, good correlation could be revealed between the foregoing bile acids and ALT, AST. It indicated that taurine conjugated bile acids as TUDCA, TCDCA, TCA and TDCA along with CA could be considered as sensitive biomarkers of ET and DB induced liver injury. This work can provide the base for the further research on the evaluation and mechanism of hepatotoxicity caused by Dioscorea bulbifera L.

Topics: Animals; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Cholic Acid; Chromatography, High Pressure Liquid; Dioscorea; Drugs, Chinese Herbal; Heterocyclic Compounds, 4 or More Rings; Least-Squares Analysis; Male; Mice; Mice, Inbred ICR; Plants, Medicinal; Principal Component Analysis; Rhizome; Tandem Mass Spectrometry; Taurochenodeoxycholic Acid; Taurocholic Acid; Taurodeoxycholic Acid