tetracycline and Fatty-Liver

Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents.

Topics: Amiodarone; Animals; Camptothecin; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Fatty Liver; Hepatocytes; Humans; Irinotecan; Lipid Metabolism; Liver; Methotrexate; Mitochondria, Liver; Organoplatinum Compounds; Oxaliplatin; Perhexiline; Tamoxifen; Tetracycline; Valproic Acid

Topics: Acute Disease; Eclampsia; Fatty Liver; Female; Humans; Liver; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Third; Tetracycline

One important consideration to be appreciated from the examples of "lethal synthesis" presented in this paper is that the mechanisms of toxic substances must be further explored, a true understanding of the complex modalities of cellular injury achieved, and the significance of cellular changes determined before we can preestablish the hazards of chemical or environmental contaminants. The identification of compounds that may modify the intracellular milieu by adduction of marcromolecules and those that may be activated to produce proximate toxins could be accomplished on the basis of their distinguishing structure and metabolism. Assaying for the levels and functions of xenobiotic systems may help us to preduct the potential risk to individuals. It is incumbent upon us now to become more critical of the side-effects of "therapy", to weigh the jeopardy against the benefits involved. And to do so, we must attain a better comprehension of the complicated mechanisms of cellular injury.

Topics: Biotransformation; Cell Survival; Chloroform; Diet; Drug-Related Side Effects and Adverse Reactions; Fatty Liver; Free Radicals; Glucosephosphate Dehydrogenase Deficiency; Halothane; Heinz Bodies; Humans; Iatrogenic Disease; Membranes; Parenteral Nutrition, Total; Peroxides; Primaquine; Tetracycline

Topics: Administration, Oral; Chemical and Drug Induced Liver Injury; Child; Fatty Liver; Female; Glomerular Filtration Rate; Humans; Liver; Male; Pancreatitis; Pregnancy; Pregnancy Complications; Protein Biosynthesis; Tetracycline; Uremia

Topics: Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Fatty Liver; Granuloma; Hemorrhagic Disorders; Humans; Liver; Liver Diseases; Pharmaceutical Preparations; Tetracycline

To investigate biochemical mechanisms for the tetracycline-induced steatosis in rats, targeted proteins of oxidative modification were profiled. The results showed that tetracycline induced lipid accumulation, oxidative stress, and cell viability decline in HepG2 cells only under the circumstances of palmitic acid overload. Tetracycline administration in rats led to significant decrement in blood lipids, while resulted in more than four times increment in intrahepatic triacylglycerol and typical microvesicular steatosis in the livers. The triacylglycerol levels were positively correlated with oxidative stress. Proteomic profiles of carbonylated proteins revealed 26 targeted proteins susceptible to oxidative modification and most of them located in mitochondria. Among them, the long-chain specific acyl-CoA dehydrogenase was one of the key enzymes regulating fatty acid β-oxidation. Oxidative modification of the enzyme in the tetracycline group depressed its enzymatic activity. In conclusion, the increased influx of lipid into the livers is the first hit of tetracycline-induced microvesicular steatosis. Oxidative stress is an essential part of the second hit, which may arise from the lipid overload and attack a series of functional proteins, aggravating the development of steatosis. The 26 targeted proteins revealed here provide a potential direct link between oxidative stress and tetracycline-induced steatosis.

Topics: Animals; Anti-Bacterial Agents; Fatty Acids; Fatty Liver; Hep G2 Cells; Humans; Liver; Male; Protein Carbonylation; Protein Interaction Maps; Proteins; Proteomics; Rats; Rats, Sprague-Dawley; Tetracycline

Pathological levels of oxidative stress (OS) have been implicated in a broad spectrum of diseases. Carbonylation is an irreversible PTM that is considered as a universal indicator of OS. The development of new enrichment techniques coupled with the introduction of highly sensitive mass spectrometers has allowed the identification of carbonylated proteins in biological systems. In this study, Deng et al. (Proteomics 2015, 15, 148-159) utilized one of these methods to isolate and identify carbonylated proteins that are involved in tetracycline-induced steatosis. They identified 26 proteins that are targets of OS and most of them were located in the mitochondria. A key carbonylated protein that was identified is long chain specific acyl-CoA dehydrogenase, which has a major role in the β-oxidation of fatty acids. The researchers concluded that tetracycline-induced steatosis is a two-step process that involves lipid overload followed by OS.

Topics: Animals; Anti-Bacterial Agents; Fatty Liver; Humans; Liver; Male; Protein Carbonylation; Proteins; Tetracycline

The small heterodimer partner (SHP) (NR0B2) is an atypical nuclear receptor that lacks a DNA-binding domain. It interacts with and inhibits many transcription factors, affecting key metabolic processes, including bile acid, cholesterol, fatty acid, and drug metabolism. Our aim was to determine the influence of steatotic drugs and nonalcoholic fatty liver disease (NAFLD) on SHP expression and investigate the potential mechanisms. SHP was found to be repressed by steatotic drugs (valproate, doxycycline, tetracycline, and cyclosporin A) in cultured hepatic cells and the livers of different animal models of NAFLD: iatrogenic (tetracycline-treated rats), genetic (glycine N-methyltransferase-deficient mice), and nutritional (mice fed a methionine- and choline-deficient diet). Among the different transcription factors investigated, CCAAT-enhancer-binding protein α (C/EBPα) showed the strongest dominant-repressive effect on SHP expression in HepG2 and human hepatocytes. Reporter assays revealed that the inhibitory effect of C/EBPα and steatotic drugs colocalize between -340 and -509 base pair of the SHP promoter, and mutation of a predicted C/EBPα response element at -473 base pair abolished SHP repression by both C/EBPα and drugs. Moreover, inhibition of major stress signaling pathways demonstrated that the mitogen-activated protein kinase kinase 1/2 pathway activates, while the phosphatidylinositol 3 kinase pathway represses SHP in a C/EBP-dependent manner. We conclude that SHP is downregulated by several steatotic drugs and in advanced NAFLD. These conditions can activate signals that target C/EBPα and consequently repress SHP, thus favoring the progression and severity of NAFLD.

Topics: Animals; CCAAT-Enhancer-Binding Protein-alpha; Cells, Cultured; Cyclosporine; Doxycycline; Fatty Liver; Humans; Male; Mice; Mitogen-Activated Protein Kinase 1; Non-alcoholic Fatty Liver Disease; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Tetracycline; Thiazepines; Transcription, Genetic; Valproic Acid

Although drug induced steatosis represents a mild type of hepatotoxicity it can progress into more severe non-alcoholic steatohepatitis. Current models used for safety assessment in drug development and chemical risk assessment do not accurately predict steatosis in humans. Therefore, new models need to be developed to screen compounds for steatogenic properties. We have studied the usefulness of mouse precision-cut liver slices (PCLS) as an alternative to animal testing to gain more insight into the mechanisms involved in the steatogenesis. To this end, PCLS were incubated 24 h with the model steatogenic compounds: amiodarone (AMI), valproic acid (VA), and tetracycline (TET). Transcriptome analysis using DNA microarrays was used to identify genes and processes affected by these compounds. AMI and VA upregulated lipid metabolism, whereas processes associated with extracellular matrix remodelling and inflammation were downregulated. TET downregulated mitochondrial functions, lipid metabolism, and fibrosis. Furthermore, on the basis of the transcriptomics data it was hypothesized that all three compounds affect peroxisome proliferator activated-receptor (PPAR) signaling. Application of PPAR reporter assays classified AMI and VA as PPARγ and triple PPARα/(β/δ)/γ agonist, respectively, whereas TET had no effect on any of the PPARs. Some of the differentially expressed genes were considered as potential candidate biomarkers to identify PPAR agonists (i.e. AMI and VA) or compounds impairing mitochondrial functions (i.e. TET). Finally, comparison of our findings with publicly available transcriptomics data showed that a number of processes altered in the mouse PCLS was also affected in mouse livers and human primary hepatocytes exposed to known PPAR agonists. Thus mouse PCLS are a valuable model to identify early mechanisms of action of compounds altering lipid metabolism.

Topics: Amiodarone; Animals; Enzyme Inhibitors; Extracellular Matrix; Fatty Liver; Gene Expression; Gene Expression Profiling; Hepatocytes; Humans; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondria; Models, Biological; Oligonucleotide Array Sequence Analysis; PPAR alpha; PPAR gamma; PPAR-beta; Tetracycline; Tissue Culture Techniques; Transcriptome; Valproic Acid

Metabolic syndrome is a combination of medical disorders that increases the risk of developing cardiovascular disease and diabetes. Constitutive overexpression of 11β-HSD1 in adipose tissue in mice leads to metabolic syndrome. In the process of generating transgenic mice overexpressing 11β-HSD1 in an inducible manner, we found a metabolic syndrome phenotype in control, transgenic mice, expressing the reverse tetracycline-transactivator (rtTA) in adipose tissue. The control mice exhibited all four sequelae of metabolic syndrome (visceral obesity, insulin resistance, dyslipidemia, and hypertension), a pro-inflammatory state and marked hepatic steatosis. Gene expression profiling of the adipose tissue, muscle and liver of these mice revealed changes in expression of genes involved in lipid metabolism, insulin resistance, and inflammation. Transient transfection of rtTA, but not tTS, into 3T3-L1 cells resulted in lipid accumulation. We conclude that expression of rtTA in adipose tissue causes metabolic syndrome in mice.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 3T3-L1 Cells; Adipose Tissue; Animals; Blood Pressure; Chromosomes, Mammalian; DNA Fragmentation; Fatty Liver; Gene Expression Profiling; Insulin Resistance; Lipid Metabolism; Male; Metabolic Syndrome; Mice; Mice, Transgenic; Muscles; Phenotype; Tetracycline; Trans-Activators; Transcriptional Activation; Transfection; Transgenes

Drug-induced liver injury occurs in general after several weeks and is often unpredictable. It is characterized by a large spectrum of lesions that includes steatosis and phospholipidosis. Many drugs such as amiodarone and tetracycline have been reported to cause phospholipidosis and/or steatosis. In this study, acute and chronic hepatic effects of these two drugs were investigated using well-differentiated human hepatoma HepaRG cells. Accumulation of typical lipid droplets, labeled with Oil Red O, was observed in hepatocyte-like HepaRG cells after repeat exposure to either drug. Amiodarone caused the formation of additional intracytoplasmic vesicles that did not stain in all HepaRG cells. At the electron microscopic level, these vesicles appeared as typical lamellar bodies and were associated with an increase of phosphatidylethanolamine and phosphatidylcholine. A dose-dependent induction of triglycerides (TG) was observed after repeat exposure to either amiodarone or tetracycline. Several genes known to be related to lipogenesis were induced after treatment by these two drugs. By contrast, opposite deregulation of some of these genes (FASN, SCD1, and THSRP) was observed in fat HepaRG cells induced by oleic acid overload, supporting the conclusion that different mechanisms were involved in the induction of steatosis by drugs and oleic acid. Moreover, several genes related to lipid droplet formation (ADFP, PLIN4) were up-regulated after exposure to both drugs and oleic acid.. Our results show that amiodarone causes phospholipidosis after short-term treatment and, like tetracycline, induces vesicular steatosis after repeat exposure in HepaRG cells. These data represent the first demonstration that drugs can induce vesicular steatosis in vitro and show a direct relationship between TG accumulation and enhanced expression of lipogenic genes.

Topics: Amiodarone; Carcinoma, Hepatocellular; Carrier Proteins; Cell Line, Tumor; Down-Regulation; Fatty Acid Synthase, Type I; Fatty Liver; Humans; Lipid Metabolism; Lipogenesis; Liver Neoplasms; Membrane Proteins; Oleic Acid; Perilipin-2; Perilipin-4; Phosphoproteins; Stearoyl-CoA Desaturase; Tetracycline; Triglycerides; Up-Regulation

In order to find sensitive serum markers in non-alcoholic steatohepatitis, liver-specific injury markers were thoroughly examined in mild models of NASH in rats.. Wistar and Sprague-Dawley rats were fed a choline-deficient diet for 4 weeks, and serum activities of liver-specific enzyme markers were examined. In the drug-induced steatohepatitis model, tetracycline (0.4 mmol/kg) was given i.p. to rats and the course of hepatotoxicity was evaluated with serum markers, together with the accumulation of total lipid and thiobarbituric acid-reactive substances in the liver.. In Wistar rats, serum activities of most enzymes tested were significantly increased. In Sprague-Dawley rats, in contrast, the serum level of ornithine carbamyltransferase and glutamate dehydrogenase were markedly elevated in the choline-deficient diet group compared with the control diet groups, whereas other markers were not significantly increased. In the tetracycline-induced steatohepatitis model, the extent of the increase was much higher in mitochondrial markers and the peak of the increase in these markers corresponded with the increase of hepatic total lipid and thiobarbituric acid-reactive substance.. These observations show that serum mitochondrial enzyme markers are potent markers for non-alcoholic steatohepatitis in rats and are possibly applicable to humans.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Biomarkers; Choline Deficiency; Diet; Disease Models, Animal; Enzymes; Fatty Liver; Glutamate Dehydrogenase; Injections, Intraperitoneal; Lipid Peroxidation; Liver; Male; Mitochondria, Liver; Mitochondrial Proteins; Ornithine Carbamoyltransferase; Rats; Rats, Sprague-Dawley; Rats, Wistar; Severity of Illness Index; Tetracycline; Thiobarbituric Acid Reactive Substances; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation

Peroxisome proliferators-activated receptor alpha (PPARalpha) and oxidative stress are two important pathological factors in non-alcoholic fatty liver disease (NAFLD). Tetracycline-induced fatty liver was partly due to the disturbance of mitochondrial fatty acids beta-oxidation regulated by PPARalpha. Bicyclol was found to protect against high fat diet-induced fatty liver through modulating PPARalpha and clearing reactive oxygen species (ROS). The present study was performed to further investigate the effect of bicyclol on tetracycline-induced fatty liver and related mechanism in mice. Bicyclol (75, 150, 300 mg/kg) was given orally three times in two consecutive days. Tetracycline (200 mg/kg) was injected intraperitoneally 1h after the last administration of bicyclol. Oxidative stress, mitochondrial function, PPARalpha and its target genes were evaluated by biochemical and RT-PCR analysis. The activity of CYP4A was assessed by liquid chromatography/mass spectrometry (LC/MS) method. Bicyclol significantly protected against tetracycline-induced fatty liver by reducing the accumulation of hepatic lipids and elevation of serum aminotransferase. In addition, bicyclol remarkably alleviated the over-production of thiobarbituric acid-reactive substance. The reduced activity of mitochondrial respiratory chain (MRC) complexes I and IV and mitochondrial permeability transition (MPT) were also improved by bicyclol. Furthermore, bicyclol inhibited the decrease of PPARalpha expression and its target genes, including long-chain acyl CoA dehydrogenase (LCAD), acetyl CoA oxidase (AOX) and CYP4A at mRNA and enzyme activity level. Bicyclol protected against tetracycline-induced fatty liver mainly through modulating the disturbance of PPARalpha pathway and ameliorating mitochondrial function.

Topics: Acyl-CoA Dehydrogenase, Long-Chain; Acyl-CoA Oxidase; Administration, Oral; Alanine Transaminase; Animals; Aspartate Aminotransferases; Biphenyl Compounds; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP4A; Disease Models, Animal; Electron Transport Complex I; Electron Transport Complex IV; Fatty Acids; Fatty Liver; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred ICR; Mitochondria, Liver; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Oxidative Stress; PPAR alpha; Protective Agents; Tetracycline; Time Factors

This paper aimed to explore three-dimensionally cultured hepatocytes for testing drug-induced nonalcoholic steatohepatitis. Gel entrapped rat hepatocytes were applied for investigation of the tetracycline-induced steatohepatitis, while hepatocyte monolayer was set as a control. The toxic responses of hepatocytes were systematically evaluated by measuring cell viability, liver-specific function, lipid accumulation, oxidative stress, adenosine triphosphate content and mitochondrial membrane potential. The results suggested that gel entrapped hepatocytes showed cell death after 96 h of tetracycline treatment at 25 muM which is equivalent to toxic serum concentration in rats, while hepatocyte monolayer showed cell death at a high dose of 200 muM. The concentration-dependent accumulation of lipid as well as mitochondrial damage were regarded as two early events for tetracycline hepatotoxicity in gel entrapment culture due to their detectability ahead of subsequent increase of oxidative stress and a final cell death. Furthermore, the potent protection of fenofibrate and fructose-1,6-diphosphate were evidenced in only gel entrapment culture with higher expressions on the genes related to beta-oxidation than hepatocyte monolayer, suggesting the mediation of lipid metabolism and mitochondrial damage in tetracycline toxicity. Overall, gel entrapped hepatocytes in three-dimension reflected more of the tetracycline toxicity in vivo than hepatocyte monolayer and thus was suggested as a more relevant system for evaluating steatogenic drugs.

Topics: Animals; Anti-Bacterial Agents; Cell Culture Techniques; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Liver; Gels; Hepatocytes; Lipid Peroxidation; Male; Mitochondrial Membranes; Oxidative Stress; Rats; Rats, Sprague-Dawley; Tetracycline

To study the effect of bicyclol on lipid disorder and liver damage induced by tetracycline in mice, mice were given (ig) bicyclol (75, 150, and 300 mg x kg(-1)) three times before or after administration of tetracycline (180 mg x kg(-1)). The contents of hepatic lipids, MDA and GSH, serum lipids and ALT/AST levels were measured 24 hours after the injection (ip) of tetracycline. The beta-oxidation rate of hepatic mitochondrial fatty acid and hepatic secretion of VLDL were also observed. Bicyclol (150 and 300 mg x kg(-1)) provided significant protection against fatty liver by inhibiting the elevation of hepatic TG and CHO, adjusting abnormal serum lipids, inhibiting the elevation of serum ALT, AST, and ameliorating the severity of pathological changes. Furthermore, bicyclol significantly accelerated the VLDL (TG) secretion and reversed the impairment of mitochondrial oxidation, resulting in the lipid homeostasis. The increase of MDA formation and depletion of GSH that reflect lipid peroxidation induced by tetracycline were also inhibited by bicyclol administration. The results indicated that the hepatoprotection of bicyclol was mostly due to the improvement on lipid oxidation and transportation as well as the inhibition of lipid peroxidation in tetracycline-intoxicated mice.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Biphenyl Compounds; Cholesterol; Cholesterol, VLDL; Fatty Acids; Fatty Liver; Glutathione; Lipid Peroxidation; Liver; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Mitochondria, Liver; Protective Agents; Random Allocation; Tetracycline; Triglycerides

Tetracycline is one of a group of drugs known to induce microvesicular steatosis. In the present study, we investigated the effects of tetracycline on gene expression in mouse liver, using Applied Biosystems Mouse Genome Survey Microarrays. A single oral dose of 0.1 or 1 g/kg tetracycline was administered to male ICR mice, and liver samples were obtained after 6, 24, or 72 h. Histopathological evaluation showed microvesicular steatosis in the high-dose group at 24 h. In total, 96 genes were identified as tetracycline responsive. Their level of expression differed significantly from controls (two-way analysis of variance; p < 0.05), after adjustment by the Benjamini-Hochberg multiple testing correction, and displayed a twofold or greater induction or repression. The largest groups of gene products affected by tetracycline exposure were those involved in signal transduction, nucleic acid metabolism, developmental processes, and protein metabolism. The expression of genes known to be involved in lipid metabolism was examined, using two-sample Student's t-test for each treatment group versus a corresponding control group. The overall net effects on expression of lipid metabolism genes indicated an increase in cholesterol and triglyceride biosynthesis and a decrease in beta-oxidation of fatty acids. Our data support a proposed mechanism for tetracycline-induced steatogenic hepatotoxicity that involves these processes. Moreover, we demonstrated global changes in hepatic gene expression following tetracycline exposure; many of these genes have the potential to be used as biomarkers of exposure to steatogenic hepatotoxic agents.

Topics: Administration, Oral; Analysis of Variance; Animals; Cluster Analysis; Dose-Response Relationship, Drug; Fatty Liver; Gene Expression Profiling; Homeostasis; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred ICR; Oligonucleotide Array Sequence Analysis; Protein Synthesis Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tetracycline; Time Factors

Although many steatogenic drugs inhibit mitochondrial fatty acid beta-oxidation, limited information is available on possible effects on hepatic lipoprotein secretion. In the endoplasmic reticulum (ER) lumen, microsomal triglyceride transfer protein (MTP) lipidates apolipoprotein B (Apo B), to form triglyceride (TG)-rich very low density lipoprotein (VLDL) particles, which follow vesicular flow to the plasma membrane to be secreted, whereas incompletely lipidated Apo B particles are partly degraded. We studied hepatic MTP activity, the lipoproteins present in the ER lumen, and hepatic lipoprotein secretion 4 hours after administration of a single dose of amineptine (1 mmol/kg), amiodarone (1 mmol/kg), doxycycline (0.25 mmol/kg), tetracycline (0.25 mmol/kg), tianeptine (0.5 mmol/kg), or pirprofen (2 mmol/kg) in mice. These various doses have been shown previously to markedly inhibit fatty acid oxidation after a single dose, and to trigger steatosis either after repeated doses (doxycycline) or a single dose (other compounds) in mice. In the present study, amineptine, amiodarone, pirprofen, tetracycline, and tianeptine, but not doxycycline, inhibited MTP activity in vitro, decreased ex vivo MTP activity in the hepatic homogenate of treated mice, decreased TG in the luminal VLDL fraction of hepatic microsomes of treated mice, and decreased in vivo hepatic lipoprotein secretion (TG and Apo B). In conclusion, several steatogenic drugs inhibit not only mitochondrial beta-oxidation, as previously shown, but also MTP activity, Apo B lipidation into TG-rich VLDL particles, and hepatic lipoprotein secretion. Drugs with these dual effects may be more steatogenic than drugs acting only on beta-oxidation or only MTP.

Topics: Amiodarone; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Tricyclic; Apolipoproteins B; Carrier Proteins; Dibenzocycloheptenes; Doxycycline; Enzyme Inhibitors; Fatty Liver; Lipoproteins, VLDL; Mice; Microsomes, Liver; Mitochondria, Liver; Oxidation-Reduction; Phenylpropionates; Sonication; Tetracycline; Thiazepines; Triglycerides

Primary hepatocyte cultures prepared from male beagle dog liver were used to determine susceptibility of the canine liver to tetracycline-induced steatosis. The effects of the drug on mitochondrial lipid metabolism and intracellular triglyceride accumulation were monitored at the same time that steatosis was detected by light microscopy and quantitated using lipid-specific stains. Exposure of primary canine hepatocyte cultures to tetracycline for 24-48 h resulted in concentration-dependent, significant increases in the Oil Red O-stained lipid inclusions. Microscopic examination of the total stained areas suggested that increases over control levels were due primarily to the increase in the size of the lipid inclusions rather than in the number. Biochemical analyses for triglyceride content and histological staining with Nile red, another neutral lipid-specific dye, confirmed a specific increase in intracellular triglyceride following a 24-h exposure to noncytotoxic levels of tetracycline beta-oxidation studies based on the oxidation of [14C]palmitic acid or [14C]palmitoyl carnitine demonstrated a concentration-dependent inhibition of mitochondrial but not peroxisomal beta-oxidation in hepatocytes after a 24-h exposure to tetracycline. In vitro incubation of tetracycline with mitochondria isolated from dog liver showed similar concentration-dependent inhibition. This study clearly indicates that the canine hepatocyte is susceptible to tetracycline-induced steatosis. Triglyceride accumulation was concomitant with the inhibition of mitochondrial lipid metabolism, indicating that this is a primary mechanism leading to steatosis in dog hepatocytes following tetracycline exposure.

Topics: Animals; Anti-Bacterial Agents; Azo Compounds; Carbon Radioisotopes; Cells, Cultured; Coloring Agents; Disease Susceptibility; Dogs; Dose-Response Relationship, Drug; Fatty Liver; Fluorescent Dyes; Histocytochemistry; Lipid Metabolism; Liver; Male; Mice; Mitochondria, Liver; Oxazines; Palmitic Acid; Palmitoylcarnitine; Rats; Tetracycline; Triglycerides

Several liver diseases that are characterized by chronic steatosis lead to steatohepatitis lesions in some susceptible subjects. We tested the hypothesis that acute or chronic steatosis may lead to lipid peroxidation.. Diverse steatogenic treatments were administered to mice, and lipid peroxidation was assessed by measuring thiobarbituric acid reactants in the liver and the exhalation of ethane in breath.. Administration of ethanol (5 g/kg), tetracycline, chlortetracycline, demeclocycline (0.25 mmol/kg each), amineptine (1 mmol/kg), amiodarone (1 mmol/kg), pirprofen (2 mmol/kg), or valproate (2 mmol/kg) led to microvesicular steatosis of the liver and lipid peroxidation. After tetracycline administration, hepatic triglycerides reached a maximum at 24 h and then declined; ethane exhalation followed a similar time course. Microvesicular steatosis and lipid peroxidation were also observed after 4 days of treatment with either ethionine (0.02 mmol/kg daily) or dexamethasone (0.25 mmol/kg daily) or after 7 days of tetracycline (0.25 mmol/kg daily) administration. Administration of ethanol in the drinking water for 5.5 months led to macrovacuolar and microvesicular steatosis, lipid peroxidation, and a few necrotic hepatocytes.. We conclude that acute or chronic fat deposition due to a variety of compounds was associated with lipid peroxidation in mice. We suggest that the presence of oxidizable fat in the liver leads to peroxidation, and that chronic lipid peroxidation might represent the common (but not exclusive) mechanism for the possible development of steatohepatitis lesions in conditions characterized by chronic steatosis.

Topics: Acute Disease; Animals; Chronic Disease; Disease Progression; Ethane; Ethanol; Fatty Liver; Lipid Peroxidation; Liver; Male; Mice; Tetracycline; Triglycerides

Fatty tetracycline-induced steatosis is shown to reduce levels of mitochondrial and microsomal cytochromes. A decrease of microsomal cytochromes in the liver of hypoxia-resistant animals was similar to that of hypoxia-sensitive ones. This decrease was different for hypoxia-resistant and hypoxia-sensitive animals: for the former only cytochrome a declined, in the latter case cytochromes c+, c1 and a.

Topics: Acute Disease; Animals; Cytochromes; Fatty Liver; Hypoxia; Male; Microsomes, Liver; Mitochondria, Liver; Rats; Tetracycline

Pregnant women, especially those in their third trimester, are particularly susceptible to tetracycline-induced fatty liver. Experimental evidence obtained in rats suggest that the precipitous fall in maternal liver choline concentration nearing the end of pregnancy could lead to a severe reduction in the lipotropic activity of the liver. It is hypothesised that the liver in this state will be at much greater risk of developing fatty degeneration, especially if it is exposed to hepatotoxic agents such as tetracycline.

Topics: Animals; Choline; Choline Deficiency; Fatty Liver; Female; Humans; Lipotropic Agents; Liver; Pregnancy; Pregnancy Complications; Rats; Tetracycline

Topics: Adult; Bone and Bones; Fatty Liver; Female; Humans; Pregnancy; Pregnancy Complications; Tetracycline

Two cases of tetracycline-associated fatty liver of pregnancy are reported. In one, the history was negative for antibiotic use, yet autopsy revealed typical gross and microscopic bone fluorescence of tetracycline. Tissue extraction and chemical analysis showed qualitative evidence of tetracycline, whereas quantitation revealed 60 microgram/gm of wet bone tissue. Findings in our cases and in those from the literature indicate that the association of tetracycline use and fatty liver of pregnancy is even more common than has been suggested.

Topics: Adult; Fatty Liver; Female; Humans; Liver; Pregnancy; Pregnancy Complications; Risk; Tetracycline

A comparative study on the effect of rolitetracycline (50 micrograms/g i.v.) on the hepatic content of triglycerides and the release of esterified fatty acids from the liver into the blood was performed in young and adult NMRI mice of both sexes. Rolitetracycline caused an accumulation of triglycerides only in the livers of adult animals, the effect being much more pronounced in females than in males. In agreement with this a very strong inhibition of lipid release from the liver and a significant decrease of the esterified fatty acids of the serum was produced only in adult females. The results suggest that the livers of young animals of both sexes are relatively resistant to the steatotic effect of rolitetracycline.

Topics: Age Factors; Animals; Fatty Acids; Fatty Liver; Female; Lipid Metabolism; Liver; Male; Mice; Rolitetracycline; Sex Factors; Tetracycline; Triglycerides

The effect of vitamin B12 on the metabolic alterations due to tetracycline toxicity was studied experimentally on laboratory animals. Treatment of Sprague-Dawley rats with 120 or 250 mg tetracycline (i.p.) per kg per day for two or three days caused an accumulation of lipids, mainly triglycerides in the liver of 75% of animals studied, while phospholipid level tend to decrease. These doses are approximately twice and four times the recommended maximum dose for man. In the present work no direct relationship was observed between dose of tetracycline and hepatic accumulation of triglyceride, although livers of rats treated with 250 mg tetracycline/kg appeared uniformly pale yellow. Elevated serum triglyceride was found predominantly in rats treated with 120 mg/kg, while there was no obvious difference between serum triglyceride of rats treated with 250 mg tetracycline and control rats, indicating a block in the release of hepatic triglycerides. Where protection by vitamin B12 was studied, the vitamin was given i.m. (50 microgram/animal) 3 hours before the injection of 120 mg tetracycline per kg. There was a good evidence that lipid abnormalities caused by tetracycline improved by vitamin B12. Thus both hepatic and serum total lipid and triglycerides were significantly lower than those of rats treated with tetracycline, although hepatic total cholesterol was significantly increased as in case of tetracycline only.

Topics: Animals; Cholesterol; Fatty Liver; Female; Lipid Metabolism; Male; Phospholipids; Rats; Tetracycline; Triglycerides; Vitamin B 12

Steatosis of the liver is a harmless symptom of disturbed lipid metabolism but not a disease. The cause of the steatosis, and not the fat accumulation by itself, produces cirrhosis. There is no evidence so far in man that cirrhosis may be caused by nutritional deficiencies alone. Even cirrhosis after small bowel bypass procedures seems to be result from metabolic rather than nutritional disturbances.

Topics: Adrenal Cortex Hormones; Alcoholism; Animals; Bile Acids and Salts; Blind Loop Syndrome; Diabetes Complications; Dogs; Fatty Liver; Humans; Hyperlipidemias; Ileum; Jejunum; Kwashiorkor; Lipid Metabolism; Liver Cirrhosis; Malabsorption Syndromes; Obesity; Postoperative Complications; Protein Deficiency; Remission, Spontaneous; Tetracycline

Dose-response relationships, biochemical mechanisms, and sex differences in the experimental fatty liver induced by tetracycline were studied in the intact rat and with the isolated perfused rat liver in vitro. In the intact male and female rat, no direct relationship was observed between dose of tetracycline and hepatic accumulation of triglyceride. With provision of adequate oleic acid as a substrate for the isolated perfused liver, a direct relationship was observed between dose of tetracycline and both accumulation of triglyceride in the liver and depression of output of triglyceride by livers from male and female rats. Marked differences were observed between female and male rats with regard to base line (control) hepatic concentration of triglyceride and output of triglyceride. Accumulation of hepatic triglyceride, as a per cent of control values, in response to graded doses of tetracycline, did not differ significantly between male, female and pregnant rat livers. However, livers from female, and especially pregnant female rats, were strikingly resistant to the effects of tetracycline on depression of output of triglyceride under these experimental conditions. These differences between the sexes could not be related to altered disposition of tetracycline or altered uptake of oleic acid. Depressed hepatic secretion of triglyceride accounted only for 30 to 50% of accumulated hepatic triglyceride, indicating that additional mechanisms must be involved in the production of the triglyceride-rich fatty liver in response to tetracycline.

Topics: Animals; Depression, Chemical; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Liver; Female; Liver; Male; Oleic Acids; Pregnancy; Rats; Sex Factors; Tetracycline; Triglycerides

Topics: Acetaminophen; Adult; Alcoholism; Azathioprine; Bilirubin; Chemical and Drug Induced Liver Injury; Chlorpromazine; Cholestasis; Dihydroxyphenylalanine; Enzyme Induction; Fatty Liver; Female; Granuloma; Halothane; Hepatomegaly; Humans; Male; Middle Aged; Oxyphenisatin Acetate; Pregnancy; Sulfonamides; Tetracycline

Topics: Agranulocytosis; Anemia, Aplastic; Anti-Bacterial Agents; Bronchial Spasm; Cephalosporins; Chloramphenicol; Drug Eruptions; Exanthema; Fatty Liver; Fever; Gentamicins; Hearing Disorders; Humans; Nalidixic Acid; Nitrofurantoin; Penicillins; Sulfanilamides; Tetracycline; Urticaria

Topics: Ampicillin; Candida albicans; Candidiasis; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Diagnosis, Differential; Fatty Liver; Female; Halothane; Humans; Hydronephrosis; Injections, Intravenous; Jaundice; Liver; Nitrofurantoin; Postoperative Complications; Sulfisoxazole; Tetracycline; Urinary Tract Infections; Vesico-Ureteral Reflux

Topics: Adult; Alcoholism; Ampicillin; Cephalothin; Chloramphenicol; Escherichia coli Infections; Fatty Liver; Female; Hepatitis; Humans; Klebsiella Infections; Liver Cirrhosis; Male; Methicillin; Middle Aged; Penicillins; Peritonitis; Pneumococcal Infections; Streptomycin; Syndrome; Tetracycline

Topics: Anemia, Hemolytic; Chemical and Drug Induced Liver Injury; Disseminated Intravascular Coagulation; Fatty Liver; Female; Humans; Kidney Failure, Chronic; Liver; Pregnancy; Pregnancy Complications, Hematologic; Tetracycline

Topics: Adult; Age Factors; Bilirubin; Cell Membrane; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Hypersensitivity; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Fatty Liver; Female; Halothane; Humans; Infant, Newborn; Liver; Liver Cirrhosis; Male; Methotrexate; Microsomes, Liver; Pharmaceutical Preparations; Pregnancy; Tetracycline

Topics: Acute Kidney Injury; Chemical and Drug Induced Liver Injury; Cholestasis; Contraceptives, Oral; Fatty Liver; Female; Halothane; Hepatitis A; Humans; Jaundice; Jaundice, Chronic Idiopathic; Liver; Liver Cirrhosis; Liver Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Rupture, Spontaneous; Tetracycline

Topics: Adipose Tissue; Brain Diseases; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Hepatitis; Humans; Infant; Kidney Diseases; Liver; Tetracycline; Virus Diseases

Topics: Acute Kidney Injury; Disseminated Intravascular Coagulation; Fatty Liver; Female; Humans; Pregnancy; Pregnancy Complications, Hematologic; Tetracycline

Topics: Cholestasis; Fatty Liver; Female; Halothane; Hepatitis; Hepatitis A; Hepatitis B; Hepatitis B Antigens; Humans; Hysterectomy; Liver Diseases; Liver Function Tests; Liver Regeneration; Maternal Mortality; Methoxyflurane; Middle Aged; Postoperative Complications; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Tetracycline; Transfusion Reaction

Topics: Animals; Endoplasmic Reticulum; Fatty Liver; Female; Injections, Intraperitoneal; Lethal Dose 50; Liver; Mitochondria, Liver; Mitochondrial Swelling; Rats; Rats, Inbred Strains; Tetracycline; Time Factors

Topics: Cholestasis; Contraceptives, Oral; Fatty Liver; Female; Humans; Jaundice; Pregnancy; Pregnancy Complications; Pruritus; Tetracycline

Topics: Anti-Bacterial Agents; Bile Duct Neoplasms; Bile Ducts; Biopsy; Cholangitis; Cholestasis; Colectomy; Colitis, Ulcerative; Fatty Liver; Follow-Up Studies; Hepatitis; Humans; Inflammation; Liver; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Diseases; Liver Function Tests; Portal System; Prednisolone; Sepsis; Tetracycline

Topics: Adult; Alkaline Phosphatase; Chlorpromazine; Esophagogastric Junction; Fatty Liver; Female; Humans; Kidney; Liver; Pregnancy; Pregnancy Complications; Tetracycline

Topics: Aged; Autopsy; Fatty Liver; Humans; Liver; Male; Sex Factors; Tetracycline

Topics: Acidosis, Renal Tubular; Aged; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Hemorrhagic Disorders; Humans; Hypoproteinemia; Jaundice; Kidney Diseases; Male; Middle Aged; Tetracycline; Uremia

Topics: Ethionine; Fatty Liver; Female; Humans; Infant, Newborn; Jaundice; Lipid Metabolism; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Tetracycline

Topics: Cell Nucleus; Culture Techniques; Cytoplasm; Fatty Liver; Humans; Liver; Microscopy, Electron; Microscopy, Fluorescence; Staining and Labeling; Tetracycline

Topics: Animals; Fatty Liver; Female; Hyperlipidemias; Liver; Plasma Volume; Protein Biosynthesis; Rats; Secretory Rate; Surface-Active Agents; Tetracycline; Triglycerides

Topics: Alanine Transaminase; Animals; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Liver Diseases; Male; Necrosis; Ornithine Carbamoyltransferase; Perfusion; Rats; Tetracycline

Topics: Adolescent; Adult; Fatty Liver; Female; Humans; Middle Aged; Pregnancy; Tetracycline

Topics: Adenosine Triphosphate; Animals; Fatty Liver; Female; Fluorometry; Glycerides; Lipids; Liver; Pregnancy; Pregnancy, Animal; Rats; Tetracycline; Triglycerides

Topics: Adolescent; Adrenal Glands; Fatty Liver; Female; Humans; Necrosis; Pancreas; Pregnancy; Pregnancy Complications; Pyelonephritis; Tetracycline

Topics: Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Humans; Pregnancy; Pregnancy Complications; Tetracycline

Topics: Adult; Aged; Fatty Liver; Female; Humans; Jaundice; Middle Aged; Neoplasms; Pancreatitis; Postoperative Complications; Pregnancy; Pregnancy Complications; Tetracycline

Topics: Adult; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Humans; Pregnancy; Pregnancy Complications; Tetracycline

Topics: Animals; Fatty Liver; Kidney; Rats; Tetracycline

Topics: Drug Therapy; Fatty Liver; Female; Maternal Death; Maternal Mortality; Pregnancy; Pregnancy Complications; Tetracycline; Toxicology

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy; Fatty Liver; Female; Hepatitis; Hepatitis A; Pregnancy; Pregnancy Complications; Pregnancy Complications, Infectious; Tetracycline; Toxicology

Topics: Anti-Bacterial Agents; Brain Diseases; Drug Therapy; Fatty Liver; Female; Kidney Diseases; Pancreatitis; Pregnancy; Pregnancy Complications; Pyelonephritis; Tetracycline; Toxicology

Topics: Fatty Liver; Female; Humans; Pregnancy; Pregnancy Complications; Protein Synthesis Inhibitors; Tetracycline; Toxicology

Topics: Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Child; Chloramphenicol; Chlortetracycline; Fatty Liver; Female; Hepatitis; Oxytetracycline; Pregnancy; Pregnancy Complications; Prochlorperazine; Tetracycline; Toxicology

Topics: Acidosis; Cesarean Section; Fatty Liver; Female; Hematemesis; Humans; Hypoproteinemia; Hypotension; Hysterectomy; Jaundice; Liver Diseases; Melena; Oxytetracycline; Pathology; Placenta Previa; Pneumonia; Postpartum Hemorrhage; Postpartum Period; Pregnancy; Pregnancy Complications; Tetracycline; Toxicology

Topics: Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Hepatitis; Liver Diseases; Pathology; Pregnancy; Pregnancy Complications; Pyelonephritis; Tetracycline; Toxicology

Topics: Chemical and Drug Induced Liver Injury; Fatty Liver; Hepatitis; Insulin; Liver Glycogen; Pharmacology; Rats; Research; Tetracycline; Toxicology

Topics: Chlortetracycline; Fatty Liver; Humans; Tetracycline