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- W1507087726 abstract "The liver is the primary site of drug metabolism and plays a major role in metabolism,digestion, detoxification, and elimination of drugs and toxins from the body.Consequently, drugs affect the liver more frequently than any other organ and placethe liver at increased risk for toxic damage. Drug-induced liver injury (DILI) is acommon cause of acute liver failure and the most frequent reason for the withdrawalof approved drugs, representing a serious challenge for the pharmaceutical industry.The risk of developing hepatotoxicity is not only due to the chemical properties of thedrug but also to environmental factors, pre-existing diseases and genetic factors,leading to the classification into either predictable (high incidence) or unpredictable(low incidence) hepatotoxicity. Drugs that produce predictable liver injury aregenerally a result of direct liver toxicity of the parent drug or its metabolites. However,the majority of adverse drug-induced hepatic events are unpredictable and theunderlying mechanisms are mostly unknown, but assumed to be either immunemediatedhypersensitivity reactions or idiosyncratic and are able to alter thesusceptibility to adverse events. In recent years mitochondrial dysfunction has beenrecognized as β-oxidation of fatty acids, inhibition or uncoupling of the respiratorychain, or through a primary effect on the mitochondrial genome.One aim of this thesis was to investigate the juvenile visceral steatosis (jvs) mouse,which is characterized by microvesicular steatosis of the liver and to impaired renalreabsorption leading to systemic carnitine deficiency. The main focus was put on theassessment of the hepatic toxicity of valproate, an antiepileptic drug known to induceliver injury, and to investigate whether the underlying carnitine deficiency is a riskfactor for valproate-associated hepatotoxicity. Furthermore, in vitro studies usingseveral hepatic cell lines were performed to estimate the suitability as screeningsystems for hepatic metabolism and CYP induction, and one study was conducted toevaluate the hepatotoxic effect of the plant cimicifuga racemosa.Initially we assessed the carnitine homeostasis and energy metabolism in carnitinedeficient(jvs-/-) mice after cessation of carnitine substitution (Chapter 6). It is wellestablished that sufficient carnitine plasma and tissue levels in jvs mice can beobtained by carnitine substitution, correcting carnitine deficiency. We studied thekinetics of carnitine loss from plasma and tissue carnitine stores and markers ofenergy metabolism after carnitine deprivation for a maximum of ten days. The totalcarnitine concentrations in plasma, liver and skeletal muscle were significantlydecreased, whereas carnitine concentration decreased rapidly in plasma but muchslower in tissue. Deprivation of carnitine was also associated with a further drop inthe plasma β-hydroxybutyrate levels and hepatic fat accumulation.In a second in vivo experiment (Chapter7) we investigated whether carnitinedeficiency is a risk factor for valproate-associated hepatotoxicity in jvs mice, and weassessed the effects of valproate on carnitine plasma and tissue stores in thesemice. Therefore, we treated heterozygous jvs+/- and the corresponding wild typemice with subtoxic oral doses of valproate for two weeks. Our study shows that jvs+/-mice treated with VPA have impaired hepatic mitochondrial β-oxidation andincreased hepatic fat accumulation, findings associated with increased activities ofserum transaminases and alkaline phosphatase, and hepatocellular damage.Furthermore, the effect of VPA treatment on the carnitine plasma and tissue storeswas much more dramatic in JVS+/- than in wild type mice, leading to additional andsubstantial losses in the plasma and tissue carnitine pools. In conclusion, hepatictoxicity of VPA was more pronounced in JVS+/- mice than in corresponding wild typemice, and systemic carnitine deficiency can therefore be considered to be a riskfactor for hepatotoxicity associated with VPA.In an in vitro study using hepatic cell lines (Chapter 8), drug-induced changes in theactivity of cytochrome P450 isoforms were assessed. Since the activity of most CYPscan be regulated by induction and/or inhibition by specific drugs, and possiblyaffecting the metabolism of other drugs or even their own metabolism, weinvestigated the expression and induction of several CYP isozymes and the humanpregnane X receptor in immortalized human hepatocytes for their suitability asscreening systems for hepatic drug metabolism. Our investigations demonstrated thathHepLT5 cells contain the main human CYP isozymes CYP1A2 and CYP3A4 whichare important for drug metabolism. Summarized, hHepLT5 cells appear therefore tobe a valuable alternative for primary human hepatocytes for studying pharmacologicaland toxicological features of new drug entities.The last described study (Chapter 9) was conducted to assess the hepatotoxicity ofcimicifuga racemosa in experimental animals in vivo, in hepatocyte cultures and inisolated liver mitochondria. Ethanolic cimicifuga racemosa extract was administeredorally to rats and liver sections were analyzed for microvesicular steatosis by electronmicroscopy. Tests for cytotoxicity, mitochondrial toxicity and apoptosis/necrosis wereperformed using HepG2 cells, and mitochondrial toxicity was studied using isolatedrat liver mitochondria. The main findings in vivo and in vitro were hepaticmitochondrial toxicity, as evidenced by microvesicular steatosis and inhibition of β-oxidation, eventually resulting in apoptotic cell death. These findings suggest thatinhibition of β-oxidation is the initial hepatotoxic event of cimicifuga extract, whicheventually may result in apoptosis of the hepatocytes." @default.
- W1507087726 created "2016-06-24" @default.
- W1507087726 creator A5044218901 @default.
- W1507087726 date "2008-01-01" @default.
- W1507087726 modified "2023-09-24" @default.
- W1507087726 title "Characterization of in vitro and in vivo models for the investigation of hepatotoxicity" @default.
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