Cytochrome P450 and Steatosis
Abstract:The term fatty liver identifies a liver in which lipids account for more than 5% of the liver's wet weight. When fat accumulates, the lipids primarily stored as triglycerides (TG) result in steatosis and provide substrates for lipid peroxidation. Accumulation of neutral lipids in hepatocytes leads to micro- and macro-vesicular steatosis and to balloon-cell degeneration. Increased fat deposition in the liver is generally believed to be the result of an imbalance between fatty acids (FA) inflow/oxidation, and TG synthesis and excretion. Fat accumulation is not necessarily a pathological condition, but has been suggested to be the setting for more severe liver diseases, including nonalcoholic steatohepatitis (NASH) or cirrhosis. Since steatosis is notably present in the Western world, there is increased interest to know its potential consequences for the liver function. However, the information available to date about the impact of steatosis on the human liver metabolism is very scarce. Specifically, the impaired metabolism of a number of drugs has been associated with fatty liver. In relation to this, changes in some cytochrome P450 (CYP) enzymes have been found in livers of patients with steatosis, in vivo models of steatosis in experimental animals and in vitro models of fat-overloaded cells. These findings suggest an association between increased lipid deposition and impaired CYP enzymes. This paper presents an overview of the impact of steatosis in the liver's drug-metabolizing capability. Moreover, the possible molecular mechanisms involved in the transcriptional regulation of the CYP expression in fatty liver are discussed.
Document Type: Research Article
Publication date: 2009-09-01
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- Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.