Does Hepatic Steatosis Affect Drug Metabolizing Enzymes in the Liver?

Christa      Buechler; Thomas      S. Weiss

doi:10.2174/138920011794520035

Abstract

Bioavailability and effects of xenobiotics are dependent on absorption, metabolism and elimination of the respective compounds. Hepatocytes are critically important in drug modification and excretion. Molecules like organic anion transporters mediate hepatocyte uptake of xenobiotics which are subsequently modified by phase I enzymes with cytochrome (CYP) P450 isoenzymes like CYP3A4 being the most important. Phase II enzymes including glucuronosyltransferases further increase aqueous solubility of the respective compounds. The canalicular transport of these substances into the bile is mainly arranged by ATP-binding cassette transporters. Variations in the activity of these enzymes and transporters explain altered drug activity, elimination and eventually increased half-life and toxicity of xenobiotics. Body composition affects distribution of several drugs and fat mass may have to be taken into account in determining appropriate doses of lipophilic compounds. Adiposity is increasingly prevalent in western countries and about half of the adult population is overweight or even obese. Obesity is often associated with an enhanced storage of fat in hepatocytes and hepatic steatosis is diagnosed in nearly 30% of adults. Although this is a benign condition fatty liver is more susceptible to insults leading to non-alcoholic steatohepatitis (NASH) associated with inflammation and liver fibrosis. There is increasing evidence that drug metabolizing enzymes/ transporters are differentially expressed in hepatic steatosis and NASH. Data obtained from animals, patients and in-vitro models suggesting altered expression of transcription factors, transporters and enzymes involved in drug metabolism in non-alcoholic fatty liver disease are summarized in the current review.

Keywords: Drug metabolizing enzymes, hepatic steatosis, steatohepatitis, xenobiotics, CYP3A4, cytochrome P450 2E1, Adiposity, cirrhosis, Adiponectin, ATP-binding cassette, fibrotic disease