Vol. 291, Issue 3, 953-959, December 1999

Down-Regulation of Rat Hepatic Microsomal Cytochromes P-450 in Microvesicular Steatosis Induced by Orotic Acid¹

Gloria M. Su , Rachel M. Sefton and Michael Murray

School of Physiology and Pharmacology, University of New South Wales, Sydney, Australia (G.M.S., M.M.); and Molecular Pharmacology Unit, Heart Research Institute, Camperdown, Australia (G.M.S., R.M.S., M.M.)

Microvesicular steatosis is an important component of the overall pathogenesis of drug-mediated liver injury. Although mitochondrial damage has a role in the development of microvesicular steatosis, the consequences of fatty change for hepatic gene function are unclear. The present study was undertaken to evaluate hepatic cytochrome P-450 (CYP) function in a rat model of microvesicular steatosis produced by the intake of diets containing 1% orotic acid (OA) that were administered for 5, 10, or 21 days. Hepatic triglyceride levels were increased to 3-fold of control after 5 days and were elevated further at 10 and 21 days. Cholesterol and phospholipid contents were increased after 10 and 21 days but not by 5 days of feeding. Microsomal androst-4-ene-3,17-dione hydroxylation activities mediated by CYP2C11 (16-hydroxylation) and CYP3A2 (6-hydroxylation) were decreased in liver from OA-fed rats for only 5 days, whereas CYP2A1/2-mediated steroid 7-hydroxylation was decreased after 10 days; these observations were complemented by immunoblot analysis that demonstrated the impaired expression of the corresponding CYP proteins. CYP2C11 mRNA, the major CYP in male rat liver, was down-regulated in steatotic liver to 52 ± 4% of control. Thus, microvesicular steatosis induced by short-term intake of OA-containing diets is histologically similar to that produced by hepatotoxic drugs and produces the rapid down-regulation of constitutive CYPs in rat liver. Analogous processes of lipid deposition in human liver after drug- or disease-related injury could precipitate adverse effects during subsequent drug therapy.