Down-regulation of rat hepatic microsomal cytochromes P-450 in microvesicular steatosis induced by orotic acid

J Pharmacol Exp Ther. 1999 Dec;291(3):953-9.


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 (16alpha-hydroxylation) and CYP3A2 (6beta-hydroxylation) were decreased in liver from OA-fed rats for only 5 days, whereas CYP2A1/2-mediated steroid 7alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstenedione / metabolism
  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Body Weight
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / biosynthesis*
  • Cytochrome P450 Family 2
  • Diet
  • Down-Regulation / drug effects*
  • Fatty Liver / chemically induced*
  • Fatty Liver / enzymology*
  • Hydroxylation
  • Lipid Metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Membrane Proteins
  • Microcirculation / enzymology
  • Microcirculation / pathology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Microsomes, Liver / ultrastructure
  • NADPH-Ferrihemoprotein Reductase / metabolism
  • Oligonucleotide Probes / pharmacology
  • Orotic Acid*
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Wistar
  • Steroid 16-alpha-Hydroxylase*
  • Steroid Hydroxylases / biosynthesis
  • Steroids / metabolism


  • Membrane Proteins
  • Oligonucleotide Probes
  • RNA, Messenger
  • Steroids
  • Androstenedione
  • Orotic Acid
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C11 protein, rat
  • CYP2C8 protein, human
  • Cyp3a2 protein, rat
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • Cytochrome P450 Family 2
  • Steroid 16-alpha-Hydroxylase
  • NADPH-Ferrihemoprotein Reductase