Co-induction of microsomal cytochrome P-452 and the peroxisomal fatty acid beta-oxidation pathway in the rat by clofibrate and di-(2-ethylhexyl)phthalate. Dose-response studies

Biochem Pharmacol. 1988 Apr 1;37(7):1203-6. doi: 10.1016/0006-2952(88)90771-x.

Abstract

Male Wistar rats have been pretreated with either clofibrate or diethylhexylphthalate and the dose-dependency of induction of the microsomal, cytochrome P-452-driven fatty acid hydroxylase and peroxisomal fatty acid beta-oxidation system investigated. Both clofibrate and DEHP specifically induced (approximately 10-fold) the 12-hydroxylation of lauric acid in a dose-dependent manner and only marginally increased the associated 11-hydroxylase activity. This dose-dependent increase in fatty acid hydroxylase activity was accompanied by a similar ten-fold increase in the specific content of the cytochrome P-452 isoenzyme responsible for this activity, as assessed by an immunochemical-based ELISA method. Similarly, both clofibrate and DEHP induced the peroxisomal fatty acid beta-oxidation pathway in a dose-dependent manner. Furthermore, our results provide evidence that, after oral administration, clofibrate has a higher in vivo potency in inducing the above enzymes of fatty acid metabolism than is exhibited by DEHP. A correlation matrix analysis of the above data indicated a close association between the induction of microsomal cytochrome P-452 (and its associated fatty acid hydroxylase activity) and peroxisomal beta-oxidation enzymes, implicating a mechanistic inter-relationship between changes in fatty acid metabolising enzymes in these two hepatic subcellular organelles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Clofibrate / pharmacology*
  • Cytochromes / biosynthesis*
  • Diethylhexyl Phthalate / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Fatty Acids / metabolism*
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Microbodies / metabolism*
  • Microsomes, Liver / enzymology*
  • Oxidation-Reduction
  • Phthalic Acids / pharmacology*
  • Rats
  • Rats, Inbred Strains

Substances

  • Cytochromes
  • Fatty Acids
  • Phthalic Acids
  • cytochrome P-452
  • Diethylhexyl Phthalate
  • Clofibrate