Differential effects of human recombinant interleukin-1 beta and dexamethasone on hepatic drug-metabolizing enzymes in male and female rats

Biochem Pharmacol. 1993 Jun 9;45(11):2269-77. doi: 10.1016/0006-2952(93)90198-6.

Abstract

Interleukin-1 beta (IL-1) is one of the major inflammation mediators, commonly reported to be an inhibitor of hepatic drug metabolism. We studied the effect of IL-1 treatment on various drug-metabolizing enzymes in male and female rats. IL-1 induced both cytochrome P450 (P450) 3A1 activity and protein in females, but in males, IL-1 repressed P450 3A2 activity, without decreasing the protein. P450 1A1 was impaired in males, but was retained after dexamethasone pretreatment. IL-1 did not change P450 2B1/2 activity and protein, but counteracted their induction by dexamethasone. Uridine diphospho-glucuronosyltransferase (UGT) 1A2 (bilirubin) activity and its induction by dexamethasone were not affected by IL-1 treatment. Both P450 2C11 and epoxide hydrolase activities were repressed by IL-1 treatment, and both activities were impaired after dexamethasone treatment. These results clearly demonstrate that IL-1 acts at different steps of protein synthesis and gene expression. The effect of IL-1 on P450 was isoform-dependent, indicating that IL-1 can act on pretranscriptional events. The discrepancy between the variations of the activities and the protein of P450 3A2 suggests a post-translational regulation. For P450 2C11, 3A1, and for microsomal epoxide hydrolase, but not for P450 1A1 and 2B1/2, IL-1 mimics the glucocorticoid effects. These differential effects can affect the kinetics and the bioavailability of drugs used in pathologies in which IL-1 is increased.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme System / analysis*
  • Dexamethasone / pharmacology*
  • Epoxide Hydrolases / analysis*
  • Female
  • Gene Expression
  • Glucuronosyltransferase / analysis*
  • Humans
  • Interleukin-1 / pharmacology*
  • Liver / drug effects
  • Liver / enzymology*
  • Male
  • Rats
  • Rats, Wistar
  • Recombinant Proteins / pharmacology

Substances

  • Interleukin-1
  • Recombinant Proteins
  • Dexamethasone
  • Cytochrome P-450 Enzyme System
  • Glucuronosyltransferase
  • Epoxide Hydrolases