Differential effects of human recombinant interleukin-1 beta and dexamethasone on hepatic drug-metabolizing enzymes in male and female rats.
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.
Ferrari
L
L
Centre du Médicament, Unité de Recherche Associée au CNRS No 597, Faculté des Sciences Pharmaceutiques et Biologiques, Nancy, France.
Herber
R
R
Batt
A M
AM
Siest
G
G
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D003907:Dexamethasone / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000032:analysis*; D005260:Female; D015870:Gene Expression; D014453:Glucuronosyltransferase / Q000032:analysis*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology
D007375:Interleukin-1; D011994:Recombinant Proteins; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D004851:Epoxide Hydrolases