DIFFERENTIAL-EFFECTS OF HUMAN RECOMBINANT INTERLEUKIN-1-BETA AND DEXAMETHASONE ON HEPATIC DRUG-METABOLIZING-ENZYMES IN MALE AND FEMALE RATS

被引:37
作者
FERRARI, L [1 ]
HERBER, R [1 ]
BATT, AM [1 ]
SIEST, G [1 ]
机构
[1] FAC SCI PHARMACEUT & BIOL NANCY,CTR MED,CNRS,UNITE RECH 597,30 RUE LIONNOIS,F-54000 NANCY,FRANCE
关键词
D O I
10.1016/0006-2952(93)90198-6
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Interleukin-1beta (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 posttranslational 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.
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页码:2269 / 2277
页数:9
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