NEGATIVE REGULATION BY DEXAMETHASONE OF FLUVASTATIN-INDUCIBLE CYP2B EXPRESSION IN PRIMARY CULTURES OF RAT HEPATOCYTES - ROLE OF CYP3A

Fluvastatin (Fluva), a synthetic inhibitor of 3-hydroxy-3-methylglutar yl coenzyme A reductase, induces CYP2B1/2 in rat liver and primary cul tured rat hepatocytes. However, the overall profile of CYP induction, which includes induction of CYP4A, suggests that Fluva is not a typica l ''phenobarbital (PB)-like'' inducer. Several treatments affecting di verse cell signaling pathways have been reported to modify PB-inducibl e CYP2B expression in primary cultured rat hepatocytes. We examined th e effects of selected treatments on the ability of Fluva to induce CYP 2B1/2 mRNA. Only dexamethasone (Dex) produced effects on Fluva-inducib le CYP2B1/2 mRNA expression that differed from those produced on PB-in ducible CYP2B1/2 mRNA expression. Dex concentrations up to 10(-7) M of potentiated PB (10(-4) M)-mediated CYP2B1/2 mRNA induction, while hig her Dex concentrations produced a progressive reduction in PB-induced CYP2B1/2 mRNA levels. By contrast, Dex concentrations up to 10(-8) M h ad no effect on Fluva (3 x 10(-5) M)-induced CYP2B1/2 mRNA levels, whi le Dex concentrations of 10(-7) M and higher markedly suppressed Fluva -mediated CYP2B1/2 mRNA induction. The concentrations of several gluco corticoids that produced suppression of Fluva-induced CYP2B1/2 mRNA le vels were the same concentrations that induced CYP3A mRNA. Treatment w ith pregnenolone 16 alpha-carbonitrile also produced a concentration-d ependent suppression of Fluva-induced CYP2B1/2 mRNA levels. Dex-mediat ed suppression of Fluva-induced CYP2B1/2 mRNA was concentration-depend ently reversed when hepatocytes were cotreated with troleandomycin, a selective CYP3A inhibitor. The amounts of Fluva detected in culture me dium and cells were reduced significantly when hepatocytes were incuba ted with Dex. However, Dex-mediated suppression of Fluva-induced CYP2B 1/2 mRNA expression was not overcome when hepatocytes were incubated w ith Fluva concentrations greater than 3 x 10(-5) M, suggesting that me chanisms other than CYP3A-catalyzed metabolism may contribute to Dex-m ediated suppression of Fluva-induced CYP2B1/2 expression. (C) 1998 Els evier Science Inc.