Kocarek T A, Reddy A B
Institute of Chemical Toxicology, Wayne State University, Detroit, MI 48201, USA.
Biochem Pharmacol. 1998 May 1;55(9):1435-43. doi: 10.1016/s0006-2952(97)00658-8.
Fluvastatin (Fluva), a synthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, induces CYP2B1/2 in rat liver and primary cultured rat hepatocytes. However, the overall profile of CYP induction, which includes induction of CYP4A, suggests that Fluva is not a typical "phenobarbital (PB)-like" inducer. Several treatments affecting diverse cell signaling pathways have been reported to modify PB-inducible CYP2B expression in primary cultured rat hepatocytes. We examined the effects of selected treatments on the ability of Fluva to induce CYP2B1/2 mRNA. Only dexamethasone (Dex) produced effects on Fluva-inducible CYP2B1/2 mRNA expression that differed from those produced on PB-inducible CYP2B1/2 mRNA expression. Dex concentrations up to 10(-7) M of potentiated PB (10(-4) M)-mediated CYP2B1/2 mRNA induction, while higher Dex concentrations produced a progressive reduction in PB-induced CYP2B1/2 mRNA levels. By contrast, Dex concentrations up to 10(-8) M had no effect on Fluva (3 x 10(-5) M)-induced CYP2B1/2 mRNA levels, while Dex concentrations of 10(-7) M and higher markedly suppressed Fluva-mediated CYP2B1/2 mRNA induction. The concentrations of several glucocorticoids that produced suppression of Fluva-induced CYP2B1/2 mRNA levels were the same concentrations that induced CYP3A mRNA. Treatment with pregnenolone 16 alpha-carbonitrile also produced a concentration-dependent suppression of Fluva-induced CYP2B1/2 mRNA levels. Dex-mediated suppression of Fluva-induced CYP2B1/2 mRNA was concentration-dependently reversed when hepatocytes were cotreated with troleandomycin, a selective CYP3A inhibitor. The amounts of Fluva detected in culture medium and cells were reduced significantly when hepatocytes were incubated with Dex. However, Dex-mediated suppression of Fluva-induced CYP2B1/2 mRNA expression was not overcome when hepatocytes were incubated with Fluva concentrations greater than 3 x 10(-5) M, suggesting that mechanisms other than CYP3A-catalyzed metabolism may contribute to Dex-mediated suppression of Fluva-induced CYP2B1/2 expression.
氟伐他汀（Fluva）是一种3-羟基-3-甲基戊二酰辅酶A还原酶的合成抑制剂，可诱导大鼠肝脏和原代培养的大鼠肝细胞中的CYP2B1/2。然而，包括CYP4A诱导在内的CYP诱导的总体情况表明，氟伐他汀不是典型的“苯巴比妥（PB）样”诱导剂。据报道，几种影响不同细胞信号通路的处理可改变原代培养的大鼠肝细胞中PB诱导的CYP2B表达。我们研究了所选处理对氟伐他汀诱导CYP2B1/2 mRNA能力的影响。只有地塞米松（Dex）对氟伐他汀诱导的CYP2B1/2 mRNA表达产生的影响与对PB诱导的CYP2B1/2 mRNA表达产生的影响不同。高达10^(-7) M的地塞米松浓度增强了PB（10^(-4) M）介导的CYP2B1/2 mRNA诱导，而更高的地塞米松浓度则使PB诱导的CYP2B1/2 mRNA水平逐渐降低。相比之下，高达10^(-8) M的地塞米松浓度对氟伐他汀（3×10^(-5) M）诱导的CYP2B1/2 mRNA水平没有影响，而10^(-7) M及更高的地塞米松浓度则显著抑制氟伐他汀介导的CYP2B1/2 mRNA诱导。几种产生氟伐他汀诱导的CYP2B1/2 mRNA水平抑制作用的糖皮质激素浓度与诱导CYP3A mRNA的浓度相同。用孕烯醇酮16α-腈处理也产生了氟伐他汀诱导的CYP2B1/2 mRNA水平的浓度依赖性抑制。当肝细胞与选择性CYP3A抑制剂三乙酰竹桃霉素共同处理时，地塞米松介导的氟伐他汀诱导的CYP2B1/2 mRNA抑制作用呈浓度依赖性逆转。当肝细胞与地塞米松孵育时，培养基和细胞中检测到的氟伐他汀量显著减少。然而，当肝细胞与大于3×10^(-5) M的氟伐他汀浓度孵育时，地塞米松介导的氟伐他汀诱导的CYP2B1/2 mRNA表达抑制作用并未被克服，这表明除CYP3A催化的代谢外的其他机制可能导致地塞米松介导的氟伐他汀诱导的CYP2B1/2表达抑制。
