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目的:探讨Caspase抑制剂F1013对大鼠肝CYPs含量及其主要亚型CYP1A2,CYP2D1,CYP2E1,CYP2C11,CYP3A1 mRNA相对表达水平的影响。方法:Wistar大鼠40只,随机分成空白组、诱导剂组、F1013低、中、高剂量组。空白组和诱导剂组分别灌胃给予0.9%氯化钠溶液和地塞米松50 mg·kg-1.d-1,F1013低、中、高组分别肌内注射F1013 1.25,2.5,5.0 mg·kg-1.d-1,每日1次,连续6 d。取大鼠肝组织制备肝微粒体,测定微粒体蛋白浓度及CYP总酶含量。并采用实时定量荧光RT-PCR法分析大鼠CYP各主要亚型mRNA的相对表达水平。结果:F1013低、中、高组肝微粒体CYP总酶含量与空白组比有显著增高(P<0.05),提示该药对CYP总酶有诱导作用。低剂量组CYP2D1酶活性显著升高(为空白组2.54倍,P<0.05);中剂量组CYP1A2及CYP2E1酶活性显著升高,分别为空白组4.24和2.46倍(P<0.05);3个剂量的F1013对CYP2C11均无显著诱导作用。结论:F1013在1.25,2.5,5.0 mg.kg-1剂量范围内,可显著诱导CYP总酶活性。F1013 1.25 mg·kg-1可诱导CYP 2D1 mRNA表达,2.5 mg·kg-1剂量可诱导CYP1A2及CYP2E1 mRNA的表达,其诱导机制可能与升高各主要亚酶mRNA相对表达水平有关。
Objective: To investigate the effects of F1013, a Caspase inhibitor, on hepatic CYPs content and relative expression of major CYP1A2, CYP2D1, CYP2E1, CYP2C11 and CYP3A1 mRNA in rats. Methods: Forty Wistar rats were randomly divided into blank group, induction group and F1013 low, medium and high dose groups. 0.9% sodium chloride solution and dexamethasone 50 mg · kg-1.d-1 were administered orally to the blank group and the inducer group, respectively. F1013 1.25, 2.5 and 5.0 mg · kg -1 kg-1.d-1, once daily for 6 days. The liver microsomes were prepared and the microsomal protein concentration and total CYP enzyme content were determined. Real-time quantitative fluorescent RT-PCR was used to analyze the relative expression levels of major CYP mRNAs in rats. Results: The levels of total CYP enzyme in liver microsomes of F1013 low, medium and high groups were significantly higher than that of the blank group (P <0.05), suggesting that the drug induced CYP total enzymes. (P <0.05). The activities of CYP1A2 and CYP2E1 in the medium dose group were significantly increased (4.24 and 2.46 folds, respectively, P <0.05), while those in the low dose group were significantly increased F1013 had no significant effect on CYP2C11. Conclusion: F1013 can significantly induce total enzyme activity of CYP in the dosage of 1.25, 2.5, 5.0 mg.kg-1. F1013 1.25 mg · kg-1 could induce the expression of CYP 2D1 mRNA. The dose-dependent manner of 2.5 mg · kg -1 could induce the expression of CYP1A2 and CYP2E1 mRNA.