Bay41-4109对大鼠肝脏P450酶系诱导作用的研究

Induction of rat liver cytochrome P450 by 2-heteroaryl-dihydropyrimidines (Bay41-4109)

目的:观察Bay41-4109(2-heteroaryl-dihydropyrimidines,HAP,异芳基二氢嘧啶类化合物)诱导处理对大鼠肝细胞色素P450(CYP450)及其主要亚型的影响,并探讨其可能的机制。方法:雄性Wistar大鼠分别用Bay41- 4109 7.5,30和120 mg·kg^(-1)·d^(-1)连续灌胃诱导处理5 d,测定肝脏脏器系数、微粒体总CYP450含量和CYP1A2,2B1/2和3A4亚型活性,并以苯巴比妥为对照。结果:经Bay41-4109三个不同剂量诱导后,大鼠肝脏脏器系数、总P450含量、CYP1A2,281/2和3A4活性与对照相比均有不同程度升高,并有明确的剂量效应关系,其诱导CYP450代谢酶谱的改变与苯巴比妥基本一致;且Bay41-4109在7.5 mg·kg^(-1)·d^(-1)时即对CYP2B1/2和CYP1A2有非常显著的诱导作用,120 mg·kg^(-1)·d^(-1)时引起此两种亚型活性变化大致与苯巴比妥60 mg·kg^(-1)·d^(-1)相当。结论:Bay41-4109属于苯巴比妥类的肝药酶强诱导剂,可能通过药物代谢酶系统影响其他药物的代谢。

Objective：To study the induction effect and its probable mechanism of 2-heteroaryl-dihydropyrimidines （Bay41-4109, HAP） on rat cytochrome P450 and the related subtypes. Methods： Oral Bay41-4109 at 7.5, 30, 120 mg·kg^-1·d^-1 was administered to male Wistar rats for 5 days. Then liver/body weight ratios, total cytochrome 17450 contents of microsome and the activities of P450 subtypes, CYP1A2, 2B1/2 and 3A4, in liver tissue were detected. Phenobarbital was used as a positive control. Results： Bay41-4109 dose-dependently increased the liver/body weight ratios, total CYP450 contents, and the activities of CYP1A2, 2B1/2 and 3A4, respectively. The profile of CYP450 induction by Bay41-4109 was similar to that by phenobarbital. Bay41-4109 even at 7.5 mg·kg^-1·d^-1 significantly increased the activities of CYP1A2 and CYP2B1/2 in liver microsome （P 〈 0.05, compared with the negative control） , and the effect of Bay41-4109 at 120 mg·kg^-1·d^-1 on both enzymes was roughly equivalent to that of phenobarbital 60 mg·kg^-1·d^-1. Conclusion： Bay41-4109 is an inducer of liver cytochrome P450 as potent as phenobarbital. More attention should be paid to the interaction of Bay41-4109 with other drugs in clinic because it can alter the metabolism of other chemicals by inducing liver cytochrome P450.