Anari M R, Cribb A E, Renton K W
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Drug Metab Dispos. 1995 May;23(5):536-41.
Interferon (IFN) has long been recognized to downregulate cytochrome P450-mediated drug metabolism. Some investigations have shown that induced P450 enzymes tend to be more resistant to the depressant effect of IFN, whereas constitutive forms of P450 are uniformly depressed by IFN. We examined the effect of varying the period of induction of P450 proteins (CYP1A1, CYP2B, and CYP2E1) in two animal species. In mice, the IFN inducer polyinosinic acid-polycytidylic acid depressed the constitutive and induced enzyme activities of ethoxyresorufin O-deethylase, benzyl-oxyresorufin O-dealkylase, and p-nitrophenol hydroxylase at all levels of induction. The depression of P450 proteins (CYP1A1, CYP2B10, and CYP2E1) was confirmed by immunoblotting. In contrast, the downregulation of the same enzyme activities observed at 0 and 24 hr of induction did not occur after 48 or 72 hr of induction in the rat. Immunoblotting confirmed that CYP1A1, CYP2B1, and CYP2E1 levels were downregulated in control and at low levels of induction, but were not affected at high levels of induction. The response of constitutive enzyme activities to downregulation by IFN was not influenced by any of the induction protocols in rats or mice. Thus, cytochrome P450 induction does not invariably confer resistance to IFN-mediated downregulation of the enzymes, and the mechanism of induction does not determine the response to IFN. It seems that the species and duration or level of induction are the major influences on the observed response of P450 enzymes to IFN-evoked downregulation.
长期以来，人们一直认为干扰素（IFN）会下调细胞色素P450介导的药物代谢。一些研究表明，诱导型P450酶往往对IFN的抑制作用更具抗性，而组成型P450则会被IFN一致抑制。我们研究了在两种动物物种中改变P450蛋白（CYP1A1、CYP2B和CYP2E1）诱导期的影响。在小鼠中，IFN诱导剂聚肌苷酸-聚胞苷酸在所有诱导水平下均抑制了乙氧异吩唑酮O-脱乙基酶、苄氧异吩唑酮O-脱烷基酶和对硝基苯酚羟化酶的组成型和诱导型酶活性。通过免疫印迹证实了P450蛋白（CYP1A1、CYP2B10和CYP2E1）的减少。相比之下，在大鼠中，诱导48或72小时后未出现诱导0和24小时时观察到的相同酶活性下调情况。免疫印迹证实，CYP1A1、CYP2B1和CYP2E1水平在对照和低诱导水平下下调，但在高诱导水平下不受影响。IFN对组成型酶活性下调的反应不受大鼠或小鼠任何诱导方案的影响。因此，细胞色素P450诱导并不总是赋予对IFN介导的酶下调的抗性，诱导机制也不能决定对IFN的反应。似乎物种以及诱导的持续时间或水平是对观察到的P450酶对IFN引起的下调反应的主要影响因素。
