Grossman S J, Herold E G, Drey J M, Alberts D W, Umbenhauer D R, Patrick D H, Nicoll-Griffith D, Chauret N, Yergey J A
Department of Safety Assessment, Merck Research Laboratories, West Point, PA 19486.
Drug Metab Dispos. 1993 Nov-Dec;21(6):1029-36.
It has previously been shown that Verlukast is converted to Verlukast dihydrodiol in microsomes from beta-naphthoflavone (BNF)-treated, but not uninduced Swiss Webster mice and Sprague-Dawley rats. We have examined the involvement of CYP1A1 in this reaction in more detail. It is concluded that this reaction is catalyzed exclusively by CYP1A1 in rats, mice, and humans based on the following criteria: 1) the epoxidation of Verlukast is negligible in uninduced rats, which express CYP1A2 but not CYP1A1; 2) Verlukast epoxidation is highly inducible by BNF treatment (60- to 200-fold); 3) Verlukast epoxidation in BNF-treated rat microsomes was inhibited by alpha-naphthoflavone (ANF) treatment, indicating that this activity was mediated by the CYP1A subfamily; 4) > 95% of Verlukast epoxidation in BNF-treated rat microsomes was inhibited by antibodies raised against CYP1A1; and 5) Verlukast was epoxidized by human CYP1A1 but not CYP1A2. Thus, Verlukast epoxidation appears to be specific for rat, mouse, and human CYP1A1. Additional studies showed that Verlukast was metabolized to Verlukast dihydrodiol in microsomes from uninduced rhesus monkeys. This reaction was inhibited by nanomolar concentrations of ANF in rhesus monkey microsomes implicating the involvement of the CYP1A subfamily. In addition, the 8-hydroxylation of R-warfarin, a pathway that is selective for rodent and human CYP1A1 activity, was also catalyzed at significant rates by rhesus monkey microsomes. These findings indicate that, unlike rats, mice, and humans, which have very low constitutive levels of hepatic CYP1A1 activity, the uninduced rhesus monkey is able to catalyze reactions specific to CYP1A1 in rodents and humans.(ABSTRACT TRUNCATED AT 250 WORDS)
先前已有研究表明，在经β-萘黄酮（BNF）处理的瑞士韦伯斯特小鼠和斯普拉格-道利大鼠的微粒体中，维鲁司特可转化为维鲁司特二氢二醇，但在未诱导的情况下则不会。我们更详细地研究了CYP1A1在该反应中的作用。基于以下标准得出结论：该反应在大鼠、小鼠和人类中仅由CYP1A1催化：1）在未诱导的大鼠中，维鲁司特的环氧化作用可忽略不计，这些大鼠表达CYP1A2但不表达CYP1A1；2）BNF处理可高度诱导维鲁司特环氧化（60至200倍）；3）α-萘黄酮（ANF）处理可抑制BNF处理的大鼠微粒体中的维鲁司特环氧化，表明该活性由CYP1A亚家族介导；4）针对CYP1A1产生的抗体可抑制BNF处理的大鼠微粒体中>95%的维鲁司特环氧化；5）人CYP1A1可使维鲁司特环氧化，但CYP1A2则不能。因此，维鲁司特环氧化似乎对大鼠、小鼠和人类的CYP1A1具有特异性。额外的研究表明，维鲁司特在未诱导的恒河猴的微粒体中代谢为维鲁司特二氢二醇。在恒河猴微粒体中，纳摩尔浓度的ANF可抑制该反应，这表明CYP1A亚家族参与其中。此外，恒河猴微粒体也能以显著速率催化R-华法林的8-羟基化反应，这是一种对啮齿动物和人类CYP1A1活性具有选择性的途径。这些发现表明，与大鼠、小鼠和人类肝CYP1A1活性的组成型水平非常低不同，未诱导的恒河猴能够催化啮齿动物和人类中特定于CYP1A1的反应。（摘要截短于250字）
