Division of Pharmacy, University Hospital, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.
Drug Metab Dispos. 2011 Nov;39(11):2045-8. doi: 10.1124/dmd.111.039586. Epub 2011 Aug 5.
There are a number of reports indicating that CYP2B66 (c.516G>T and c.785A>G) is responsible for decreased clearance of efavirenz (EFV), although increased disposition of cyclophosphamide (CPA) in individuals with this polymorphism was observed. Thus, we hypothesized that the effects of the two single nucleotide polymorphisms (SNPs) of CYP2B66 on the metabolism of drugs might be considerably different between these two agents. To clarify this possibility, we expressed two major variants of this enzyme, CYP2B6.6 (Q172H and K262R) and CYP2B6.4 (K262R), and investigated metabolic activities of these variants toward EFV and CPA. Kinetic analyses clearly indicated that CYP2B6.4 possessed enhanced metabolic activity toward EFV compared with that of the wild-type enzyme (CYP2B6.1), whereas CPA was metabolized less efficiently by CYP2B6.4 than by CYP2B6.1. On the other hand, CYP2B6.6 showed a completely opposite character, suggesting that Q172H gives inverse effects on metabolic activities of CYP2B6 affected by K262R. Although it is recognized that effects of amino acid change in cytochrome P450 on the metabolic activity depend on substrates, this study revealed SNPs giving an opposite effect on the metabolism of two clinically important drugs currently used. Furthermore, this study provides the first evidence that Q172H can reverse the direction of the effect caused by K262R in CYP2B6 on the metabolism of certain drugs.
有许多报告表明，CYP2B66（c.516G>T 和 c.785A>G）负责降低依非韦伦（EFV）的清除率，尽管观察到具有这种多态性的个体中环磷酰胺（CPA）的处置增加。因此，我们假设 CYP2B66 的这两个单核苷酸多态性（SNP）对两种药物代谢的影响可能在这两种药物之间有很大的不同。为了澄清这种可能性，我们表达了这种酶的两种主要变体，CYP2B6.6（Q172H 和 K262R）和 CYP2B6.4（K262R），并研究了这些变体对 EFV 和 CPA 的代谢活性。动力学分析清楚地表明，与野生型酶（CYP2B6.1）相比，CYP2B6.4 对 EFV 的代谢活性增强，而 CPA 由 CYP2B6.4 代谢的效率低于 CYP2B6.1。另一方面，CYP2B6.6 表现出完全相反的特征，表明 Q172H 对 K262R 影响的 CYP2B6 代谢活性产生相反的影响。尽管人们认识到细胞色素 P450 中氨基酸变化对代谢活性的影响取决于底物，但本研究揭示了 SNP 对目前两种临床重要药物的代谢产生相反影响。此外，这项研究首次提供了证据表明，Q172H 可以逆转 K262R 在 CYP2B6 对某些药物代谢中引起的作用方向。
