Pfizer Global Research & Development, 10646 Science Center Dr., San Diego, CA 92121, USA.
Drug Metab Dispos. 2010 Feb;38(2):347-56. doi: 10.1124/dmd.109.030270. Epub 2009 Nov 18.
Several antihistamine drugs including terfenadine, ebastine, and astemizole have been identified as substrates for CYP2J2. The overall importance of this enzyme in drug metabolism has not been fully explored. In this study, 139 marketed therapeutic agents and compounds were screened as potential CYP2J2 substrates. Eight novel substrates were identified that vary in size and overall topology from relatively rigid structures (amiodarone) to larger complex structures (cyclosporine). The substrates displayed in vitro intrinsic clearance values ranging from 0.06 to 3.98 mul/min/pmol CYP2J2. Substrates identified for CYP2J2 are also metabolized by CYP3A4. Extracted ion chromatograms of metabolites observed for albendazole, amiodarone, astemizole, thioridazine, mesoridazine, and danazol showed marked differences in the regioselectivity of CYP2J2 and CYP3A4. CYP3A4 commonly metabolized compounds at multiple sites, whereas CYP2J2 metabolism was more restrictive and limited, in general, to a single site for large compounds. Although the CYP2J2 active site can accommodate large substrates, it may be more narrow than CYP3A4, limiting metabolism to moieties that can extend closer toward the active heme iron. For albendazole, CYP2J2 forms a unique metabolite compared with CYP3A4. Albendazole and amiodarone were evaluated in various in vitro systems including recombinant CYP2J2 and CYP3A4, pooled human liver microsomes (HLM), and human intestinal microsomes (HIM). The Michaelis-Menten-derived intrinsic clearance of N-desethyl amiodarone was 4.6 greater in HLM than in HIM and 17-fold greater in recombinant CYP3A4 than in recombinant CYP2J2. The resulting data suggest that CYP2J2 may be an unrecognized participant in first-pass metabolism, but its contribution is minor relative to that of CYP3A4.
几种抗组胺药物，包括特非那定、依巴斯汀和阿司咪唑，已被确定为 CYP2J2 的底物。这种酶在药物代谢中的整体重要性尚未得到充分探索。在这项研究中，筛选了 139 种市售治疗药物和化合物作为潜在的 CYP2J2 底物。鉴定出了 8 种新型的底物，它们在大小和整体拓扑结构上从相对刚性的结构（胺碘酮）到更大的复杂结构（环孢素）各不相同。这些底物的体外固有清除率值范围为 0.06 至 3.98 mul/min/pmol CYP2J2。CYP2J2 鉴定的底物也被 CYP3A4 代谢。阿苯达唑、胺碘酮、阿司咪唑、硫利达嗪、甲硫哒嗪和达那唑的代谢物的提取离子色谱图显示，CYP2J2 和 CYP3A4 的区域选择性有明显差异。CYP3A4 通常在多个部位代谢化合物，而 CYP2J2 代谢则更为受限，通常限于大化合物的单个部位。虽然 CYP2J2 的活性部位可以容纳大的底物，但它可能比 CYP3A4 更窄，限制代谢为可以更接近活性血红素铁的部分。与 CYP3A4 相比，CYP2J2 形成了一种独特的阿苯达唑代谢物。在包括重组 CYP2J2 和 CYP3A4、人肝微粒体 (HLM) 和人肠微粒体 (HIM) 的各种体外系统中评估了阿苯达唑和胺碘酮。N-去乙基胺碘酮的米氏常数衍生的内在清除率在 HLM 中比在 HIM 中高 4.6 倍，在重组 CYP3A4 中比在重组 CYP2J2 中高 17 倍。所得数据表明，CYP2J2 可能是首过代谢中的一个未被识别的参与者，但与 CYP3A4 相比，其贡献较小。
