Selective metabolism of vincristine in vitro by CYP3A5
Selective metabolism of vincristine in vitro by CYP3A5
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DOI：
10.1124/dmd.106.009902
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发表时间：
2006-08-01
影响因子：
3.9
通讯作者：
Hall, Stephen D.
中科院分区：
文献类型：
--
作者：
Dennison, Jennifer B.;Kulanthaivel, Palaniappan;Hall, Stephen D.
长春新碱治疗的临床结果（神经毒性和疗效）是不可预测的，并且报道的长春新碱药代动力学具有相当大的个体差异。体外和体内数据支持 CYP3A 酶在长春新碱消除中的主导作用。因此，细胞色素 P450 (P450) 表达的遗传多态性可能导致临床反应的个体差异，但个体 P450 的贡献和长春新碱代谢的主要途径尚未确定。在本研究中，长春新碱与 cDNA 表达的 P450 文库一起孵育，并鉴定了主要的氧化代谢物。 CYP3A4 和 CYP3A5 是唯一支持母体药物大量损失和先前未鉴定的主要代谢物 (M1) 形成的 P450。 M1的结构是由长春新碱二氢羟基长春花碱单元的哌啶环氧化裂解而产生的，在转化为合适的衍生物并进行光谱分析后，最终确定了M1的结构，并提出了长春新碱代谢的新途径。与 CYP3A4 相比，CYP3A5 在催化 M1 形成方面更有效（CYP3A5 的内在清除率高 9 至 14 倍）。共表达细胞色素 b(5) 的存在会刺激 M1 的形成（3 倍），但 CYP3A4 和 CYP3A5 形成 M1 的相对效率不受影响。我们的研究结果表明，与大多数 CYP3A 生物转化相比，CYP3A5 的长春新碱氧化效率明显高于 CYP3A4。我们得出的结论是，CYP3A5 表达的常见遗传多态性可能导致长春新碱系统消除的个体间差异。
Clinical outcomes of vincristine therapy, both neurotoxicity and efficacy, are unpredictable, and the reported pharmacokinetics of vincristine have considerable interindividual variability. In vitro and in vivo data support a dominant role for CYP3A enzymes in the elimination of vincristine. Consequently, genetic polymorphisms in cytochrome P450 (P450) expression may contribute to the interindividual variability in clinical response, but the contributions of individual P450s and the primary pathways of vincristine metabolism have not been defined. In the present study, vincristine was incubated with a library of cDNA-expressed P450s, and the major oxidative metabolites were identified. CYP3A4 and CYP3A5 were the only P450s to support substantial loss of parent drug and formation of the previously unidentified, major metabolite (M1). The structure of M1, arising as a result of an oxidative cleavage of the piperidine ring of the dihydro-hydroxycatharanthine unit of vincristine, was conclusively established after conversion to suitable derivatives followed by spectroscopic analysis, and a new pathway for vincristine metabolism is proposed. CYP3A5 was more efficient in catalyzing the formation of M1 compared with CYP3A4 (9- to 14-fold higher intrinsic clearance for CYP3A5). The formation of M1 was stimulated (3-fold) by the presence of coexpressed cytochrome b(5), but the relative efficiencies of M1 formation by CYP3A4 and CYP3A5 were unaffected. Our findings demonstrate that in contrast to most CYP3A biotransformations, the oxidation of vincristine is considerably more efficient with CYP3A5 than with CYP3A4. We conclude that common genetic polymorphisms in CYP3A5 expression may contribute to the interindividual variability in the systemic elimination of vincristine.