Cresteil T, Monsarrat B, Alvinerie P, Tréluyer J M, Vieira I, Wright M
INSERM U75, Université René Descartes, Paris, France.
Cancer Res. 1994 Jan 15;54(2):386-92.
The biotransformation of taxol by human liver was investigated in vitro with microsomes isolated from adult and developing human tissues. In vitro, no metabolism was detected with kidney microsomes, whereas two metabolites were generated by liver microsomes. The most prominent metabolite, termed M5, corresponded to an hydroxylation at the C6 position on the taxane ring, while the other metabolite, termed M4, corresponded to an hydroxylation at the para-position on the phenyl ring at the C3'-position of the C13 side chain. These two taxol derivatives have been shown to be the major metabolites recovered in bile from a patient infused with taxol. Several approaches have been used to identify the cytochrome P450 (CYP) isozymes involved in these reactions. No positive correlation was observed between the in vitro synthesis of these two metabolites, suggesting that two cytochrome P450 isozymes could be involved, although they could not be distinguished by their apparent affinities (Km approximately 15 microM). The formation of metabolite M4 was substantially reduced both by antibody directed against CYP3A and by the addition of CYP3A substrates such as orphenadrine, erythromycin, troleandomycin, and testosterone. Conversely, the formation of metabolite M5 remained unaffected by antibodies against CYP3A and by CYP3A substrates but was sensitive to diazepam inhibition, a preferential substrate of CYP2C. Correlation between CYP2C content or diazepam demethylation and the synthesis of metabolite M5 was highly positive. The formation of metabolite M4 developed during the early postnatal period. In contrast, the synthesis of metabolite M5 rose only after 3 months of age. These data clearly implicate CYP3A in the formation of metabolite M4 and CYP2C in the synthesis of metabolite M5. Microsomes from patients treated with barbiturates and benzodiazepines increased the formation of metabolite M4 to the level of metabolite M5, demonstrating that drug interactions could modify the human metabolism of taxol.
利用从成人及发育中的人体组织中分离出的微粒体，在体外研究了人肝脏对紫杉醇的生物转化。在体外，肾脏微粒体未检测到代谢情况，而肝脏微粒体产生了两种代谢产物。最主要的代谢产物称为M5，对应于紫杉烷环C6位的羟基化，而另一种代谢产物称为M4，对应于C13侧链C3'-位苯环对位的羟基化。这两种紫杉醇衍生物已被证明是输注紫杉醇患者胆汁中回收的主要代谢产物。已采用多种方法来鉴定参与这些反应的细胞色素P450（CYP）同工酶。这两种代谢产物的体外合成之间未观察到正相关，表明可能涉及两种细胞色素P450同工酶，尽管它们的表观亲和力（Km约为15 microM）无法区分。代谢产物M4的形成通过针对CYP3A的抗体以及添加CYP3A底物（如奥芬那君、红霉素、三乙酰竹桃霉素和睾酮）而大幅减少。相反，代谢产物M5的形成不受抗CYP3A抗体和CYP3A底物的影响，但对CYP2C的优先底物地西泮抑制敏感。CYP2C含量或地西泮去甲基化与代谢产物M5合成之间的相关性高度正相关。代谢产物M4的形成在出生后早期出现。相比之下，代谢产物M5的合成仅在3个月大后上升。这些数据清楚地表明CYP3A参与代谢产物M4的形成，而CYP2C参与代谢产物M5的合成。用巴比妥类药物和苯二氮䓬类药物治疗的患者的微粒体将代谢产物M4的形成增加到代谢产物M5的水平，表明药物相互作用可改变人对紫杉醇的代谢。
