Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid
Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid
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DOI：
10.1097/00008571-200110000-00006
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发表时间：
2001-10-01
期刊：
影响因子：
--
通讯作者：
Goldstein, JA
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文献类型：
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作者：
Dai, D;Zeldin, DC;Goldstein, JA
细胞色素P450（CYP 2C 8）是负责抗癌药物紫杉醇（Taxol）代谢的主要酶。它也是主要的P450，负责在人肝脏和肾脏中将花生四烯酸代谢为具有生物活性的环氧二十碳三烯酸（Epoxyeicosatrienoic Acids，ESTs）。在这项研究中，我们描述了两个新的CYP 2C 8等位基因包含编码变化：CYP 2C 8 *2在外显子5中有Ile（269）Phe取代，CYP 2C 8 *3在外显子3和8中包含Arg（139）Lys和Lys（399）Arg氨基酸取代。CYP 2C 8 *2仅见于非裔美国人，而CYP 2C 8 *3主要见于高加索人。亚洲人也没有。CYP 2C 8 *2等位基因在非裔美国人中的频率为0.18，在高加索人中的频率为0.13。在大肠杆菌中表达CYP 2C 8 *1（野生型）、CYP 2C 8 *2和CYP 2C 8 *3 cDNA，并评估这些酶代谢紫杉醇和花生四烯酸的能力。重组CYP 2C 8 *3在两种底物的代谢中均存在缺陷。紫杉醇的CYP 2C 8 *3转换数为CPY 2C 8 *1的15%。与CYP 2C 8 *1相比，CYP 2C 8 *2对紫杉醇的K-m高两倍，固有清除率低两倍。CYP 2C 8 *3在将花生四烯酸代谢为11，12-和14，15-EET方面也有明显缺陷（周转数为CYP 2C 8 *1的35-40%）。因此，CYP 2C 8 *3在两种重要的CYP 2C 8底物的代谢中存在缺陷：抗癌药物紫杉醇和生理上重要的化合物花生四烯酸。这种多态性在该等位基因纯合子个体中具有重要的临床和生理意义。药理遗传学11：597-607（C）2001 Lippincott威廉姆斯和威尔金斯。
Cytochrome P450 (CYP) 2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (Taxol). It is also the predominant P450 responsible for the metabolism of arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs) in human liver and kidney. In this study, we describe two new CYP2C8 alleles containing coding changes: CYP2C8*2 has an Ile(269)Phe substitution in exon 5 and CYP2C8*3 includes both Arg(139)Lys and Lys(399)Arg amino acid substitutions in exons 3 and 8. CYP2C8*2 was found only in African-Americans, while CYP2C8*3 occurred primarily in Caucasians. Neither occurred in Asians. The frequency of the CYP2C8*2 allele was 0.18 in African-Americans, and that of CYP2C8*3 was 0.13 in Caucasians. CYP2C8*1 (wild-type), CYP2C8*2 and CYP2C8*3 cDNAs were expressed in Escherichia coli, and the ability of these enzymes to metabolize both paclitaxel and arachidonic acid was assessed. Recombinant CYP2C8*3 was defective in the metabolism of both substrates. The turnover number of CYP2C8*3 for paclitaxel was 15% of CPY2C8*1. CYP2C8*2 had a two-fold higher K-m and two-fold lower intrinsic clearance for paclitaxel than CYP2C8*1. CYP2C8*3 was also markedly defective in the metabolism of arachidonic acid to 11,12- and 14,15-EET (turnover numbers 35-40% that of CYP2C8*1). Thus, CYP2C8*3 is defective in the metabolism of two important CYP2C8 substrates: the anticancer drug paclitaxel and the physiologically important compound arachidonic acid. This polymorphism has important clinical and physiological implications in individuals homozygous for this allele. Pharmacogenetics 11:597-607 (C) 2001 Lippincott Williams & Wilkins.