Identification and functional characterization of eight CYP3A4 protein variants
Identification and functional characterization of eight CYP3A4 protein variants
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DOI：
10.1097/00008571-200107000-00008
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发表时间：
2001-07-01
期刊：
影响因子：
--
通讯作者：
Wojnowski, L
中科院分区：
文献类型：
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作者：
Eiselt, R;Domanski, TL;Wojnowski, L
据估计，CYP 3A 4活性个体间变异性的遗传成分在60%至90%之间，但潜在的遗传因素在很大程度上仍然未知。对213个中欧和西欧DNA样本的研究发现了18个新的CYP 3A 4变异体，其中包括8个蛋白变异体，共有7.5%的研究群体被发现为这些变异体之一的杂合，在细菌异源表达系统中，两个突变体R130 Q和P416 L没有产生可检测的P450全蛋白。一种突变体T363 M的表达水平显著低于野生型CYP 3A 4，G56 D、V170 I、D174 H和M445 T在表达或类固醇羟化酶活性方面与野生型CYP 3A 4相比无显著差异，L373 F显示睾酮代谢产物谱显著改变，1 '-OH咪达唑仑形成的K-m值增加4倍。结果表明，CYP 3A 4蛋白变异体对高加索人CYP 3A 4活性的个体间变异性的贡献有限，然而，某些变异体可能在对药物的非典型反应或对致癌物的敏感性改变中发挥作用。药物遗传学11：447-458（C）2001 Lippincott威廉姆斯和威尔金斯。
The genetic component of the inter-individual variability in CYP3A4 activity has been estimated to be between 60% and 90%, but the underlying genetic factors remain largely unknown. A study of 213 Middle and Western European DNA samples resulted in the identification of 18 new CYP3A4 variants, including eight protein variants, A total of 7.5% of the population studied was found to be heterozygous for one of these variants, in a bacterial heterologous expression system, two mutants, R130Q and P416L, did not result in detectable P450 holoprotein. One mutant, T363M, expressed at significantly lower levels than wild-type CYP3A4, G56D, V170I, D174H and M445T were not significantly different when compared with wild-type CYP3A4 in expression or steroid hydroxylase activity, L373F displayed a significantly altered testosterone metabolite profile and a four-fold increase in the K-m value for 1'-OH midazolam formation. The results suggest a limited contribution of CYP3A4 protein variants to the inter-individual variability of CYP3A4 activity in Caucasians, Some variants may, however, play a role in the atypical response to drugs or altered sensitivity to carcinogens. Pharmacogenetics 11:447-458 (C) 2001 Lippincott Williams & Wilkins.