Pharmacogenomics of CYP2C9: Functional and Clinical Considerations.
Pharmacogenomics of CYP2C9: Functional and Clinical Considerations.
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DOI：
10.3390/jpm8010001
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发表时间：
2017-12-28
影响因子：
--
通讯作者：
Miners JO
中科院分区：
文献类型：
--
作者：
Daly AK;Rettie AE;Fowler DM;Miners JO
CYP2C9是人类肝脏中最丰富的CYP2C亚家族酶，也是该亚家族中最重要的药物代谢贡献者。CYP2C9基因的多态性导致酶活性降低是常见的，再加上几种关键药物底物的治疗指标狭窄，导致了一些与药物安全性和有效性相关的重要问题。CYP2C9底物选择性是详细的，基于酶的晶体结构，我们描述了CYP2C9如何催化这些反应。详细讨论了CYP2C9底物临床反应的相关因素，包括抑制、诱导和遗传多态性。特别是，我们考虑的问题，在模式和频率的遗传多态性和临床意义的种族差异。华法林是研究最多的CYP2C9底物；本文回顾了最近在使用包括CYP2C9基因型的给药算法以提高患者在华法林开始给药时的安全性方面的工作，并考虑了其临床实施的前景。最后，我们讨论了一种新的方法来编目罕见的“不确定意义变异”的功能能力，随着越来越多的外显子组和基因组测序的进行，这些变异越来越多地被检测到。
CYP2C9 is the most abundant CYP2C subfamily enzyme in human liver and the most important contributor from this subfamily to drug metabolism. Polymorphisms resulting in decreased enzyme activity are common in the CYP2C9 gene and this, combined with narrow therapeutic indices for several key drug substrates, results in some important issues relating to drug safety and efficacy. CYP2C9 substrate selectivity is detailed and, based on crystal structures for the enzyme, we describe how CYP2C9 catalyzes these reactions. Factors relevant to clinical response to CYP2C9 substrates including inhibition, induction and genetic polymorphism are discussed in detail. In particular, we consider the issue of ethnic variation in pattern and frequency of genetic polymorphisms and clinical implications. Warfarin is the most well studied CYP2C9 substrate; recent work on use of dosing algorithms that include CYP2C9 genotype to improve patient safety during initiation of warfarin dosing are reviewed and prospects for their clinical implementation considered. Finally, we discuss a novel approach to cataloging the functional capabilities of rare ‘variants of uncertain significance’, which are increasingly detected as more exome and genome sequencing of diverse populations is conducted.
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影响因子：
2.6
作者：
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通讯作者：
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DOI：
10.1073/pnas.95.21.12208
发表时间：
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影响因子：
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作者：
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