Cytochrome P450 enzyme variant alleles have shown evidence that functional consequences differ between substrates. A systematic effort has not yet been made to confirm substrate-dependent activity. This review will discuss the challenges of assessing three examples (CYP2C8*3, CYP2D6*10, and CYP2C9*2) where substrate-dependent activity has been hypothesized with differing levels of evidence and their potential clinical implications. Data supports bidirectional substrate-dependent activity for CYP2C8*3. Although some data suggests CYP2D6*10 causes differences in the magnitude of effect across substrates, confirmatory studies are needed. Convincing evidence for CYP2C9*2 was lacking likely due to compensatory CYP450 metabolism or experimental variability. Confirmed substrate-dependent activity has the potential to impact clinical use of pharmacogenomics, and must be taken into consideration to ensure the goal of improving treatment through personalization is met. It is important for the pharmacogenomics community to begin thinking about this important topic and how it can be best accommodated in clinical practice.

中文翻译：

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评估 CYP450 酶中底物依赖性等位基因效应的挑战和潜在的临床意义。

细胞色素 P450 酶变体等位基因已证明底物之间的功能后果不同。尚未进行系统的努力来确认底物依赖性活性。本综述将讨论评估三个示例（CYP2C8*3、CYP2D6*10 和 CYP2C9*2）所面临的挑战，在这些示例中，以不同水平的证据假设底物依赖性活性及其潜在的临床意义。数据支持 CYP2C8*3 的双向底物依赖性活性。尽管一些数据表明 CYP2D6*10 会导致不同底物的影响幅度存在差异，但仍需要进行验证性研究。CYP2C9*2 缺乏令人信服的证据可能是由于代偿性 CYP450 代谢或实验变异性所致。已确认的底物依赖性活性有可能影响药物基因组学的临床应用，必须加以考虑以确保实现通过个性化改善治疗的目标。对于药物基因组学界来说，开始思考这个重要的话题以及如何最好地适应临床实践是很重要的。