Seo Myung-Eui, Min Byung-Joo, Heo Nayoon, Lee Kye Hwa, Kim Ju Han
Seoul National University Biomedical Informatics (SNUBI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
National Forensic Service Seoul Institute, Seoul, South Korea.
Front Pharmacol. 2023 Jan 12;14:1055991. doi: 10.3389/fphar.2023.1055991. eCollection 2023.
Most hepatically cleared drugs are metabolized by cytochromes P450 (CYPs), and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide curated clinical references for CYPs to apply individual genome data for optimized drug therapy. However, incorporating novel pharmacogenetic variants into guidelines takes considerable time. We comprehensively assessed the drug metabolizing capabilities of variants discovered through population sequencing of two substrates, -mephenytoin and omeprazole. Based on established functional assays, 75% (18/24) of the variants not yet described in Pharmacogene Variation (PharmVar) had significantly altered drug metabolizing capabilities. Of them, seven variants with inappreciable protein expression were evaluated as protein damaging by all three prediction algorithms, Sorting intolerant from tolerant (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Combined annotation dependent depletion (CADD). The five variants with decreased metabolic capability (<50%) of wild type for either substrates were evaluated as protein damaging by all three prediction algorithms, except CADD exact score of NM_000769.4:c.593T>C that was 19.68 (<20.0). In the crystal structure of the five polymorphic proteins, each altered residue of all those proteins was observed to affect the key structures of drug binding specificity. We also identified polymorphic proteins indicating different tendencies of metabolic capability between the two substrates (5/24). Therefore, we propose a methodology that combines prediction algorithms and functional assays on polymorphic CYPs with multiple substrates to evaluate the changes in the metabolism of all possible genomic variants in CYP genes. The approach would reinforce existing guidelines and provide information for prescribing appropriate medicines for individual patients.
大多数经肝脏清除的药物由细胞色素P450（CYPs）代谢，临床药物基因组学实施联盟（CPIC）指南为CYPs提供了精心整理的临床参考，以便应用个体基因组数据实现优化药物治疗。然而，将新的药物遗传学变异纳入指南需要相当长的时间。我们全面评估了通过对两种底物（美芬妥英和奥美拉唑）进行群体测序发现的变异体的药物代谢能力。基于既定的功能分析，药物基因变异（PharmVar）中尚未描述的变异体有75%（18/24）的药物代谢能力发生了显著改变。其中，7个蛋白质表达不明显的变异体被所有三种预测算法（从耐受中筛选不耐受（SIFT）、多态性表型分析v2（PolyPhen-2）和联合注释依赖缺失（CADD））评估为蛋白质损伤性变异。对于任一底物，代谢能力低于野生型50%的5个变异体被所有三种预测算法评估为蛋白质损伤性变异，但NM_000769.4:c.593T>C的CADD精确得分是19.68（<20.0）除外。在5种多态性蛋白质的晶体结构中，观察到所有这些蛋白质的每个改变的残基都会影响药物结合特异性的关键结构。我们还鉴定出了表明两种底物之间代谢能力存在不同倾向的多态性蛋白质（5/24）。因此，我们提出了一种方法，将对多底物多态性CYPs的预测算法和功能分析相结合，以评估CYP基因中所有可能的基因组变异的代谢变化。该方法将加强现有指南，并为为个体患者开合适的药物提供信息。
