Jung Sun Min, Shi Jian, Wang Xinwen, Zhu Hao-Jie
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan.
Translational Medicine and Clinical Pharmacology, Bristol Myers Squibb, Lawrenceville, New Jersey.
Drug Metab Dispos. 2025 Aug;53(8):100121. doi: 10.1016/j.dmd.2025.100121. Epub 2025 Jul 12.
Although racial differences in drug response have been well documented, the mechanisms underlying these variations remain incompletely understood. The racial differences may be partially attributed to variations in the expression of drug-metabolizing enzymes (DMEs) between racial groups. We conducted a proteomics analysis of selected clinically relevant DMEs, including 12 cytochrome P450s, 10 UDP-glucuronosyltransferases (UGTs), 19 transferases, and 11 hydrolases, in liver samples from White and Black Americans and compared the protein expression levels between the 2 groups. Among the DMEs examined, CYP2C9, CYP3A5, CYP2E1, UGT1A6, UGT2B15, UGT2B4, UGT2B10, GSTA1, GSTA2, MGST1, TPMT, SULT1B1, ALB, and PON3 exhibited significantly different expression levels between the 2 populations. Genetic analysis of CYP2C9 and CYP3A5 was performed to assess the impact of genetic polymorphisms on the differential protein expression. CYP2C9 protein expression levels were significantly lower in carriers of the ∗8 and ∗11 alleles, which were found exclusively in Black Americans. Although CYP2C9 expression levels were also lower in Black subjects within the ∗1/∗1 and ∗2 or ∗3 carrier groups, the differences were not statistically significant. These results indicate that the lower CYP2C9 protein expression in Black is due to both population-specific genetic variants (ie, ∗8 and ∗11) and potentially unknown genetic or nongenetic regulators. CYP3A5 protein levels were significantly higher in Black Americans compared to White counterparts, mainly due to the greater prevalence of the functional ∗1 allele in the Black population. Our findings provide crucial insights into racial differences in hepatic DME expression and support the development of ancestry-informed personalized pharmacotherapy strategies. SIGNIFICANCE STATEMENT: This study, to our knowledge, provides the first comprehensive protein-level analysis of drug-metabolizing enzymes across racial groups, revealing differences in key enzyme expression between White and Black Americans and the associated genetic polymorphisms. These findings advance our understanding of racial differences in drug metabolism, supporting the development of an ancestry-informed personalized pharmacotherapy approach.
尽管药物反应的种族差异已有充分记录，但这些差异背后的机制仍未完全明了。种族差异可能部分归因于不同种族群体之间药物代谢酶（DME）表达的差异。我们对选定的临床相关DME进行了蛋白质组学分析，这些DME包括12种细胞色素P450、10种尿苷二磷酸葡萄糖醛酸转移酶（UGT）、19种转移酶和11种水解酶，分析对象为美国白人和非裔美国人的肝脏样本，并比较了两组之间的蛋白质表达水平。在所检测的DME中，CYP2C9、CYP3A5、CYP2E1、UGT1A6、UGT2B15、UGT2B4、UGT2B10、GSTA1、GSTA2、MGST1、TPMT、SULT1B1、ALB和PON3在这两个人群中的表达水平存在显著差异。对CYP2C9和CYP3A5进行了基因分析，以评估基因多态性对蛋白质表达差异的影响。CYP2C9蛋白表达水平在∗8和∗11等位基因携带者中显著较低，这两种等位基因仅在非裔美国人中发现。虽然在∗1/∗1和∗2或∗3携带者组中的黑人受试者中CYP2C9表达水平也较低，但差异无统计学意义。这些结果表明，黑人中CYP2C9蛋白表达较低是由于群体特异性基因变异（即∗8和∗11）以及潜在的未知基因或非基因调节因素。与美国白人相比，非裔美国人的CYP3A5蛋白水平显著更高，这主要是由于功能性∗1等位基因在黑人人群中的患病率更高。我们的研究结果为肝脏DME表达的种族差异提供了关键见解，并支持制定基于祖先信息的个性化药物治疗策略。意义声明：据我们所知，本研究首次对不同种族群体的药物代谢酶进行了全面的蛋白质水平分析，揭示了美国白人和非裔美国人之间关键酶表达的差异以及相关的基因多态性。这些发现推进了我们对药物代谢种族差异的理解，支持了基于祖先信息的个性化药物治疗方法的发展。
