Differential protein expressions of hepatic drug-metabolizing enzymes between White and Black Americans and the associated genetic polymorphisms

• Published in: Drug metabolism and disposition Vol. 53; no. 8; p. 100121
• Main Authors: Jung, Sun Min, Shi, Jian, Wang, Xinwen, Zhu, Hao-Jie
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2025
• Subjects: Adult; Alleles; Black or African American - genetics; Cytochrome P-450 CYP2C9 - genetics; Cytochrome P-450 CYP2C9 - metabolism; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Drug-metabolizing enzymes; Female; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; Humans; Inactivation, Metabolic - genetics; Liver - enzymology; Liver - metabolism; Male; Middle Aged; Pharmacogenomics; Polymorphism, Genetic - genetics; Proteomics; Proteomics - methods; Racial difference; White; White People - genetics; UGT; Drug-metabolizing enzymes; HLM; PBPK; HLS9; Racial difference; LC-MS; MAF; Proteomics; DIA-TPA; CPIC; P450; PK; DIA; DME; Pharmacogenomics
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1016/j.dmd.2025.100121

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. 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.