Genetic variation in aldo‐keto reductase 1D1 (AKR1D1) affects expression and activity of multiple cytochrome P450s (292.1)

Abstract

Human liver gene regulatory network analysis identified a cytochrome P450 subnetwork with AKR1D1 as its key regulatory driver. This study assessed the biologic importance of AKR1D1 [key enzyme in synthesis of bile acids, ligand activators of FXR, PXR and CAR, known P450 regulators] to hepatic P450 expression. Overexpression of AKR1D1 in primary human hepatocytes led to increased expression of CYP3A4, 2C8, 2C9, 2C19, and 2B6. Conversely, AKR1D1 knockdown decreased expression of these P450s. Resequencing AKR1D1 from donor livers identified a 3'‐UTR (rs1872930) SNP that was significantly associated with higher AKR1D1 mRNA. AKR1D1 3'‐UTR‐luciferase reporter studies showed that variant allele resulted in higher luciferase activity, suggesting that the SNP increases AKR1D1 mRNA stability and/or translation efficiency. AKR1D1 3'‐UTR SNP was significantly associated with increased hepatic mRNA of multiple P450s (CYP3A4, 2C8, 2C9, 2C19, and 2B6) and CYP3A4, 2C8, 2C19, and 2B6 activities. After adjusting for multiple testing, association remained significant for AKR1D1, CYP2C9, and CYP2C8 mRNA and CYP2C8 activity. These results provide new insights into the variation in expression and activity of P450s that can account for interindividual differences in drug metabolism/efficacy. In conclusion, we provide the first experimental evidence supporting a role for AKR1D1 as a key genetic regulator of P450 network.