Human aldo-keto reductase (AKR) 1C1 and 1C2 act as coactivators of pregnane X receptor, a master regulator of drug-metabolizing and gluconeogenesis enzymes.

The aldo-keto reductase (AKR) 1C subfamily, comprising AKR1C1-1C4, plays a crucial role in drug metabolism and hormone biosynthesis. Recent studies have identified AKR1C3 as a co-activator of the androgen receptor. This study aimed to investigate whether AKR1Cs function as regulators of the pregnane X receptor (PXR), a member of the nuclear receptor superfamily, which upregulates drug-metabolizing enzymes such as cytochrome P450 (CYP) 3A4. Rifampicin-activated CYP3A4 induction was attenuated by AKR1C1/1C2 knockdown in ShP51 cells (PXR-overexpressing HepG2 cells), HepaRG cells, and HepaSH cells (hepatocytes from humanized liver mice). Co-immunoprecipitation analysis revealed that AKR1Cs interact with PXR. Immunofluorescent staining revealed that AKR1Cs are translocated into the nucleus with PXR by rifampicin in HepaRG cells. These results suggested that AKR1C1/1C2 has an ability to enhance transactivity of PXR. Consistent with the results of knockdown experiments, PXR-mediated CYP3A4 induction was significantly attenuated by treatment with AKR1C1/1C2 inhibitors, diazepam or flunitrazepam, in ShP51, HepaRG, and HepaSH cells. Furthermore, the induction of CYP2B6, CYP2C9, glucose 6-phosphatase, and phosphoenolpyruvate carboxykinase 1, all regulated by PXR, was attenuated by AKR1C1/1C2 inhibitors. Collectively, we demonstrated that AKR1C1/1C2 upregulates PXR transactivation. Clinically used drugs that inhibit AKR1C1/1C2 may suppress PXR-mediated transactivation of genes encoding drug-metabolizing and gluconeogenesis enzymes.