Cyclin-dependent kinase 2 down-regulates expression of drug-metabolizing enzymes UGT1A1 and CYP3A4 through phosphorylation of nuclear receptor PXR

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We investigated how the expression of drug-metabolizing enzymes including UGT1A1and CYP3A4 is regulated by cell signals associated with cell-cycle progression. While the active form of CDK2(phospho-CDK2) peaked at 2 h and 4 h, respectively, and these levels dropped at 8 h, UGT1A1 and CYP2B6 were present at very low levels at 0 h to 6 h and started accumulating at 8 h. While CDK2 inhibitor roscovitine enhanced the expression of UGT1A1 and CYP3A4, it suppressed the expression of UGT1A1 and CYP3A4 in the cells transfected with S350D PXR. Phosphomimetic mutant at serine-350 of PXR was detected in the nuclei and lost the binding with RXR, and co-transfection with co-activator SRC-2 but not SRC-1 recovered PXR activity. These results indicate that roscovitine stimulated expression of UGT1A1 and CYP3A4 through inhibiting CDK2, which phosphorylated PXR at serine-350 to suppress the transactivation in the nuclei.