Tyrosine kinase inhibitors suppress cytochrome P450 2C8 and 2J2 functions and their expression in renal cell carcinoma.

Cytochrome P450 (P450 or CYP) isoforms, CYP2C8 and CYP2J2, metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs), which are involved in cell proliferation and vasodilation, and are expressed in human kidneys and various cancer cells. However, the effects of renal cell carcinoma-targeted tyrosine kinase inhibitors (TKIs) on these P450 forms have not been determined. We evaluated the effects of TKIs on the catalytic activities and gene expression of CYP2C8 and CYP2J2 and EET formation. Both sorafenib and axitinib strongly inhibited CYP2C8-mediated paclitaxel 6α-hydroxylation and CYP2J2-mediated rivaroxaban hydroxylation and reduced 14,15-EET formation from arachidonic acid catalyzed by CYP2C8 and CYP2J2. Since sorafenib strongly inhibited these reactions, its impact on gene expression was further prioritized. Exposure of the human kidney adenocarcinoma cell line ACHN to 3.0 μM sorafenib for 7 days decreased mRNA levels of CYP2C8, CYP2J2, peroxisome proliferator-activated receptor α, and the β-catenin target gene AXIN2. siRNA-mediated knockdown of β-catenin similarly reduced CYP2C8, CYP2J2, and AXIN2 mRNA expression. These results suggest that TKIs inhibit CYP2C8- and CYP2J2-mediated metabolism, with suppression of their gene expression at least partly mediated by proliferator-activated receptor α and β-catenin, and that inhibition of EET production may contribute to the anticancer and hypertensive effects of these drugs.