Inhibition of CYP2S1 mediated metabolism of anticancer prodrug AQ4N by liarozole.

ABSTRACT CYP2S1 is an orphan Cytochrome P450 whose expression is elevated in numerous epithelial derived cancers; however, little is known about CYP2S1 inhibitors. Our results indicate that liarozole acts as an effective inhibitor of CYP2S1, and decreases the turnover of the prodrug AQ4N to its active metabolites AQ4M and AQ4. Our studies also found that the active drug AQ4 is found only in the perinuclear location, whereas the prodrug AQ4N is located in the cytoplasm. In addition, we showed that AQ4N is non-geno/cytotoxic whereas the bioreduced metabolite AQ4 is both genotoxic and cytotoxic. Finally, we observed that CYP2S1 metabolizes AQ4N under anoxic conditions and that increasing the CYP2S1 concentration leads to more AQ4N turnover. The important enzymatic role of CYPS21 with regard to the metabolism of the anticancer prodrug AQ4N into Liarozole was confirmed.