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Description
Cytochrome P450 2U1 (CYP2U1) is an extrahepatic, lipid-metabolizing membrane enzyme. Due to its high expression in the thymus, this study investigated CYP2U1-mediated biotransformation of two tumor-targeting tyrosine kinase inhibitors, sorafenib and sunitinib, both commonly prescribed for thymus cancers. For comparison, CYP2U1 and CYP2D6 were incorporated into nanodiscs, and their metabolic activities toward these drugs were examined. Metabolite profiling revealed that both CYP2U1 and CYP2D6 oxidized sorafenib to generate sorafenib N-oxide, and catalyzed the dealkylation of sunitinib to form N-desethyl sunitinib. Spectroscopic studies (UV-Visible and fluorescence) confirmed favorable binding interactions between the drugs and both CYPs; while molecular dynamics simulations highlighted binding of sorafenib and sunitinib in the CYP2U1 active site, identifying key interactions between the drug molecules and key residues at the protein’s active site. Targeted metabolomics quantified the rates of metabolite formation, followed by cellular assays to assess biological activity. Sorafenib N-oxide retained tyrosine kinase inhibitory activity at levels similar to that from parent compound sorafenib, whereas the metabolite is approximately twice as potent as the parent compound in inhibiting cancer cell migration. In contrast, N-desethyl sunitinib exhibited a complete loss of bioactivity in the same assays. Together, these findings highlight the potential role of extrahepatic CYP2U1 in the local metabolism of tyrosine kinase inhibitors and suggest that CYP2U1-mediated transformations may directly influence antitumor efficacy at thymic tumor sites.
