A Mechanism of O-Demethylation of Aristolochic Acid I by Cytochromes P450 and Their Contributions to This Reaction in Human and Rat Livers: Experimental and Theoretical Approaches.

摘要: Aristolochic acid I (AAI) is a plant alkaloid causing aristolochic nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. AAI detoxified by cytochrome P450 (CYP)-mediated O-demethylation to 8-hydroxyaristolochic (aristolochic Ia, AAIa). We previously investigated the efficiencies of human rat CYPs in presence two other components mixed-functions-oxidase system, NADPH:CYP oxidoreductase b5, oxidize AAI. Human CYP1A are major enzymes oxidizing Other such as CYP2C, 3A4, 2D6, 2E1, 1B1, also form AAIa, but with much lower efficiency than CYP1A. Based on velocities AAIa formation examined expression levels livers, here we determined contributions individual oxidation these organs. CYP1A2 followed CYP2C9, 3A4 1A1 were contributing liver, while CYP2C 1A most important liver. employed flexible silico docking methods explain differences liver CYP1A1, 1A2, 2C9, that all O-demethylate AAI, different effectiveness. found binding orientations methoxy group centers CYP energies active sites dictate oxidation. Our results indicate utilization experimental theoretical an appropriate study design examine CYP-catalyzed reaction mechanisms hepatic this metabolism.