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Int. J. Mol. Sci. 2015, 16(11), 27561-27575; doi:10.3390/ijms161126047

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

1
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, Prague 2 CZ-12843, Czech Republic
2
Division of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany
3
Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King’s College London, London SE1 9NH, UK
*
Authors to whom correspondence should be addressed.
Academic Editor: Ute Roessner
Received: 14 October 2015 / Revised: 30 October 2015 / Accepted: 5 November 2015 / Published: 18 November 2015
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

Aristolochic acid I (AAI) is a plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. AAI is detoxified by cytochrome P450 (CYP)-mediated O-demethylation to 8-hydroxyaristolochic acid I (aristolochic acid Ia, AAIa). We previously investigated the efficiencies of human and rat CYPs in the presence of two other components of the mixed-functions-oxidase system, NADPH:CYP oxidoreductase and cytochrome b5, to oxidize AAI. Human and rat CYP1A are the major enzymes oxidizing AAI. Other CYPs such as CYP2C, 3A4, 2D6, 2E1, and 1B1, also form AAIa, but with much lower efficiency than CYP1A. Based on velocities of AAIa formation by examined CYPs and their expression levels in human and rat livers, here we determined the contributions of individual CYPs to AAI oxidation in these organs. Human CYP1A2 followed by CYP2C9, 3A4 and 1A1 were the major enzymes contributing to AAI oxidation in human liver, while CYP2C and 1A were most important in rat liver. We employed flexible in silico docking methods to explain the differences in AAI oxidation in the liver by human CYP1A1, 1A2, 2C9, and 3A4, the enzymes that all O-demethylate AAI, but with different effectiveness. We found that the binding orientations of the methoxy group of AAI in binding centers of the CYP enzymes and the energies of AAI binding to the CYP active sites dictate the efficiency of AAI oxidation. Our results indicate that utilization of experimental and theoretical methods is an appropriate study design to examine the CYP-catalyzed reaction mechanisms of AAI oxidation and contributions of human hepatic CYPs to this metabolism. View Full-Text
Keywords: plant nephrotoxin and carcinogen aristolochic acid I; cytochrome P450-mediated detoxification of aristolochic acid I; contribution of cytochromes P450 in detoxification of aristolochic acid I in human and rat livers; molecular modeling plant nephrotoxin and carcinogen aristolochic acid I; cytochrome P450-mediated detoxification of aristolochic acid I; contribution of cytochromes P450 in detoxification of aristolochic acid I in human and rat livers; molecular modeling
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Stiborová, M.; Bárta, F.; Levová, K.; Hodek, P.; Schmeiser, H.H.; Arlt, V.M.; Martínek, V. 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. Int. J. Mol. Sci. 2015, 16, 27561-27575.

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