Journal Article

Bioactivation versus Detoxication of the Urothelial Carcinogen Aristolochic Acid I by Human Cytochrome P450 1A1 and 1A2

Marie Stiborová, Kateřina Levová, František Bárta, Zhanquan Shi, Eva Frei, Heinz H. Schmeiser, Daniel W. Nebert, David H. Phillips and Volker M. Arlt

in Toxicological Sciences

Volume 125, issue 2, pages 345-358
Published in print February 2012 | ISSN: 1096-6080
Published online November 2011 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfr306
Bioactivation versus Detoxication of the Urothelial Carcinogen Aristolochic Acid I by Human Cytochrome P450 1A1 and 1A2

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Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. Individual susceptibility to AA-induced disease likely reflects individual differences in enzymes that metabolize AA. Herein, we evaluated AAI metabolism by human cytochrome P450 (CYP) 1A1 and 1A2 in two CYP1A-humanized mouse lines that carry functional human CYP1A1 and CYP1A2 genes in the absence of the mouse Cyp1a1/1a2 orthologs. Human and mouse hepatic microsomes and human CYPs were also studied. Human CYP1A1 and 1A2 were found to be principally responsible for reductive activation of AAI to form AAI-DNA adducts and for oxidative detoxication to 8-hydroxyaristolochic acid (AAIa), both in the intact mouse and in microsomes. Overall, AAI-DNA adduct levels were higher in CYP1A-humanized mice relative to wild-type mice, indicating that expression of human CYP1A1 and 1A2 in mice leads to higher AAI bioactivation than in mice containing the mouse CYP1A1 and 1A2 orthologs. Furthermore, an exclusive role of human CYP1A1 and 1A2 in AAI oxidation to AAIa was observed in human liver microsomes under the aerobic (i.e., oxidative) conditions. Because CYP1A2 levels in human liver are at least 100-fold greater than those of CYP1A1 and there exists a > 60-fold genetic variation in CYP1A2 levels in human populations, the role of CYP1A2 in AAI metabolism is clinically relevant. The results suggest that, in addition to CYP1A1 and 1A2 expression levels, in vivo oxygen concentration in specific tissues might affect the balance between AAI nitroreduction and demethylation, which in turn would influence tissue-specific toxicity or carcinogenicity.

Keywords: aristolochic acid nephropathy; Balkan endemic nephropathy; cytochrome P450; metabolism; aristolochic acid Ia; DNA adducts; CYP1A-humanized mouse models

Journal Article.  8015 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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