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Interdisciplinary Toxicology

The Journal of Institute of Experimental Pharmacology of Slovak Academy of Sciences

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Contribution of biotransformation enzymes to the development of renal injury and urothelial cancer caused by aristolochic acid: urgent questions, difficult answers

Marie Stiborová1 / Jiří Hudeček1 / Eva Frei1 / Heinz Schmeiser1

Department of Biochemistry, Faculty of Science, Charles University, 128 40 Prague 2, Czech Republic1

Division of Molecular Toxicology, German Cancer Research Center, 69120 Heidelberg, Germany2

This content is open access.

Citation Information: Interdisciplinary Toxicology. Volume 1, Issue 1, Pages 8–12, ISSN (Online) 1337-9569, ISSN (Print) 1337-6853, DOI: 10.2478/v10102-010-0023-1, November 2010

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Contribution of biotransformation enzymes to the development of renal injury and urothelial cancer caused by aristolochic acid: urgent questions, difficult answers

Ingestion of aristolochic acid (AA) is associated with the development of aristolochic acid nephropathy, which is characterized by chronic renal failure, tubulointerstitial fibrosis and urothelial cancer. AA may also cause a similar type of kidney fibrosis with malignant transformation of the urothelium, the Balkan endemic nephropathy. Understanding which enzymes are involved in AA activation and/or detoxication is important in the assessment of a susceptibility to this carcinogen. The most important human enzymes activating AA by simple nitroreduction in vitro are hepatic and renal cytosolic NAD(P)H:quinone oxidoreductase, hepatic microsomal cytochrome P450 1A2 and renal microsomal NADPH:cytcohrome P450 reductase, besides cyclooxygenase, which is highly expressed in urothelial tissue. Despite extensive research, contribution of most of these enzymes to the development of these diseases is still unknown. Hepatic cytochromes P450 were found to detoxicate AA in mice, and thereby protect the kidney from injury. However, which of cytochromes P450 are the most important in this process both in animal models and in humans have not been entirely resolved as yet. In addition, the relative contribution of enzymes found to activate AA to species responsible for induction of urothelial cancer in humans remains still to be resolved.

Keywords: Aristolochic acid; metabolism; Aristolochic acid- and Balkan endemic-nephropathy; renal injury; tumor induction

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