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Structures of Covalent Adducts between DNA and Ochratoxin A: A New Factor in Debate about Genotoxicity and Human Risk Assessment

Mantle, Peter G. and Faucet-Marquis, Virginie and Manderville, Richard A. and Squillaci, Bianca and Pfohl-Leszkowicz, Annie Structures of Covalent Adducts between DNA and Ochratoxin A: A New Factor in Debate about Genotoxicity and Human Risk Assessment. (2010) Chemical Research in Toxicology, vol. 23 (n° 1). pp. 89-98. ISSN 0893-228X

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Official URL: http://dx.doi.org/10.1021/TX900295a

Abstract

The potent renal carcinogenicity of ochratoxin A (OTA) in rats, principally in the male, raises questions about mechanism. Chromatographic evidence of DNA adducts after 32P-postlabeling analysis contrasts with experimental attempts to demonstrate the absence of OTA in such adducts. Proffered schemes for alternative epigenetic mechanisms in OTA carcinogenicity remain unsatisfying, while structural data substantiating DNA-OTA adducts has also been lacking. We report refined 32P-postlabeling methodology revealing one principal adduct isolated in small amounts from the kidneys of all five Fischer and five Dark Agouti rats to which OTA had been given on four consecutive days. We also describe structural data for the principal adduct from OTA/DNA interaction in vitro and its subsequent preparative isolation by the postlabeling methodology (as C-C8 OTA 3′dGMP), essentially creating an ochratoxin B−guanine adduct. Reasoning for the unsuitability of experimental protocols in published evidence claiming nongenotoxicity of OTA is given. In vivo exposure of renal DNA to cycles of adduction with OTA, necessarily protracted for carcinogenesis to occur, can reasonably explain an occasional focal neoplasm from which metastasizing carcinoma could develop.

Item Type:Article
Audience (journal):International peer-reviewed journal
Uncontrolled Keywords:
Institution:French research institutions > Centre National de la Recherche Scientifique - CNRS
Université de Toulouse > Institut National Polytechnique de Toulouse - INPT
Université de Toulouse > Université Paul Sabatier-Toulouse III - UPS
Other partners > GlaxoSmithKline (UNITED KINGDOM)
Other partners > Imperial College London (UNITED KINGDOM)
Other partners > University of Guelph (CANADA)
Laboratory name:
Statistics:download
Deposited By: Audrey LEFEVRE

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