2009
DOI: 10.1021/tx900295a
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Structures of Covalent Adducts between DNA and Ochratoxin A: A New Factor in Debate about Genotoxicity and Human Risk Assessment

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 (32)P-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 (32)P-postlabeling methodology revea… Show more

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Cited by 129 publications
(128 citation statements)
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“…The OTB-GSH or OTB-NAC conjugates are generated photochemically from displacement of the C5-Cl atom of OTA by the sulphur atom of GSH or NAC. The electrophilic intermediate in this reaction also reacts with dG to yield the OTB-dG adduct (21), which has been detected by LC-MS in the kidney of male rats fed a carcinogenic dose of OTA (22). Thus, OTB-GSH and OTHQ-GSH, along with the corresponding NACconjugates, were considered as appropriate biomarkers for OTA exposure.…”
Section: Discussionmentioning
confidence: 99%
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“…The OTB-GSH or OTB-NAC conjugates are generated photochemically from displacement of the C5-Cl atom of OTA by the sulphur atom of GSH or NAC. The electrophilic intermediate in this reaction also reacts with dG to yield the OTB-dG adduct (21), which has been detected by LC-MS in the kidney of male rats fed a carcinogenic dose of OTA (22). Thus, OTB-GSH and OTHQ-GSH, along with the corresponding NACconjugates, were considered as appropriate biomarkers for OTA exposure.…”
Section: Discussionmentioning
confidence: 99%
“…Oxidation of OTHQ generates the quinone electrophile OTQ that reacts with DNA to generate covalent DNA adducts, as evidenced using 32 P-postlabeling (20). OTA also reacts photochemically with 2′-deoxyguanosine (dG) to generate a carbon (C)-linked nonchlorinated ochratoxin B (OTB)-dG adduct (21) that has recently been detected in the kidney of male rats using liquid chromatography-mass spectrometry (LC-MS) (22). The C5-Cl atom of OTA plays a critical role in OTBdG formation, as the nonchlorinated OTB analog lacks direct genotoxicity and does not react photochemically with dG to generate the OTB-dG adduct (23).…”
Section: Abstract: Bioactivation Carcinogenicity Dna Adduction Glmentioning
confidence: 99%
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“…OTA-contaminated foods may be pathogenic to humans and animals (Rutqvist et al, 1978). OTA appears to be involved in Balkan endemic nephropathy (Pfohl-Leszkowicz et al, 2002;Castegnaro et al, 2006), and is genotoxic, immunotoxic, and carcinogenic (IARC, 1993;PfohlLeszkowicz and Manderville, 2007;Manderville and Pfohl-Leszkowicz, 2008;Mantle et al, 2010). The health risk due to OTA contamination of food necessitates establishing specific actions to protect consumer health worldwide.…”
Section: Introductionmentioning
confidence: 99%