Evidence for Covalent DNA Adduction by Ochratoxin A |
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15377164
1: Chem Res Toxicol. 2004 Sep 20;17(9):1289-1296.
Evidence for Covalent DNA Adduction by Ochratoxin A following Chronic
Exposure to Rat and Subacute Exposure to Pig
Faucet V, Pfohl-Leszkowicz A, Dai J, Castegnaro M, Manderville RA.
Department Toxicology & Food Safety, Lab. Genie Chimique, Ecole
Nationale Superieure Agronomique de Toulouse, UMR-CNRS 5503, Agrobiopole-BP
107, F31326 Castanet, Tolosan Cedex, France, Department of Chemistry,
Wake Forest University, Winston-Salem, North Carolina 27109-7486, IARC,
150 Cours Albert Thomas, 69000 Lyon, France, and Department of
Chemistry, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
Ochratoxin A (OTA) is a nephrotoxic mycotoxin that is a potent renal
carcinogen in male rats and is suspected of being the etiological agent
of Balkan endemic nephropathy (BEN) and its associated urinary tract
cancers. Conflicting results have been obtained regarding the
genotoxicity of OTA and its ability to react directly with DNA upon
oxidative bioactivation to yield covalent DNA adducts. To characterize
DNA adduction by OTA, the present study utilizes the photooxidative
properties of the toxin to generate authentic C8
OTA-3'-monophosphate-deoxyguanosine (3'-dGMP) adducts for use as
cochromatographic standards for (32)P-postlabeling detection of
OTA-mediated DNA adduction in the kidney of rat and pig. Our results
show evidence for the photooxidation of OTA to yield carbon (C)- and
oxygen (O)-bonded C8-3'-dGMP adducts (C-C8 and O-C8) that have been
isolated and characterized by LC/MS with in-line UV and electrospray
negative ionization (ES(-)) detection. A comparison to previously
published work on related C8-dG adducts supports C8 attachment by OTA.
The C-C8 OTA-3'-dGMP adduct standard is shown by (32)P-postlabeling to
comigrate with the major lesion detected in the kidney of rat following
chronic exposure to OTA and with one of four adducts detected in the
kidney of pig following subacute exposure to the toxin. The O-C8
OTA-3'-dGMP adduct standard is also shown to coelute with a lesion
detected in rat kidney. These findings suggest a role for the OTA
phenoxyl radical in OTA-mediated DNA adduction in vivo, provide a
rationale for the tumorigenesis of OTA, and strengthen the OTA
hypothesis in the etiology of BEN and the associated urinary tract
tumors. |
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