Evidence for covalent DNA adduction by ochratoxin A following chronic exposure to rat and subacute exposure to pig.

Abstract

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.

• Authors: Virginie Faucet, Annie Pfohl-Leszkowicz, Jian Dai, Marcel Castegnaro, Richard A Manderville
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 17 Issue 9 Pg. 1289-96 (Sep 2004) ISSN: 0893-228X [Print] United States
• PMID: 15377164 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA Adducts
• Mycotoxins
• Ochratoxins
• ochratoxin A
• Deoxyguanosine

Topics

• Animals
• DNA Adducts (drug effects)
• Deoxyguanosine (metabolism)
• Kidney (drug effects, metabolism)
• Kidney Diseases (chemically induced, metabolism)
• Male
• Mycotoxins (toxicity)
• Ochratoxins (toxicity)
• Rats
• Reference Values
• Swine
• Toxicity Tests, Acute
• Toxicity Tests, Chronic