Structures of covalent adducts between DNA and ochratoxin a: a new factor in debate about genotoxicity and human risk assessment.
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 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.
Mantle
Peter G
PG
Centre for Environmental Policy, Imperial College London, London SW7 2AZ, U.K. p.mantle@imperial.ac.uk
Faucet-Marquis
Virginie
V
Manderville
Richard A
RA
Squillaci
Bianca
B
Pfohl-Leszkowicz
Annie
A
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D006801:Humans; D007668:Kidney / Q000473:pathology; D008297:Male; D009793:Ochratoxins / Q000633:toxicity*; D010761:Phosphorus Radioisotopes; D051381:Rats; D018570:Risk Assessment; D053719:Tandem Mass Spectrometry
D002273:Carcinogens; D018736:DNA Adducts; D009793:Ochratoxins; D010761:Phosphorus Radioisotopes; C025589:ochratoxin A