Differential DNA adduct formation and disappearance in three mouse tissues after treatment with the mycotoxin ochratoxin A.
Ochratoxin A (OTA) is a mycotoxin which has been implicated in Balkan endemic nephropathy, a disease characterized by a high incidence of urinary tract tumors. It induces DNA single-strand breaks and has been shown to be carcinogenic in two rodent species. For a better understanding of the OTA genotoxic effect, OTA-DNA adduct formation and disappearance has been measured using the 32P-post-labelling method after oral administration of 2.5 mg/kg of OTA to mice. In kidney, liver and spleen, several modified nucleotides were clearly detected in DNA, 24 h after administration of OTA, but their level varied significantly in a tissue and time dependent manner over a 16-day period. Total DNA adducts reached a maximum at 48 h when 103, 42 and 2.2 adducts per 10(9) nucleotides were found respectively in kidney, liver and spleen, indicating that kidney is the main target of the genotoxicity and likely carcinogenicity of OTA. The major adduct differed between kidney and liver. All adducts disappeared in liver and spleen 5 days after compound administration, whereas some adducts persisted for at least 16 days in the kidney. Some adducts were organ specific. The finding that the adducts are not quantitatively and qualitatively the same in the three organs examined is likely due to differences of metabolism in these organs, leading to different ultimate carcinogens and may also result from differences in the efficiency of repair processes.
Pfohl-Leszkowicz
A
A
Institut de Biologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, Strasbourg, France.
Grosse
Y
Y
Kane
A
A
Creppy
E E
EE
Dirheimer
G
G
D000818:Animals; D001345:Autoradiography / Q000379:methods; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism*; D004249:DNA Damage; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009793:Ochratoxins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D009928:Organ Specificity; D010761:Phosphorus Radioisotopes; D013154:Spleen / Q000378:metabolism
D002273:Carcinogens; D009793:Ochratoxins; D010761:Phosphorus Radioisotopes; C025589:ochratoxin A; D004247:DNA