Formation and persistence of specific purine DNA adducts by 32P-postlabelling in target and non-target organs of rats treated with aristolochic acid I.
Binding of the naturally occurring carcinogen, aristolochic acid I (AAI), to DNA in male Wistar rats has been examined. Rats were treated orally with a single dose (13.8 mmol) of AAI and sacrificed 1 day and 1, 2, 4, 16 and 36 weeks after treatment. The formation and persistence of two specific purine AAI-DNA adducts were studied utilizing the nuclease P1 enhancement method of the 32P-postlabelling assay. Both adducts, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI) and 7-(deoxyguanosin-N2-yl)-aristolactam I (dG-AAI), were detectable for up to 36 weeks in all target (forestomach) and non-target (glandular stomach, liver, lung, urinary bladder) organs and showed differential rates of removal and persistence. In all organs, dA-AAI was the major adduct present. In the target organ (forestomach), both adducts were removed rapidly within the first two weeks; thereafter, extensive removal of dG-AAI continued, whereas dA-AAI attained constant levels (4-36 weeks). Of interest was the marked decrease of both adducts in glandular stomach, the neighbouring non-target tissue to the forestomach. These results suggest that the persistence of a specific AAI-DNA adduct, namely dA-AAI, in the target organ may be the critical lesion responsible for initiation of carcinogenesis by AAI.
Fernando
R C
RC
Department of Molecular Toxicology, German Cancer Research Centre, Heidelberg.
Schmeiser
H H
HH
Scherf
H R
HR
Wiessler
M
M
D000818:Animals; D034341:Aristolochic Acids; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D003839:Deoxyadenosines / Q000737:chemistry; D003849:Deoxyguanosine / Q000737:chemistry; D005753:Gastric Mucosa / Q000378:metabolism; D008297:Male; D010616:Phenanthrenes / Q000633:toxicity*; D010761:Phosphorus Radioisotopes; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects; D013274:Stomach Neoplasms / Q000139:chemically induced; D014018:Tissue Distribution
D034341:Aristolochic Acids; D002273:Carcinogens; D003839:Deoxyadenosines; D010616:Phenanthrenes; D010761:Phosphorus Radioisotopes; D004247:DNA; C000228:aristolochic acid I; D003849:Deoxyguanosine