The persistence of pyridyloxobutyl DNA adducts in lung and liver of F-344 rats treated with the tobacco-specific nitrosamine 4-(methybiitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was investigated. The levels of these adducts were determined at various time points up to 4 weeks post s.c. injection of [5-3H]NNK (0.8 mg/kg body wt). Maximal levels of the adducts were observed between 4 and 24 h in both tissues. The disappearance of the adducts from lung and liver DNA was multiphasic with initial half-lives of 50 and 38 h respectively. In both cases, detectable levels of the pyridyloxobutyl adducts were observed at 4 weeks post injection. The in vitro rate of adduct disappearance was studied using calf thymus DNA reacted with 4-(acetoxymethylnitrosamino)-l-(3-[5-3H]pyridyI)-l-butanone in the presence of esterase. Adduct levels were measured for up to 2 weeks after the initiation of the experiment. The decomposition of these adducts was triphasic with half-lives of 6, 120 and 430 h. The multiphasic disappearance of the pyridyloxobutyl adducts suggests that there is more than a single adduct generated upon pyridyloxobutylation of DNA and that at least one of these adducts has a significant lifetime in DNA.
Bibliographical noteFunding Information:
The authors thank David Gong for his technical assistance. This study was supported by Grant No. 44377 from the National Cancer Institute. This is paper no. 136 in 'A Study of Chemical Carcinogenesis'.
Copyright 2010 Elsevier B.V., All rights reserved.