TOXI 31 |
| 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK) and its metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol(NNAL), are both potent pulmonary carcinogens in rodents. (S)-NNAL, similar to NNK, was more tumorigenic than (R)-NNAL in A/J mice. (S)-NNAL was preferentially retained in tissues and converted to NNK. Cytochrome P450s-mediated α-methylhydroxylation of NNK, followed by DNA alkylation, results in the formation of pyridyloxobutyl(POB)-DNA adducts, i.e. O6-POB-dGuo, 7-POB-Gua, O2-POB-Thy, and O2-POB-Cyt. In this study, F344 male rats were treated with 10 ppm of NNK, (R)-NNAL, or (S)-NNAL in drinking water. After 1, 2, 5, 10, 16, or 20-weeks treatment, POB-DNA adducts were quantitated by HPLC-ESI-MS/MS analysis of liver and lung DNA. Total adduct levels were higher in lung than liver for all three groups. The total adduct levels in the (S)-NNAL group were 0.6-1.4 times as great as the NNK group, and 6-17 times higher than (R)-NNAL group. This study supports the hypothesis that preferential retention in vivo and conversion of (S)-NNAL to NNK may be responsible for its tumorigenicity. |
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General Papers: Young Investigator Session
8:00 AM-12:00 PM, Tuesday, 12 September 2006 Moscone Center -- Room 308, Oral
Division of Chemical Toxicology |