Investigations of metabolic precursors to hemoglobin and DNA adducts of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
Levels of DNA and/or hemoglobin pyridyloxobutylation were compared in A/J mice or F344 rats treated with a single dose of [5-3H]4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone ([5-3H]NNK), [5-3H]4-hydroxy-1-(3-pyridyl)-1-butanone ([5-3H]4-HPB) or [5-3H]4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone ([5-3H]NNKOAc), a compound that generates the proposed pyridyloxobutylating agent in situ upon esterase hydrolysis. The lung and liver DNA samples isolated from A/J mice treated with the various compounds were subjected to acid hydrolysis and the hydrolysates were analyzed for the presence of [5-3H]4-HPB. No detectable levels were found in the lung DNA isolated from [5-3H]4-HPB-treated animals, whereas significant amounts of [5-3H]4-HPB were released from lung and liver DNA isolated from [5-3H]NNK- and [5-3H]NNKOAc-treated mice. The levels of total binding and [5-3H]4-HPB released from the globin isolated from these animals showed a similar trend. That is, low binding levels were detected in the globin isolated from [5-3H]4-HPB-treated animals and significantly higher levels of binding were detected in the globin from the [5-3H]NNKOAc- and [5-3H]NNK-treated animals. Comparable findings were obtained in the rat experiments. These studies clearly demonstrate that methyl hydroxylation of NNK leads to a species that is capable of reacting covalently with nucleophiles in DNA and protein. Thus, the levels of 4-HPB released from DNA and globin can be attributed to the activation of NNK and not to the direct binding of 4-HPB.
Peterson
L A
LA
Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, NY 10595.
Carmella
S G
SG
Hecht
S S
SS
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D005260:Female; D006454:Hemoglobins / Q000378:metabolism*; D008297:Male; D051379:Mice; D009602:Nitrosamines / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D006454:Hemoglobins; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D004247:DNA