4-(Hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide has the potential to form 2'-deoxyguanosine and N-acetylcysteine adducts.

4-(Hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide has the potential to form 2'-deoxyguanosine and N-acetylcysteine adducts. J Toxicol Sci. 2019;44(10):693-699 Authors: Nishiyama T, Hayashi N, Yanagita H, Ohnuma T, Ogura K, Hiratsuka A Abstract Cigarette smoking is a risk factor for the development of various cancers, such as lung, nasal, liver and bladder cancers. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, is implicated in human lung cancer. NNK-induced DNA adducts are found in target tissues for NNK carcinogenesis. NNK is activated by cytochrome P450 dependent α-hydroxylation at either the methylene carbon or methyl carbon adjacent to the N-nitroso group. The former leads to the formation of the methylating agent, and the latter produce the pyridyloxobutylating agent. NNK and some of its metabolites are further metabolized by UDP-glucuronosyltransferases (UGTs). Glucuronides generally are much less active than the parent aglycon therefore the glucuronides of NNK-related metabolites are thought to be inactive. However, 4-(hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide (HO-methyl NNK glucuronide) can be transported to the target organs of NNK carcinogenesis where subsequent hydrolysis causes the release of the reactive intermediate. Regeneration of HO-methyl NNK could play an important role in the tissue-specific carcinogenicity of NNK. In the present study, w...
Source: Journal of Toxicological Sciences - Category: Toxicology Tags: J Toxicol Sci Source Type: research