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- Title
Formation and stability of 4-(hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone glucuronide, a stable form of reactive intermediate produced from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, in mice.
- Authors
Takahito Nishiyama; Nahoko Hayashi; Naoki Kakurai; Hiromi Yanagita; Ai Kuriyama; Chika Miyamoto; Yumi Ishihara; Kenichiro Ogura; Tomokazu Ohnuma; Akira Hiratsuka
- Abstract
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, induced lung tumors in rodents and is likely involved in human lung cancer. 4-(Hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (HO-methyl NNK) glucuronide, a glucuronide of the reactive intermediate of NNK, has been identified in rats. The aim of this study is to estimate the role of HO-methyl NNK glucuronide in the tumorigenic effects of NNK. We investigated the urinary excretion and tissue distribution of HO-methyl NNK glucuronide in A/J mice, which are susceptible to NNK carcinogenesis, and C57BL/6J mice, which are resistant to NNK carcinogenesis. The cumulative urinary excretion of the HO-methyl NNK glucuronide in the C57BL/6J mice was more than 20 times higher than in the A/J mouse urine. Tissue concentrations of HO-methyl NNK glucuronide were also higher in the C57BL/6J mice than in the A/J mice. Assessment of the stability of HO-methyl NNK glucuronide in liver homogenates at physiological pH conditions showed that more than 60% of the glucuronide remained until 2 hr of incubation. These results suggested that HO-methyl NNK glucuronide is likely to be a detoxified metabolite and could be one reason for differences in the susceptibility to NNK tumorigenesis between the two strains. Once HO-methyl NNK is formed in tissues, C57BL/6J mice have a high ability to form HO-methyl NNK glucuronide so that HO-methyl NNK, the reactive intermediate formed from NNK, is readily excreted in urine as a stable form.
- Subjects
CHEMICAL stability; HYDROXYMETHYL compounds; NITROSAMIDES; LUNG cancer treatment; METHYL ethyl ketone; GLUCURONIDES; LABORATORY mice
- Publication
Journal of Toxicological Sciences, 2014, Vol 39, Issue 4, p515
- ISSN
0388-1350
- Publication type
Article
- DOI
10.2131/jts.39.515