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.
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.
authors: Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences.
authors: Takahito
authors: T
authors: Nishiyama
authors: Nahoko
authors: N
authors: Hayashi
authors: Naoki
authors: N
authors: Kakurai
authors: Hiromi
authors: H
authors: Yanagita
authors: Ai
authors: A
authors: Kuriyama
authors: Chika
authors: C
authors: Miyamoto
authors: Yumi
authors: Y
authors: Ishihara
authors: Kenichiro
authors: K
authors: Ogura
authors: Tomokazu
authors: T
authors: Ohnuma
authors: Akira
authors: A
authors: Hiratsuka
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced*; D004198:Disease Susceptibility; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009602:Nitrosamines / Q000378:metabolism* / Q000633:toxicity* / Q000652:urine; D014018:Tissue Distribution
chemical_list: D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone