title: Tissue distributions 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 the rat.
abstract: The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), induces lung tumors in rodents and has been suggested as a causative factor in human lung cancer. NNK is activated by α-hydroxylation at either the methyl or methylene carbon adjacent to the N-nitroso group to yield unstable intermediates that spontaneously decompose to produce alkylating agents. 4-(Hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (HO-methyl NNK) glucuronide, a glucuronide of the reactive intermediate of NNK has been identified. However, there are no available data concerning HO-methyl NNK glucuronide. In the present study, we investigated the tissue distribution of HO-methyl NNK glucuronide in control and phenobarbital (PB)-treated rats after intraperitoneal administration of NNK. In PB-treated rats, HO-methyl NNK glucuronide was detected in plasma, kidney, liver, lung, and pancreas. On the contrary, in the control rats, HO-methyl NNK glucuronide was detected only in plasma, kidney and liver at low concentrations compared with PB-treated rats. The results of cumulative urinary excretion of HO-methyl NNK glucuronide in Wistar and Gunn rats suggested that PB-inducible UDP-glucuronosyltransferase 2B isoforms mainly contribute to the formation of HO-methyl NNK glucuronide.
authors.affiliation: Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences.
authors.forename: Takahito
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ogura
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ohnuma
authors.forename: Akira
authors.initials: A
authors.lastname: Hiratsuka
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D020719:Glucuronides / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D014453:Glucuronosyltransferase / Q000502:physiology; D006801:Humans; D007274:Injections, Intraperitoneal; D007527:Isoenzymes; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D015778:Minor Histocompatibility Antigens; D009602:Nitrosamines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D010179:Pancreas / Q000378:metabolism; D010634:Phenobarbital; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D014018:Tissue Distribution; D014026:Nicotiana
chemical_list: D020719:Glucuronides; D007527:Isoenzymes; D015778:Minor Histocompatibility Antigens; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D014453:Glucuronosyltransferase; C583026:glucuronosyltransferase 2B, rat; D010634:Phenobarbital