Glucuronidation of 4-[(Hydroxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone, a Metabolically Activated Form of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, by Phenobarbital-Treated Rats
| Autor: | Maria G. Nunes, Deborah A. Spina, Dominic A. Pullo, Sharon E. Murphy |
|---|---|
| Rok vydání: | 1995 |
| Předmět: |
Male
Nitrosamines Metabolite Glucuronidation Spectrometry Mass Secondary Ion Glucuronates Toxicology chemistry.chemical_compound Cytochrome P-450 Enzyme System medicine Animals Hydroxymethyl Biotransformation Cells Cultured Chromatography High Pressure Liquid Carcinogen Active metabolite Glucuronidase Chemistry Acetylation General Medicine Rats Inbred F344 Rats Liver Biochemistry Nitrosamine Phenobarbital Carcinogens Glucuronide medicine.drug |
| Zdroj: | Chemical Research in Toxicology. 8:772-779 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/tx00047a018 |
| Popis: | In the rat, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lung tumors independent of the route of administration. To exert its carcinogenic potential, NNK must be metabolically activated. Like most nitrosamines NNK is activated by alpha-hydroxylation. The striking tissue specificity of tumor induction by nitrosamines has been primarily attributed to the efficient alpha-hydroxylation of a particular nitrosamine by its target tissue. Two other factors which may contribute to this are the following: the relative capacity of different tissues to detoxify the alpha-hydroxynitrosamine and the preferential uptake of the active metabolite by the target tissue. In the present study we report the characterization of the O-glucuronide of 4-((hydroxymethyl)nitrosamino)-1-(3-pyridyl)-1-butanone (alpha-hydroxymethylNNK-Gluc). The formation of this glucuronide could either serve as a detoxification pathway or provide a stable transport form of the alpha-hydroxylated metabolite. In addition, the metabolism of NNK to a glucuronide of the alpha-hydroxynitrosamine provides the first definitive evidence for the formation of alpha-hydroxymethylNNK. alpha-HydroxymethylNNK-Gluc was present in the urine of rats treated with phenobarbital (PB) and NNK. It was also formed by hepatocytes from PB-treated rats, accounting for 4% of the total metabolites in the media following incubation with 1 microM NNK. The data that support the identity of this metabolite as alpha-hydroxymethylNNK-Gluc are as follows. (1) Incubation of this metabolite with beta-glucuronidase resulted in the quantitative release of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB), the decomposition product of alpha-hydroxymethylNNK.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|