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.
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)
Murphy
S E
SE
American Health Foundation, Valhalla, New York 10595, USA.
Spina
D A
DA
Nunes
M G
MG
Pullo
D A
DA
D000107:Acetylation; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism; D008099:Liver / Q000166:cytology; D008297:Male; D009602:Nitrosamines / Q000378:metabolism*; D010634:Phenobarbital / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D018629:Spectrometry, Mass, Secondary Ion
C096097:4-((hydroxymethyl)nitrosamino)-1-(3-pyridyl)-1-butanone; D002273:Carcinogens; D005965:Glucuronates; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D003577:Cytochrome P-450 Enzyme System; D005966:Glucuronidase; D010634:Phenobarbital