COMPARATIVE METABOLISM OF N'-NITROSONORNICOTINE AND 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE BY CULTURED F344 RAT ORAL-TISSUE AND ESOPHAGUS

  • 1 August 1990
    • journal article
    • research article
    • Vol. 50  (15) , 4685-4691
Abstract
The metabolism and DNA binding of N''-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cultured F344 rat oral tissue and esophagus were investigated over a range of concentrations. The metabolites present in the culture media were separated by high performance liquid chromatography and were identified by comparison to standards. .alpha.-Hydroxylation of NNN, an esophageal carcinogen, was the major pathway for metabolism of this nitrosamine in both tissues. The metabolites formed from 2''-hydroxylation were between 3.0 and 3.9 times those formed from 5''-hydroxylation. 2''-Hydroxylation results in a pyridyloxobutylating species. DNA from esophagus cultured with [5-3H]NNN contained a pyridyloxobutylated adduct which upon acid hydrolysis released 3.8 pmol [5-3H]-4-hydroxy-1-(3-pyridyl)-1-butanone/.mu.mol guanine. DNA from oral tissue cultured under the same conditions, where the extent of metabolism was the same, contained no measurable [5-3H]NNN DNA adduct. This suggests that factors, as yet unknown, cause the DNA of oral cavity tissue to be protected from pyridyloxobutylation by NNN. The metabolism of NNK by .alpha.-hydroxylation was as much as 10-fold less than the metabolism of NNN by this pathway in both tissues. .alpha.-Hydroxylation of NNK results in either a methylating species or a pyridyloxobutylating species. DNA from oral tissue cultured with [C3H3]NNK contained between 1.7 and 4.3 pmol 7-methylguanine/.mu.mol guanine, respectively. No pyridyloxobutylated DNA (< 0.2 pmol/.mu.mol guanine) was detected in oral tissue incubated with [5-3H]NNK. The DNA from esophagi incubated with [C3H3]NNK contained no 7-methylguanine (< 0.4 pmol/.mu.mol guanine). The level of pyridyloxobutylation of DNA from esophagi incubated with [5-3H]NNK was 0.17 pmol/.mu.mol guanine. The ability of the esophagus to metabolize NNN to a greater extent than NNK to a reactive species which pyridyloxobutylates DNA may be important in determining the carcinogenicity of NNN in the esophagus. In contrast, the metabolism of NNK to a methylating species by oral cavity tissue suggests that this tobacco-specific nitrosamine is important in tobacco-related oral cavity carcinogenesis.

This publication has 19 references indexed in Scilit: