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)

The systemic bioavailability of polynuclear aromatic hydrocarbons (PAH) from ingested soils containing manufactured gas plant (MGP) tar was evaluated in mice. Soil and organic extract of each soil were incorporated into a diet and fed to mice for two weeks. 1-Hydroxypyrene levels in urine and chemical:DNA adduct levels in lungs were used as biomarkers of PAH systemic bioavailability. Estimates of PAH relative bioavailability were determined by comparing the bioavailability observed between each soil and corresponding organic extract. In all but one case, bioavailability estimates based on 1-hydroxypyrene levels in urine indicate that the presence of MGP tar on soil results in a considerable decrease in PAH systemic bioavailability (9−75%). Similarly, PAH bioavailability estimates based on chemical:DNA adduct formation ranged from nondetectable to 76%. These results clearly indicate that the bioavailability of PAH is less than 100% when soil contaminated with MGP tar is ingested by mice. In addition, the experimental methods employed in this study appear suitable for evaluating the effects of soil on the gastrointestinal absorption and systemic bioavailability of PAH from soil containing complex organic mixtures.

The tobacco-specific nitrosamine N'-nitrosonornicotine (NNN) induces esophageal but not liver tumors in the rat. This may in part be due to tissue-specific differences in the activation of this nitrosamine. Therefore, the metabolism of NNN by microsomes from the mucosa of the rat esophagus was characterized and compared to its metabolism by liver microsomes. Esophageal microsomes metabolized NNN to both 4-hydroxy-1-(3-pyridyl)-1-butanone and 2-hydroxy-5-(3-pyridyl)tetrahydrofuran, the products of 2'- and 5'-hydroxylation of the pyrrolidine ring, respectively. This activity required an NADPH-generating system and was inhibited by carbon monoxide, suggesting that it is mediated by a cytochrome P450 enzyme. The apparent KM for total alpha-hydroxylation of NNN by esophageal microsomes was 49 +/- 6.5 microM and Vmax was 113 +/- 3.7 pmol/mg/min. The ratio of 2'-hydroxylation to 5'-hydroxylation was 3.2 +/- 0.5 when the NNN concentration was varied from 1 microM to 2 mM. 2'-Hydroxylation is believed to be the activation pathway responsible for the tumorigenicity of NNN. In contrast, the ratio of 2'- to 5'-hydroxylation of NNN by liver microsomes was between 0.71 and 0.23 depending on the concentration of NNN used. Hepatic microsomal metabolism of NNN was not saturated at 2 mM NNN, the highest concentration of NNN used. These results confirm the existence of an esophageal enzyme with high affinity for alpha-hydroxylation of NNN; it is probably a cytochrome P450. If this enzyme exists in the liver its activity is masked by high KM, high Vmax enzymes which also alpha-hydroxylate NNN. These enzymes are not present in the esophagus. The presence of a low KM esophageal enzyme that 2'-hydroxylates NNN is consistent with the hypothesis that NNN esophageal tumorigenicity is at least in part due to the efficient activation of NNN in this tissue.

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