Intestinal first-pass metabolism of nitrosamines. 2. Metabolism of N-nitrosodibutylamine in isolated perfused rat small intestinal segments

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Abstract
In a previous study a high first-pass metabolism of N -nitrosodi-[1- 14 C]butylamine (NDBA, O.32–730p.μM) has been shown in isolated perfused rat small intestinal segments. In the present work the identification and quantitation of metabolitesin samples of perfusate and absorbed fluid (absorbate) is reported. After HPLC enrichment and purification five metabolites could be identified by GLC-MS: N -nitrosobutyl-(3-hydroxybutyl)amine (NB3HBA), N -nitrosobutyl-(4-hydroxybutyl)amine (NB4HBA), N -nitrosobutyl-(3-carboxypropyl)amine (NB3CPA), N -nitrosobutyl-(2-hydroxy-3-carboxypropyl)amine (NB2H3CPA) and N -nitrosobutylcarboxymethylamine (NBCMA), representing > 95% of total metabolites. ω-hydroxylatlon leading to NB4HBA and NB3CPA accounted for 75–95% of total metabolites. The formation of their follow-up products NB2H3CPA and NBCMA was too small for quantitative analysis. In absorbate NB3CPA was by far the most important metabolite. The hydroxylation of NB4HBA to NB3CPA was more efficient in jejunal as compared to ileal segments.ω-1-hydroxylation to NB3HBA and, as reported previously, α-hydroxylation were only minor metabolic pathways. In conclusion, a high first-pass metabolism of NDBA to the proximate bladder carcinogen NB3CPA takes place during its absorption in rat small intestine. This is in contrast to the observation in rat liver preparations, where α- and ω-1-hydroxylation are the predominant pathways. The intestinal first-pass metabolism may play a key role explaining the increased incidence of bladder tumors in rats after low oral doses of NDBA.