METABOLISM OF A GLUCURONIDE CONJUGATE OF 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE IN RATS

Besides 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), [4-(meth ylnitrosamino)- 1-(3-pyridyl)but-1-yl]-beta-O-d-glucosiduronic acid (N NAL-Glu) is another important metabolite of the tobacco-specific nitro samine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) which has been detected in the urine of tobacco users and non-smokers heavily ex posed to sidestream cigarette smoke. In order to evaluate the toxicolo gical significance of NNAL-Glu formation and excretion, the metabolism of [5-H-3]-NNAL-Glu was studied in rats. Five male F344 rats were adm inistered 3.7 mg/kg [5-H-3]-NNAL-Glu by i.v. injection and the metabol ites in urine analysed by HPLC. More than 90% of the radioactivity was excreted in urine within the first 24 h. Unchanged NNAL-Glu accounted for 81.2 +/- 3.1% of the total radioactivity; the remaining part of t he dose appears to be deconjugated resulting in the urinary excretion of NNAL (3.6 +/- 1.7%) and its alpha-hydroxylation (11.5 +/- 2.2%) and N-oxidation (3.6 +/- 1.6%) products. The presence of alpha-hydroxylat ion products of NNAL-Glu in urine suggests that this NNK metabolite ma y be activated in vivo to carcinogenic intermediates.