Species differences in the metabolism of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine

Hamsters and rats metabolize [1-14C]N-nitroso(2-hydroxy-propyl)(2-oxopropyl)amine (HPOP) and N-nitrosobis(2-oxo-propyl)amine (BOP) to yield N-nitrosobis(2-hydroxypropyl)-amine (BHP), glucuronic acid conjugates of HPOP and BHP, the sulfate ester of HPOP and 14C-labeled urea, all of which are excreted, and 14CO2 which is both incorporated in the urea cycle, and exhaled. The extent of metabolism and the ratios of these metabolites does not vary significantly with age or sex of the animal, however, marked species differences are evident in the metabolite composition of urine 6 h following administration of HPOP. Hamsters sulfate HPOP several times more rapidly, and reduce it to BHP more efficiently than rats. In contrast, the rat excretes more unchanged HPOP and its glucuronic acid conjugate than the hamster. Since sulfation and glucuronidattion of HPOP may be involved in its activation and detoxication, these reactions were examined in detail in order to elucidate the reason(s) for their distinctively different contributions to its metabolism in rats and hamsters. Conjugation of HPOP with glucuronic acid and sulfate occurs in the livers of both rats and hamsters and is catalyzed by microsomal glucuronyl transferases and cyto solic sulfotransferases, respectively. The levels of glucuronyl transferase activity for conjugating phenolic compounds are comparable in the livers of the two species; however, glucuronidation of HPOP is catalyzed by an isozyme the activity of which is three times greater in rat than in the hamster. In contrast to glucuronidation, sulfation of HPOP is catalyzed ˜10 times faster by hamster than rat liver cytosol. Although rat liver can catalyze sulfation of phenolic compounds very effectively, It has low activity in sulfating aliphatic alcohols and β-hydroxynitrosamines. Since both aliphatic alcohols and HPOP are sulfated by hamster liver cytosolic preparations and since these reactions are not significantly affected by the classic phenol sullotransferase inhibitors, it appears that β-hydroxynitrosamines may be sulfated by the aliphatic (hydroxysteroid) sulfotransferase isozymes. The failure of the rat to extensively sulfate HPOP in vivo may be attributed to the high Km of rat hydroxy steroid sulfotransferases for this compound. Of the four isomers of HPOP, only isomer A, in which the nitroso group is syn to the free keto group, is sulfated in vitro to an ap preciable extent. The other three isomers either are not sulfated, or become unst