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

Abstract

Hamsters and rats metabolize [1-14C]N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) and N-nitrosobis(2-oxopropyl)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 glucuronidation 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 cytosolic sulfotransferases, respectively. The levels of glucuronyl transferase activity for conjugating phenolic compounds are comparable in the livers of 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 approximately 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 beta-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 sulfotransferase inhibitors, it appears that beta-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 hydroxysteroid 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 appreciable extent. The other three isomers either are not sulfated, or become unstable and decompose when they undergo such a reaction.(ABSTRACT TRUNCATED AT 400 WORDS)

Hydrolysis of 3,4-methylenedioxymethamphetamine (MDMA) metabolite conjugates in human, squirrel monkey, and rat plasma

“…Boettcher et al [37], when comparing rats and humans, found that in rats, the sulfate conjugation of antipyrine was the predominant pathway, whereas in humans, antipyrine glucuronides were most prominent, with the sulfate formation being dose-dependent. Kokkinakis et al [38], for example, found that N -nitroso(2-hydroxy-propyl)(2-oxopropyl) amine in hamsters is conjugated with sulfuric acid ten times faster than in rats, where the glucuronic acid conjugates are predominant. Wong [39] found that sulfate conjugation of 4-hydroxy-3-methoxyphe-nylethanol is predominant in most animal species such as mouse, cat, rat, rabbit, and guinea-pig, whereas in humans, only the glucuronide was detected.…”

Dose‐ and Sex‐related Carcinogenesis by N‐Bis(2‐hydroxypropyl)nitrosamine in Wistar Rats

“…Differences in quantitative and/or qualitative metabolic degradation, route of administration, variations in strain-related enzymatic activation and other intrinsic factors might be involved in determining target organ specificity and susceptibility. 32) In line with the low incidence of preneoplastic lesions, no tumors were found in the selected organs of male or female 0.1% DHPN-treated Wistar rats. Hasegawa et al 20) and Yoshida et al 27) respectively reported incidences of 100% and 20% of neoplasias in the lung and of 5% and 7% in the thyroid gland in F344 male rats exposed to 0.1% DHPN.…”

Labeling of albumin secreted from isolated rat hepatocytes during the metabolism of N-nitrosodimethyl- and N-nitrosodiethylamine

“…Although glucuronic acid conjugation is generally considered to be a detoxifying metabolic pathway, it has been suggested that it may play a role in the activation of nitrosamine carcinogens (31). The formation of glucuronides of hydroxylated nitrosamines has also been reported by Wiessler and Rossnagel (32), Suzuki and Okada (33), and Kokkinakis and co-workers (34,35).…”