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Comparative metabolism of 2,6-dimethylnitrosomorpholine in rats, hamsters, and guinea pigs
Abstract:
The metabolism of N-[3,5-3H]nitroso-2,6-dimethylmorpholine (NDMM) was studied in female Sprague-Dawley rats. Syrian golden hamsters, and guinea pigs. NDMM induces tumors in the esophagus in rats, pancreatic cancer in hamsters, and hemangioendothelial tumors of the liver in guinea pigs. An intragastric dose of NDMM (2 mg, 2 muCi/animal) was rapidly distributed throughout the tissues of both the rat and hamster, with no apparent accumulation of radioactivity in any one tissue. At low dose levels, NDMM was metabolized rapidly by both species. The hamster appeared to metabolize the compound faster than did the rat or guinea pig. At appreciable amount of radioactivity was excreted in the urine in all three species after 8 hr: approximately 54% in the hamster, 39% in the rat; and 30% in the guinea pig. During the first 24 hr, only a small percentage of the radioactivity excreted by the hamster, rat, and guinea pig was NDMM (0.8, 2, and 0.5%, respectively). High-pressure liquid chromatography analysis of urine collected 24 hr after administration revealed 12 metabolites. Although the urinary metabolites appeared to be similar in all three species, one large difference was the presence of a major urinary metabolite in hamster urine, which was absent or present in only small quantities in the rat and guinea pig. The guinea pig urine also had relatively more radioactivity present in one major fraction than did the hamster or rat.
Insights
The metabolism of N-[3,5-3H]nitroso-2,6-dimethylmorpholine (NDMM) was studied in rats, hamsters, and guinea pigs. Hamsters rapidly metabolized NDMM and excreted more radioactivity in urine, with unique metabolites observed.
Area of Science:
- Toxicology
- Pharmacokinetics
- Comparative Metabolism
Background:
- N-[3,5-3H]nitroso-2,6-dimethylmorpholine (NDMM) is a carcinogen known to induce specific tumors in rats (esophageal), hamsters (pancreatic), and guinea pigs (liver hemangioendothelial).
- Understanding the metabolic fate and excretion pathways of NDMM is crucial for assessing its toxicological profile and interspecies differences in response.
Purpose of the Study:
- To investigate and compare the metabolic pathways and excretion of N-[3,5-3H]nitroso-2,6-dimethylmorpholine (NDMM) in three different species: rats, hamsters, and guinea pigs.
- To identify potential differences in NDMM metabolism that may correlate with species-specific tumor induction.
Main Methods:
- Administration of an intragastric dose of radiolabeled NDMM (2 mg, 2 µCi/animal) to female Sprague-Dawley rats, Syrian golden hamsters, and guinea pigs.
- Monitoring of radioactivity distribution in tissues and quantitative analysis of radioactivity excreted in urine over time.
- High-performance liquid chromatography (HPLC) analysis of urinary metabolites to identify and compare metabolic profiles across species.
Main Results:
- NDMM was rapidly distributed throughout tissues in rats and hamsters with no significant accumulation. Hamsters exhibited faster NDMM metabolism compared to rats and guinea pigs.
- Significant urinary excretion of radioactivity was observed within 8 hours: 54% in hamsters, 39% in rats, and 30% in guinea pigs. Unchanged NDMM constituted a small fraction of excreted radioactivity (<2%) within 24 hours.
- HPLC analysis revealed 12 urinary metabolites, appearing similar across species, but with a distinct major metabolite unique to hamsters. Guinea pig urine showed a higher relative radioactivity in one specific fraction.
Conclusions:
- Species-specific differences in NDMM metabolism and excretion exist, with hamsters showing more rapid metabolism and unique urinary metabolite profiles.
- These metabolic variations may contribute to the observed differences in NDMM-induced carcinogenicity across rats, hamsters, and guinea pigs.
- Further research into the identified metabolites could elucidate mechanisms of NDMM-induced carcinogenesis.