Deuterium isotope effect on metabolism of N-nitrosodimethylamine in vivo in rat
The maximal rates of metabolic oxidation of N-nitrosodimethylamine (NDMA) and N-nitrosodimethylamine-d6 (NDMA-d6) in vivo (VH and VD, respectively) have been measured by following 14CO2 exhalation in rats after intraperitoneal injection of the two 14C-labelled carcinogens at high doses (20 or 40 mg/kg). Complete deuteration of NDMA reduced only slightly the maximal rate of metabolism when the two substrates were administered separately (VH/VD approximately 1.2). However, much larger (approximately 4-fold) deuterium isotope effects were observed when mixtures of NDMA with NDMA-d6 were injected. These results are tentatively interpreted as evidence that C-H bond cleavage is not a rate limiting feature of overall metabolism, but that the complex between NDMA and the principal enzyme(s) metabolizing it in vivo freely equilibrates with unbound substrate. Single, large, intraperitoneal doses of NDMA and NDMA-d6 produced a similar alkylation of rat liver DNA and also of kidney DNA. However, a small oral dose (54 micrograms/kg) of NDMA-d6 produced 1/3 less alkylation of liver DNA and 3 times as much alkylation of kidney DNA as did an equimolar dose of NDMA. The reduction in alkylation of liver DNA correlates well with, and possibly explains, the decreased ability of NDMA-d6 to induce liver tumors in rats. The associated increase in the alkylation of kidney DNA suggests that this change is due to a decrease in the amount of nitrosamine removed from the portal blood on the first pass through the liver.
- Research Organization:
- Courtauld Institute of Biochemistry, Middlesex Hospital Medical School, London, UK
- OSTI ID:
- 5715364
- Journal Information:
- Carcinogenesis (N.Y.); (United States), Journal Name: Carcinogenesis (N.Y.); (United States) Vol. 4:7; ISSN CRNGD
- Country of Publication:
- United States
- Language:
- English
Similar Records
Administration of N-nitrosodimethylamine, N-nitrosopyrrolidine, or N'-nitrosonornicotine to nursing rats: their interactions with liver and kidney nucleic acids from sucklings
Inhibition of methylation of DNA by dimethylnitrosamine (DMN) in dehydroepiandrosterone-fed rats
Related Subjects
560305 -- Chemicals Metabolism & Toxicology-- Vertebrates-- (-1987)
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AMINES
ANIMALS
BODY
CARBON 14 COMPOUNDS
CARBON COMPOUNDS
CARBON DIOXIDE
CARBON OXIDES
CARCINOGENESIS
CHALCOGENIDES
CHROMATOGRAPHY
DEUTERIUM COMPOUNDS
DIGESTIVE SYSTEM
DNA
ENZYME ACTIVITY
FEMALES
GLANDS
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
ISOTOPE EFFECTS
KIDNEYS
LABELLED COMPOUNDS
LIQUID COLUMN CHROMATOGRAPHY
LIVER
MAMMALS
METABOLISM
NITROSAMINES
NITROSO COMPOUNDS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
OXIDES
OXYGEN COMPOUNDS
PATHOGENESIS
RATS
RESPIRATION
RODENTS
SEPARATION PROCESSES
TRACER TECHNIQUES
VERTEBRATES