In vivo inhibition of N-nitrosodimethylamine metabolism by 4-methylpyrazole: a model for endogenous nitrosation.
The endogenous formation of N-nitrosodimethylamine (NDMA) was investigated in the ferret by inhibiting metabolism and monitoring urinary NDMA levels. The addition of 1.0 mg/ml of 4-methylpyrazole (4-MP) to the drinking water was sufficient to allow a 13% urinary recovery of a 4.0 nmol oral dose of NDMA to be made in 24 h. Without 4-MP, no NDMA could be detected in urine. There was no detectable urinary NDMA when dimethylamine (DMA) alone was given but when as little as 5 mumol of nitrite and 0.75 mmol of DMA were given, the urine contained approximately 0.3 nmol NDMA/day. Nitrite doses of 0-100 mumol along with 0.75 mmol of DMA resulted in a dose-dependent excretion of less than 0.1-2.5 nmol NDMA/day. When 10 mumol of aminopyrine was substituted for DMA and 40 mumol of nitrite given, the excretion of NDMA was 10 nmol day. Administration of ascorbic acid inhibited NDMA excretion and thiocyanate increased NDMA formation. Consumption of foods containing trace amounts of NDMA resulted in the excretion of NDMA but in most cases at levels that were lower than those ingested in the food. These data suggest that mumol amounts of nitrite can result in the endogenous formation of nmol amounts of NDMA in the acidic environment of the stomach. It also suggests that short-term ingestion of 4-MP might be an approach to studying the possible endogenous formation of NDMA in humans.
Perciballi
M
M
Institute for Comparative and Environmental Toxicology, Cornell University, Ithaca, NY 14853.
Hotchkiss
J H
JH
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001711:Biotransformation; D002849:Chromatography, Gas; D004032:Diet; D004128:Dimethylnitrosamine / Q000378:metabolism*; D005289:Ferrets; D000077604:Fomepizole; D008297:Male; D009573:Nitrites / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D013861:Thiocyanates / Q000494:pharmacology
D009573:Nitrites; D011720:Pyrazoles; D013861:Thiocyanates; D000077604:Fomepizole; D004128:Dimethylnitrosamine; D001205:Ascorbic Acid