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Journal de Toxicologie Clinique Et... 1990NDMA, one of the most widely occurring carcinogenic compounds in the environment, is present in human food (meat, vegetables, cheese and alcohol beverages), in drinking... (Review)
Review
NDMA, one of the most widely occurring carcinogenic compounds in the environment, is present in human food (meat, vegetables, cheese and alcohol beverages), in drinking water, in drugs, in cosmetics, in tobacco and its smokes. Furthermore NDMA may be synthesized from nitrates and nitrites and endogen or exogen amines. Since the first observations of MAGEE and BARNES in 1956 on the carcinogenicity of NDMA, this compound was reported to be carcinogenic in a large number of animal species including mammals, birds, amphibia and fish. NDMA requires metabolic activation for its cytotoxic and carcinogenic actions. The major activation step is believed to be the oxygenation of the alpha-carbon catalysed by a Cytochrome P-450-dependent enzyme system commonly know as NDMA-demethylase. Studies on the enzymology of NDMA metabolism show that some Cytochrome P-450 isozymes exhibit significant NDMA-demethylase activity only at high NDMA concentrations. The form of P-450 inducible by factors such as, fasting, diabetes, ethanol consumption and pretreatment with acetone, pyrazole or isopropanol has the higher affinity for NDMA. The gene coding for this isozyme belongs tho the P-450 II E subfamily. Because NDMA-demethylase activity is decreased by monoamine oxidase inhibitors, some authors have suggested a possible role of MAO in NDMA demethylation. This view is not supported by others who don't find evidence for an involvement of MAO in NDMA metabolism. Likewise, there are contradictory reports about the existence of some NDMA demethylase activity in cytosol, nuclei and mitochondria. NDMA demethylation, followed by nonenzymatic cleavage of the hydroxylated methyl group gives formaldehyde and methyldiazohydroxide and then leads to the formation of, a methonium ion, which is able to methylate nucleophilic sites of cellular macromolecules such as, proteins, RNA and DNA. A lot of studies suggest the existence of an alternative pathway to the formation of a methylating agent, denitrosation. Although the nature of mechanisms of denitrosation is not completely known, authors think that the formation of nitrite may represent a detoxification pathway rather than an activation pathway.
Topics: Animals; Biotransformation; Cytochrome P-450 Enzyme System; Dimethylnitrosamine; Humans; Microsomes, Liver; Monoamine Oxidase
PubMed: 2079689
DOI: No ID Found -
Toxicology Jul 1990Dimethylnitrosamine (DMN) has been characterized as a potent hepatotoxin, carcinogen and mutagen. As described below, immunotoxicity should be added to its profile of... (Review)
Review
Dimethylnitrosamine (DMN) has been characterized as a potent hepatotoxin, carcinogen and mutagen. As described below, immunotoxicity should be added to its profile of activity. Although a broad spectrum of immune parameters is affected by DMN, humoral immunity is particularly sensitive. In order for DMN to produce its traditional profile of toxicity it requires metabolic activation to reactive intermediates which alkylate macromolecules. Similarly, DMN also must be metabolized to produce its immunological effects. However, as this review suggests, the metabolism of DMN to an intermediate capable of suppressing the humoral immune response may be qualitatively and/or quantitatively different from that which mediates hepatotoxicity and genotoxicity.
Topics: Animals; Antibody Formation; Biotransformation; Chemical Phenomena; Chemistry; Dimethylnitrosamine; Humans; Immune Tolerance; Immunity, Cellular
PubMed: 2200161
DOI: 10.1016/0300-483x(90)90064-n -
The Oncologist Jun 2020The FDA has ordered the withdrawal of all ranitidine products from the marketplace based on recent findings of increased and unacceptable levels of...
The FDA has ordered the withdrawal of all ranitidine products from the marketplace based on recent findings of increased and unacceptable levels of N‐nitrosodimethylamine (NDMA). This commentary reviews the sources and properties of NDMA, assesses the dangers it poses, and suggests measures to mitigate contamination.
Topics: Dimethylnitrosamine; Humans
PubMed: 32267983
DOI: 10.1634/theoncologist.2020-0142 -
Food and Cosmetics Toxicology Dec 1975
Topics: Dimethylnitrosamine; Food Preservation; Gelatin; Meat; Nitrites; Nitrosamines; Pyrrolidines
PubMed: 1205440
DOI: 10.1016/0015-6264(75)90156-x -
Journal of Forensic Sciences Oct 1980In an 8-h period, five members of two kindred families suddenly became ill with nausea, vomiting, and malaise. This was followed by acute liver disease, a generalized...
In an 8-h period, five members of two kindred families suddenly became ill with nausea, vomiting, and malaise. This was followed by acute liver disease, a generalized bleeding tendency, and a low platelet count. Two of the patients died four and five days after onset of illness. It was established that dimethylnitrosamine had been intentionally added to lemonade and milk that were consumed by the victims.
Topics: Adult; Child, Preschool; Dimethylnitrosamine; Disease Outbreaks; Female; Homicide; Humans; Infant; Liver; Male; Tissue Distribution
PubMed: 7430995
DOI: No ID Found -
Journal of the Science of Food and... Jul 1976
Topics: Animals; Canada; Dimethylnitrosamine; Fish Flour; Fish Products; Fishes; Nitrosamines
PubMed: 986514
DOI: 10.1002/jsfa.2740270703 -
The Annals of Pharmacotherapy Jun 2020-nitrosodimethylamine (NDMA) is a hepatotoxic agent and carcinogen contaminant in commonly used medications such as valsartan, losartan, irbesartan, and ranitidine. NDMA...
-nitrosodimethylamine (NDMA) is a hepatotoxic agent and carcinogen contaminant in commonly used medications such as valsartan, losartan, irbesartan, and ranitidine. NDMA can be produced during manufacture, introduced from contaminated ingredients procured elsewhere, or introduced from contaminated solvents and catalysts. The Food and Drug Administration has established a maximum dose of NDMA that is permissible per tablet and guidance for manufacturers. However, many unanswered questions about NDMA contamination need rigorous investigation.
Topics: Angiotensin Receptor Antagonists; Dimethylnitrosamine; Drug Contamination; Humans; Ranitidine; Tablets; United States; United States Food and Drug Administration
PubMed: 31771343
DOI: 10.1177/1060028019892222 -
The American Journal of Nursing Aug 2020
Topics: Dimethylnitrosamine; Drug Contamination; Histamine H2 Antagonists; Humans; Ranitidine; Safety-Based Drug Withdrawals; United States; United States Food and Drug Administration
PubMed: 32732474
DOI: 10.1097/01.NAJ.0000694552.42987.b0 -
IARC Monographs on the Evaluation of... May 1978
Review
Topics: Animals; Carcinogens; Chemical Phenomena; Chemistry; Dimethylnitrosamine; Female; Food Analysis; Humans; Mutagens; Nitrosamines; Pregnancy
PubMed: 355094
DOI: No ID Found -
Journal of Applied Toxicology : JAT Dec 1984Liver primary cell cultures (LPCC) with decreasing concentrations of cytochrome P-450 were used to investigate the genotoxicity of the hepatic carcinogen...
Liver primary cell cultures (LPCC) with decreasing concentrations of cytochrome P-450 were used to investigate the genotoxicity of the hepatic carcinogen dimethylnitrosamine (DMN) and the correlation between DMN genotoxicity and cytochrome P-450 levels. Hepatocytes were isolated from partially hepatectomized rats and incubated with [3H]thymidine; single-strand DNA molecular weight was determined by alkaline sucrose sedimentation. The molecular weight of DNA decreased 50% in LPCC plated either 2 or 24 h before being treated for 24 h with 70 micron DMN. Cytochrome P-450 content was 188 pmol per mg protein in freshly isolated hepatocytes, whereas it was 70 and 32 pmol per mg protein in hepatocytes that had been cultured 24 and 48 h, respectively. Incorporation of 14C into acid-insoluble material was the same in LPCC exposed 24 h to [14C]DMN starting either 2 or 24 h after cell plating. At non-toxic concentrations (0.01-1 microM), SKF 525-A, an inhibitor of mixed-function oxidase enzymes, inhibited approximately 20% of the binding of 14C from [14C]DMN to acid-insoluble material in LPCC plated either 2 or 24 h before they were exposed to DMN for 24 h. Hepatocyte cultures exposed to the direct-acting alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (at concentrations ranging between 6.8 X 10(-8) and 6.8 X 10(-5) M) starting 2 and 24 h after plating, exhibited significant unscheduled DNA synthesis. These results indicate that DMN genotoxicity was similar in LPCC differing considerably in cytochrome P-450 levels, and they suggest that DMN genotoxicity in these cultures is due mainly to similar DMN activation than to decreased DNA repair.
Topics: Animals; Carbon Radioisotopes; Cells, Cultured; Cytochrome P-450 Enzyme System; DNA; Dimethylnitrosamine; Liver; Male; Methylnitronitrosoguanidine; Mutagens; Proadifen; Rats; Rats, Inbred Strains
PubMed: 6520318
DOI: 10.1002/jat.2550040604