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Molecules (Basel, Switzerland) Nov 2020A GC-MS/MS method with EI ionization was developed and validated to detect and quantify -nitrosodimethylamine (NDMA) and seven other nitrosamines in 105 samples of...
A GC-MS/MS method with EI ionization was developed and validated to detect and quantify -nitrosodimethylamine (NDMA) and seven other nitrosamines in 105 samples of metformin tablets from 13 different manufactures. Good linearity for each compound was demonstrated over the calibration range of 0.5-9.5 ng/mL. The assay for all substances was accurate and precise. NDMA was not detected in the acquired active pharmaceutical ingredient (API); however, NDMA was detected in 64 (85.3%) and 22 (91.7%) of the finished product and prolonged finished product samples, respectively. European Medicines Agency recommends the maximum allowed limit of 0.032 ppm in the metformin products. Hence, 28 finished products and 7 pronged dosage products were found to exceed the acceptable limit of daily intake of NDMA contamination. The implications of our findings for the testing of pharmaceutical products are discussed.
Topics: Artifacts; Calibration; Dimethylnitrosamine; Drug Contamination; Drug Design; Europe; Gas Chromatography-Mass Spectrometry; Limit of Detection; Linear Models; Metformin; Pharmaceutical Preparations; Powders; Solvents; Tablets; Tandem Mass Spectrometry; Temperature
PubMed: 33202951
DOI: 10.3390/molecules25225304 -
British Journal of Experimental... Apr 1977A Porton and a hooded rat strain showed a raised LD50 for dimethylnitrosamine (DMN) when pre-conditioned on a protein-free and/or a sugar diet. Little or no such...
The effect of a protein-free diet, a sugar diet and of carbon tetrachloride administration on the toxicity and rate of metabolism of dimethylnitrosamine in different rat strains.
A Porton and a hooded rat strain showed a raised LD50 for dimethylnitrosamine (DMN) when pre-conditioned on a protein-free and/or a sugar diet. Little or no such differential toxicity between normal and diet-fed animals was found for rats of the Wistar, BDIX and CFY strains. Pre-treatment with CCl4 did not alter significantly the toxicity of DMN in the Wistar strain. All 5 rat strains treated by diet or CCl4 administration metabolized DMN at a very much slower rate than did the controls, the rates for the different strains being quantitatively similar. It is concluded that the toxicity of DMN is not necessarily related to its rate of metabolism and that the effect of diet or CCl4 treatment of DMN toxicity is dependent on the strain of rat used.
Topics: Animals; Carbon Tetrachloride; Dietary Carbohydrates; Dimethylnitrosamine; Nitrosamines; Protein Deficiency; Rats; Rats, Inbred Strains
PubMed: 861170
DOI: No ID Found -
Journal of Hazardous Materials May 2023N-nitrosamines are formed during different industrial processes and are of significant concern due to their carcinogenic and mutagenic properties. This study reports...
N-nitrosamines are formed during different industrial processes and are of significant concern due to their carcinogenic and mutagenic properties. This study reports concentrations of N-nitrosamines in eight different industrial wastewater treatment plants in Switzerland and the variability of their abundance. Only four N-nitrosamines species, N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodibutylamine (NDPA) and N-nitrosomorpholine (NMOR) were above the limit of quantification in this campaign. Remarkably high concentrations (i.e. up to 975 μg NDMA/L, 90.7 μg NDEA/L, 1.6 μg NDPA/L and 710 μg NMOR/L) of these N-nitrosamines were detected at seven of eight sites. These concentrations are two to five orders of magnitude higher than those typically detected in municipal wastewater effluents. These results suggest that industrial effluents may be a major source of N-nitrosamines. Although very high concentrations of N-nitrosamine have been detected in industrial discharges, various processes in surface water can partially mitigate their concentrations (e.g. photolysis, biodegradation and volatilization) and hence the risk to human health and aquatic ecosystems. Nevertheless, there is little information on long-term effects on aquatic organisms and therefore the discharge of N-nitrosamines to the environment should be avoided until the impact on ecosystems is assessed. During winter a less efficient mitigation of N-nitrosamines can be expected (lower biological activity, less sunlight) and therefore, emphasis should be put on this season in future risk assessment studies.
Topics: Humans; Switzerland; Ecosystem; Nitrosamines; Dimethylnitrosamine; Diethylnitrosamine
PubMed: 36867906
DOI: 10.1016/j.jhazmat.2023.131094 -
Archives of Toxicology Jun 2024Dietary exposure to N-nitrosamines has recently been assessed by the European Food Safety Authority (EFSA) to result in margins of exposure that are conceived to...
Dietary exposure to N-nitrosamines has recently been assessed by the European Food Safety Authority (EFSA) to result in margins of exposure that are conceived to indicate concern with respect to human health risk. However, evidence from more than half a century of international research shows that N-nitroso compounds (NOC) can also be formed endogenously. In this commentary of the Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG), the complex metabolic and physiological biokinetics network of nitrate, nitrite and reactive nitrogen species is discussed with emphasis on its influence on endogenous NOC formation. Pioneering approaches to monitor endogenous NOC have been based on steady-state levels of N-nitrosodimethylamine (NDMA) in human blood and on DNA adduct levels in blood cells. Further NOC have not been considered yet to a comparable extent, although their generation from endogenous or exogenous precursors is to be expected. The evidence available to date indicates that endogenous NDMA exposure could exceed dietary exposure by about 2-3 orders of magnitude. These findings require consolidation by refined toxicokinetics and DNA adduct monitoring data to achieve a credible and comprehensive human health risk assessment.
Topics: Humans; Risk Assessment; Nitrosamines; Dietary Exposure; Dimethylnitrosamine; DNA Adducts; Food Contamination; Food Safety; Animals; Nitrites; Nitrates; Reactive Nitrogen Species
PubMed: 38573336
DOI: 10.1007/s00204-024-03726-1 -
BMC Gastroenterology Nov 2015Liver sinusoidal endothelial cells (SECs), hepatic stellate cells (HSCs) and Kupffer cells (KCs) are involved in the development of liver fibrosis and represent a...
BACKGROUND/AIMS
Liver sinusoidal endothelial cells (SECs), hepatic stellate cells (HSCs) and Kupffer cells (KCs) are involved in the development of liver fibrosis and represent a potential therapeutic target. The therapeutic effects on liver fibrosis of sorafenib, a multiple tyrosine kinase inhibitor, and gadolinium chloride (GdCl3), which depletes KCs, were evaluated in rats.
METHODS
Liver fibrosis was induced in rats with dimethylnitrosamine, and the effects of sorafenib and/or GdCl3 in these rats were monitored. Interactions among ECs, HSCs and KCs were assessed by laser confocal microscopy.
RESULTS
The combination of sorafenib and GdCl3, but not each agent alone, attenuated liver fibrosis and significantly reduced liver function and hydroxyproline (Hyp). Sorafenib significantly inhibited the expression of angiogenesis-associated cell markers and cytokines, including CD31, von Willebrand factor (vWF), and vascular endothelial growth factor, whereas GdCl3 suppressed macrophage-related cell markers and cytokines, including CD68, tumor necrosis factor-α, interleukin-1β, and CCL2. Laser confocal microscopy showed that sorafenib inhibited vWF expression and GdCl3 reduced CD68 staining. Sorafenib plus GdCl3 suppressed the interactions of HSCs, ECs and KCs.
CONCLUSION
Sorafenib plus GdCl3 can suppress collagen accumulation, suggesting that this combination may be a potential therapeutic strategy in the treatment of liver fibrosis.
Topics: Angiogenic Proteins; Animals; Anti-Inflammatory Agents; Cytokines; Dimethylnitrosamine; Drug Therapy, Combination; Gadolinium; Hepatic Stellate Cells; Hepatocytes; Hydroxyproline; Kupffer Cells; Liver; Liver Cirrhosis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Rats; Rats, Wistar; Sorafenib
PubMed: 26572488
DOI: 10.1186/s12876-015-0380-5 -
Environmental Health Perspectives Mar 1993Investigation of urinary markers as indices of endogenous nitrosation and of gastric cancer etiology has been a major focus of our work. As part of this effort, studies... (Review)
Review
Investigation of urinary markers as indices of endogenous nitrosation and of gastric cancer etiology has been a major focus of our work. As part of this effort, studies have been carried out on a Colombian population at high risk for gastric cancer. In this group, nitrosoproline excretion was highly correlated with nitrate excretion in the subpopulation with advanced gastric pathology, but not in control subpopulations with more normal stomachs. Neither urinary 7-methylguanine nor 3-methyladenine was strongly related to gastric pathology or to urinary nitrate or nitrosoproline levels. More recently, as evidence has accumulated concerning the importance of nitric oxide as a cellular messenger, we have begun research toward developing markers for the presence of nitric oxide and for endogenous nitrosation via this compound. Nitric oxide is formed from arginine by activated endothelial cells as a messenger for vasodilation. We have shown that prolonged exercise leads to increased urinary nitrate and that when 15N-arginine is ingested by humans, 15N-nitrate levels increase in 24-hr urine collections. Nitrosohydroxyethylglycine and 3-nitrotyrosine were evaluated as indices for the formation of N-nitrosomorpholine and for the nitration of protein, respectively, under experimental conditions (e.g., immunostimulation) expected to enhance nitric oxide formation. Nitrotyrosine has not proved useful as a biomarker for nitration/nitrosation reactions in immunostimulated rats. Immunostimulation of rats following administration of morpholine led to increases in urinary nitrate and nitrosohydroxyethylglycine. This procedure, however, would not be appropriate for humans due to the toxicity of morpholine and the carcinogenicity of N-nitrosomorpholine.
Topics: Adenine; Alkylating Agents; Animals; Biomarkers; DNA Damage; Dimethylnitrosamine; Humans; Nitric Oxide; Nitrosamines; Nitroso Compounds; Risk Factors; Stomach Neoplasms; Tyrosine
PubMed: 8319614
DOI: 10.1289/ehp.9399155 -
Biomedicine & Pharmacotherapy =... Jul 2022Osteopontin (OPN) is a matricellular cytokine and a stress-induced profibrogenic molecule that promotes activation of stellate cells during the pathogenesis of hepatic...
Osteopontin (OPN) is a matricellular cytokine and a stress-induced profibrogenic molecule that promotes activation of stellate cells during the pathogenesis of hepatic fibrosis. We studied the protective effects of epigallocatechin-3-gallate (EGCG) to suppress oxidative stress, inhibit OPN expression, and prevent experimentally induced hepatic fibrosis. Liver injury was induced with intraperitoneal injections of N-nitrosodimethylamine (NDMA) in a dose of 1 mg/100 g body weight on 3 consecutive days of a week for 28 days. A group of rats received 0.2 mg EGCG/100 g body weight orally everyday during the study. The animals were sacrificed on day 28th from the beginning of exposure. Serum levels of AST, ALT, OPN, malondialdehyde, collagen type IV, and hyaluronic acid were measured. Immunohistochemistry and/or real-time PCR were performed for α-SMA, 4-HNE, OPN, collagen type I, and type III. Serial administrations of NDMA produced well developed fibrosis and early cirrhosis in rat liver. Treatment with EGCG significantly reduced serum/plasma levels of AST, ALT, OPN, malondialdehyde, collagen type IV, and hyaluronic acid and prevented deposition of collagen fibers in the hepatic tissue. Protein and/or mRNA levels demonstrated marked decrease in the expression of α-SMA, 4-HNE, OPN, collagen type I, and type III. Treatment with EGCG prevented excessive generation of reactive oxygen species, suppressed oxidative stress, significantly reduced serum and hepatic OPN levels, and markedly attenuated hepatic fibrosis. The results indicated that EGCG could be used as a potent therapeutic agent to prevent hepatic fibrogenesis and related adverse events.
Topics: Animals; Body Weight; Catechin; Collagen Type I; Collagen Type IV; Dimethylnitrosamine; Fibrosis; Hepatic Stellate Cells; Hyaluronic Acid; Liver; Liver Cirrhosis; Malondialdehyde; Osteopontin; Rats
PubMed: 35594711
DOI: 10.1016/j.biopha.2022.113111 -
Proceedings of the Royal Society of... Oct 1975
Topics: Animals; Diethylstilbestrol; Dimethylnitrosamine; Female; Fetal Diseases; Humans; Infant, Newborn; Maternal-Fetal Exchange; Neoplasms; Neoplasms, Radiation-Induced; Placenta; Pregnancy; Radiography; Rats; Vaginal Neoplasms
PubMed: 1208519
DOI: No ID Found -
Asian Pacific Journal of Cancer... Sep 2022Cholangiocarcinoma (CCA) is a highly aggressive tumor with a greater risk of distant metastasis. The promising anti-CCA activity and safety profile of Atractylodes...
OBJECTIVES
Cholangiocarcinoma (CCA) is a highly aggressive tumor with a greater risk of distant metastasis. The promising anti-CCA activity and safety profile of Atractylodes lancea (AL) have previously been reported in a series of in vitro, in vivo and clinical studies. The present study investigated the effect of AL extract on apoptosis and metastasis signaling pathways in the Opisthorchis viverrini/dimethylnitrosamine (OV/DMN)-induced CCA hamster model.
MATERIALS AND METHODS
Hamster liver tissues were obtained from the four groups (n = 5 per group), i.e., (i) 5-FU treated CCA (40 µg/mL); (ii) CCA; (iii) AL-treated CCA (5,000 mg/kg), and (iv) normal hamsters. Total RNA was isolated, and the expression levels of apoptosis-related and metastasis-related genes were determined by qRT-PCR analysis.
RESULTS
The expression levels of p16, caspase-3, caspase-8, caspase-9, Apaf-1, p53 and Eef1a1 were downregulated, while that of the remaining genes were upregulated in CCA hamsters compared with normal hamsters. AL treatment increased the expression of p16, caspase-9, caspase-3, Apaf-1, p53 and E-cadherin and decreased the expression of cyclin D1, cdk4, Bax, Akt/PKB, Bcl-2, Mfge-8, Lass4, S100A6, TGF-β, Smad-2, Smad-3, Smad-4, MMP-9, and N-cadherin. The expression of Eef1a1 was unchanged.
CONCLUSION
The anti-CCA activity of AL in OV/DMN-induced CCA hamsters could be due to the induction of cell cycle arrest at the G1 phase and activation of the apoptosis pathway, resulting in cancer cell death. The activation of the apoptosis pathway mainly involved the intrinsic pathway (activation of caspase-3 and caspase-9 through p53 and Mfge-8 modulation and downregulation of anti-apoptotic genes Akt and Bcl-2). In addition, AL could also inhibit the canonical TGF-β signaling pathway, MMP-9 and N-cadherin to suppress tumor metastasis.
Topics: Animals; Atractylodes; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cadherins; Caspase 3; Caspase 8; Caspase 9; Cholangiocarcinoma; Cricetinae; Cyclin D1; Dimethylnitrosamine; Fluorouracil; Humans; Matrix Metalloproteinase 9; Mesocricetus; Opisthorchiasis; Opisthorchis; Plant Extracts; Proto-Oncogene Proteins c-akt; RNA; Transforming Growth Factor beta; Tumor Suppressor Protein p53; bcl-2-Associated X Protein
PubMed: 36172672
DOI: 10.31557/APJCP.2022.23.9.3093 -
The Biochemical Journal Sep 19711. Rats fed on a protein-free high-carbohydrate diet for 7 days metabolized dimethylnitrosamine at only 55% the rate of rats fed on a commercial diet. 2....
1. Rats fed on a protein-free high-carbohydrate diet for 7 days metabolized dimethylnitrosamine at only 55% the rate of rats fed on a commercial diet. 2. Dimethylnitrosamine was metabolized by liver slices from rats fed on the protein-free diet at less than half the rate attained by slices from rats fed on a commercial diet. But kidney slices from these rats metabolized dimethylnitrosamine at the same rate as kidney slices from rats on a commercial diet. 3. Methylation by dimethylnitrosamine (70mg/kg body wt.) of N-7 of guanine of the liver RNA and DNA of rats fed on a protein-free diet was only slightly higher than in rats fed on a normal diet given 27mg/kg body wt. In contrast, the methylation by dimethylnitrosamine of guanine in kidney nucleic acids of these rats was three times that in the rats fed on a normal diet. 4. In rats fed on a protein-free diet the incidence of kidney tumours produced by a single dose of dimethylnitrosamine is increased.
Topics: Animals; DNA; Dietary Carbohydrates; Dietary Proteins; Guanine; Kidney; Kidney Neoplasms; Liver; Male; Methylation; Neoplasms, Experimental; Nitrosamines; RNA; Rats; Time Factors
PubMed: 5158489
DOI: 10.1042/bj1240283