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The Journal of Surgical Research Aug 2008Nitrosamines are associated with the potential to induce cancer in the digestive tract. Ethanol has also been shown to enhance the effects of nitrosamine-induced...
BACKGROUND
Nitrosamines are associated with the potential to induce cancer in the digestive tract. Ethanol has also been shown to enhance the effects of nitrosamine-induced carcinogenesis. The aim of this study was to investigate a murine model of the prevalence and types of epithelial lesions induced in the stomach by diethylnitrosamine (DEN), and to evaluate the influence of ethanol and N'-nitrosonornicotine (NNN) as promoters of gastric carcinogenesis.
MATERIALS AND METHODS
Two hundred eight (n = 208) mice were distributed into five groups and administered either water (G1), DEN+water (G2), DEN+NNN (G3), DEN+Ethanol (G4), or DEN+NNN+Ethanol (G5) for a period of 180 days. Mice were sacrificed; their stomachs were sectioned and stained with hematoxylin/eosin. Stomachs were analyzed for normal histology; foveolar hyperplasia; gastritis; ulcer; adenoma; metaplasia; dysplasia; squamous-cell cancer (SCC); and adenocarcinoma (ACA).
RESULTS
One hundred eighty-four (N = 184) specimens were studied. No statistically significant differences were observed between the average DEN consumption of groups (P > 0.05). Unlike G1, in all four groups exposed to carcinogens, gastric SCC and ACA were induced (P < 0.001). SCC was identified in 91 (49.5%) and ACA in 77 (41.8%) of all mice (including controls). In 47 mice (25.5%), we identified two histological types of carcinoma that occurred simultaneously. The prevalence of ACA in G5 was higher when compared with the other exposed groups (P < 0.001).
CONCLUSIONS
We created an optimal murine model for investigation of the development of gastric carcinogenesis, as there was a high rate of development of tumors, but low mortality and morbidity. The coadministration of DEN, ethanol, and NNN induced carcinogenesis to the largest extent compared with the other combinations.
Topics: Adenocarcinoma; Animals; Carcinogens; Carcinoma, Squamous Cell; Diethylnitrosamine; Disease Models, Animal; Epithelium; Ethanol; Female; Mice; Mice, Inbred Strains; Nitrosamines; Stomach Neoplasms
PubMed: 18456281
DOI: 10.1016/j.jss.2007.12.748 -
Organic & Biomolecular Chemistry Oct 2021The mechanism-based mutagenicity and carcinogenicity of diethylnitrosamine (DEN) are believed to act through interactions with cytochrome P450 (P450) enzymes. DFT...
The mechanism-based mutagenicity and carcinogenicity of diethylnitrosamine (DEN) are believed to act through interactions with cytochrome P450 (P450) enzymes. DFT calculations to explore the conceivable mechanisms underlying the reaction of P450 with DEN with and without water as a biocatalyst were performed. The results shed light on the biocatalytic role of water in lowering the H-abstraction energy barriers because of the electrostatic effect driven by hydrogen bonding. Our DFT analysis revealed how metabolites are formed in the dealkylation (toxification) and denitrosation (detoxification) pathways. Also, our findings uncovered the active position of DEN vulnerable to P450 interactions. Two factors control the toxification and detoxification rates: the stability of denitrosation products and the HS rebound barrier of the α-pathway. Thus, water biocatalytic attenuation of DEN carcinogenicity was attained by stabilizing denitrosation products and slowing the α-HS rebound process. Docking and MD simulations were performed to assess the binding modes of DEN to P450's active site and to inspect the denitrosation and dealkylation processes, respectively.
Topics: Diethylnitrosamine
PubMed: 34613323
DOI: 10.1039/d1ob01439k -
IARC Monographs on the Evaluation of... 2000
Review
Topics: Animals; Carcinogenicity Tests; Carcinogens; Cricetinae; Diethylnitrosamine; Disease Models, Animal; Environmental Exposure; Female; Humans; Male; Mice; Neoplasms; Rats
PubMed: 11100409
DOI: No ID Found -
Tissue & Cell Feb 2024To construct a new diethylnitrosamine (DEN)-induced rat hepatocellular carcinoma (HCC) model with short induction time, high incidence, and survival rate.
OBJECTIVE
To construct a new diethylnitrosamine (DEN)-induced rat hepatocellular carcinoma (HCC) model with short induction time, high incidence, and survival rate.
METHODS
60 male Sprague-Dawley rats were randomly divided into 4 groups: the control group, the model A (MA) group, the model B (MB) group, and the model C (MC) group. The control group was intraperitoneally injected with 0.9% saline for 6 weeks. The MA group was injected with the DEN solution at 30 mg/kg three times a week for 6 weeks. The MB group was injected with the DEN solution at 30 mg/kg three times a week for 6 weeks, and discontinued the induction for 2 weeks. The MC group was injected with the DEN solution at 30 mg/kg three times a week for 8 weeks. The levels of albumin (ALB), alanine transaminase (ALT), and aspartate aminotransferase (AST) in serum were assayed. Meanwhile, the pathological conditions, apoptosis of hepatocytes, expression of NF-κBp65, and the reactive oxygen species level were detected.
RESULTS
All rats in the control group and the MA group survived, and none of the rats occurred HCC. HCC occurred in rats of the MB group and the MC group. The serum ALB level in the MB group was higher than that in the MC group. The serum ALT and AST levels and the number of proliferating and apoptotic hepatocyte cells in the MB group were lower than those in the MC group. The expression of ROS- and NF-κBp6- positive cells in the MA group, MB group, and MC group were significantly higher than that of the control group.
CONCLUSION
This study developed a new DEN-induced rat HCC model with short induction time, high incidence, and survival rate. NF-κB pathway may be one of the main pathways involved in the development of this model.
Topics: Rats; Male; Animals; Carcinoma, Hepatocellular; Liver; Liver Neoplasms; Rats, Sprague-Dawley; Diethylnitrosamine
PubMed: 37951061
DOI: 10.1016/j.tice.2023.102261 -
Drug and Chemical Toxicology Nov 2019The effect of chlormethiazole (CMZ) at single and multiple doses on the toxicokinetics of diethylnitrosamine (DEN) was investigated in normal rats and those with...
The effect of chlormethiazole (CMZ) at single and multiple doses on the toxicokinetics of diethylnitrosamine (DEN) was investigated in normal rats and those with DEN-induced liver fibrosis. Twelve rats were treated with DEN (50 mg/kg) alone and in combination with a single dose of CMZ (10, 50, or 100 mg/kg) by intraperitoneal (i.p.) injection. In a multiple dose test, six rats were treated with CMZ (50 mg/kg) for 7 d with addition of DEN (50 mg/kg) on days 1 and 7. Lastly, 12 rats were treated with DEN (50 mg/kg) by i.p. injection twice a week for 4 consecutive weeks, followed by weekly injections for another 8 weeks to build the model of liver fibrosis. Following this induction, the 12 rats were given CMZ (50 mg/kg) combined with DEN (50 mg/kg) to study the inhibitory effect of CMZ on DEN metabolism in hepatofibrotic rats. Serial blood samples were also collected and analyzed by a validated high-performance liquid chromatography (HPLC) method. A single-dose CMZ treatment decreased DEN clearance (CL), prolonged the , and increased the 'area under the curve' (AUC) for DEN in normal and hepatofibrotic rats relative to rats that did not receive CMZ. Treatment with CMZ for 7 d further prolonged the for DEN but did not alter the CL and AUC relative to a single CMZ treatment. These results suggest that CMZ significantly inhibits the metabolism of DEN in normal and hepatofibrotic rats.
Topics: Animals; Area Under Curve; Chlormethiazole; Chromatography, High Pressure Liquid; Diethylnitrosamine; Dose-Response Relationship, Drug; Half-Life; Liver Cirrhosis; Male; Rats; Rats, Sprague-Dawley
PubMed: 29648470
DOI: 10.1080/01480545.2018.1455204 -
Journal of Environmental Pathology,... 1985Rivulus marmoratus were exposed to 0, 10, 21, 45, 95, or 200 mg/liter diethylnitrosamine (DEN) for 6 weeks and examined 12 weeks after the end of exposure. Fatty change,...
Rivulus marmoratus were exposed to 0, 10, 21, 45, 95, or 200 mg/liter diethylnitrosamine (DEN) for 6 weeks and examined 12 weeks after the end of exposure. Fatty change, hepatocellular glycogenosis, multiple basophilic foci, enlarged and distorted cells with or without an enlarged nucleus, and hyaline bodies and cytological alterations observed after exposure to DEN. Hemangiomas, cholangiomas, biliary cystadenomas, and glandular, trabecular and anaplastic hepatocellular carcinomas were observed at the 18th week. Only those fish exposed to 95 mg/liter DEN had cavernous hemangiomas and peliosis-like lesions, which could be a preneoplastic lesion preceding cavernous hemangiomas. Adenomatous hyperplasia of thyroid and granulomas were other chronic reactions caused by DEN toxicosis.
Topics: Animals; Carcinogens, Environmental; Diethylnitrosamine; Fishes; Liver; Liver Neoplasms; Necrosis
PubMed: 4078690
DOI: No ID Found -
IARC Monographs on the Evaluation of... May 1978
Review
Topics: Animals; Carcinogens; Chemical Phenomena; Chemistry; Diethylnitrosamine; Female; Food Analysis; Humans; Mutagens; Nitrosamines; Pregnancy
PubMed: 355108
DOI: No ID Found -
Environmental Research Jun 1983Carcinogenic N-nitrosodiethanolamine has been found at concentrations varying from 15 to 5700 mg/liter in several leading French brands of antifreeze. Moreover, mixtures... (Comparative Study)
Comparative Study
Carcinogenic N-nitrosodiethanolamine has been found at concentrations varying from 15 to 5700 mg/liter in several leading French brands of antifreeze. Moreover, mixtures of antifreezes which, separately, are innocuous, can form this nitrosamine which appears to arise from interaction of triethanolamine derivatives with sodium nitrite. It is recommended that sodium nitrite be abandoned as an anticorrosion additive.
Topics: Carcinogens; Chromatography, High Pressure Liquid; Diethylnitrosamine; Ethylene Glycols; Nitrosamines
PubMed: 6851985
DOI: 10.1016/0013-9351(83)90064-6 -
Applied Biochemistry and Biotechnology Oct 2023Thunbergia erecta L. contains cytotoxic and liver-protective compounds. Thunbergia erecta L. leaves were macerated in 70% aqueous ethanol, then fractionated with ethyl...
Thunbergia erecta L. contains cytotoxic and liver-protective compounds. Thunbergia erecta L. leaves were macerated in 70% aqueous ethanol, then fractionated with ethyl acetate (9.3 g) and butanol (12.7 g), and attenuated Den-induced liver cancer in a Wistar rat experimental model. Ethyl acetate and butanol fractions were chromatographed using column chromatography and solid-phase extraction (SPE); Vicenin-II (1), kaempferol (2), biochanin A, sissotrin 7-O-β-glucopyranoside (3), gentianose (4), acacetin 7-O-β-glucopyranoside (5), apigenin 7-O-β-glucopyranoside (6), and rosmarinic acid (7) were extracted, and their structures were determined using NMR spectroscopy and ESI-mass spectrometry. Sixty rats were divided into six groups (ten each): control group, Den group, doxorubicin/Den-treated group, butanol fraction/Den-treated group, and isolated acacetin 7-O-β-glucopyranoside/Den-treated group. The liver enzymes and proinflammatory biomarkers were used to estimate the liver function. In addition, liver tissues were collected for analysis of oxidative stress markers, gene expression, and histopathology. There is a significant increase in the levels of liver enzymes, AFP, and TNF-ἁ. This was conveyed by a significant increase of IL-1 and caspase-3, elevation of MDA and reduction of GSH, and suppression of Bcl2 and elevation of Bax expression. All parameters in butanol, ethyl acetate fractions, and isolated acacetin 7-O-β-glucopyranoside (major constituents) of T. erecta L. were significantly improved to values close to those of the control group.
Topics: Rats; Animals; Diethylnitrosamine; Rats, Wistar; Liver; Plant Leaves; Carcinogenesis; Butanols
PubMed: 36708488
DOI: 10.1007/s12010-022-04292-x -
Biological Trace Element Research Jan 2020The catalytic activity of cerium oxide nanoparticles (CeO2NPs) is responsible for its application as an antitumor agent. This activity may be due to its ability to...
The catalytic activity of cerium oxide nanoparticles (CeO2NPs) is responsible for its application as an antitumor agent. This activity may be due to its ability to switch between III and IV oxidation states thereby conferring pro- and antioxidant properties. This study was designed to assess the hepatoprotective potential of CeO2NPs in male BALB/c mice administered diethylnitrosamine (DEN). Thirty-six mice were divided equally into six groups and treated intraperitoneally with normal saline (control), DEN (200 mg/kg) alone, CeO2NPs 1 (100 μg/kg) + DEN (200 mg/kg), CeO2NPs 2 (200 μg/kg) + DEN (200 mg/kg), CeO2NPs 1 alone, and CeO2NPs 2 alone. Animals were pretreated with CeO2NPs daily for eight consecutive days, while DEN was administered 48 h before the animals were sacrificed. Administration of DEN caused a significant increase in serum alanine aminotransferase (ALT) and urea by 51% and 96%, respectively. Markers of oxidative stress (malondialdehyde) and inflammation (nitric oxide and myeloperoxidase) in hepatic tissues of DEN-treated mice were increased by 60%, 16%, and 38%, respectively. The activities of hepatic superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and level of reduced glutathione were significantly decreased in DEN-treated mice by 50%, 123%, 23%, 419%, and 78%, respectively. In addition, DEN increased the expression of hepatic Bcl and COX-2, while p53, Bax, and iNOS were mildly expressed. Pretreatment with CeO2NPs attenuated the activities of antioxidant enzymes and expression of Bcl and COX-2. Overall, CeO2NPs confers protection from DEN-induced liver damage via antioxidative activity.
Topics: Animals; Cerium; Chemical and Drug Induced Liver Injury; Diethylnitrosamine; Inflammation; Liver; Male; Mice; Mice, Inbred BALB C; Nanoparticles; Oxidative Stress
PubMed: 30993490
DOI: 10.1007/s12011-019-01696-5