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Laboratory Animals Apr 2015The toxic properties of various nitrosamines in animals and humans are well established. The parenteral or oral administration of the smallest quantities of...
The toxic properties of various nitrosamines in animals and humans are well established. The parenteral or oral administration of the smallest quantities of diethylnitrosamine (DEN) or dimethylnitrosamine (DMN) results in severe liver damage. Most prominent are intense neutrophilic infiltration, extensive centrilobular haemorrhagic necrosis, bile duct proliferation, fibrosis, and bridging necrosis that ends in hepatocarcinogenesis. Due to the robustness of the induced hepatic alterations, the application of DEN in rodents has become an attractive experimental model for studies aimed at understanding the pathogenetic alterations underlying the formation of liver cancer, which represents one of the most common malignancies in humans worldwide. However, several studies have shown that the hepatocarcinogenic effects of nitrosamines might vary with the genetic background of the animals, their sex, their age, and other factors that might impact the outcome of experimentation. We present general guidelines for working with DEN, and a detailed protocol that allows the establishment of highly reproducible liver cancer in mice. The outcome of liver injury after the application of DEN in mice, as estimated by the formation of cirrhosis and cancer, appears to be a suitable animal model for the analysis of some aspects and processes that promote the pathogenesis of hepatocellular carcinoma in humans.
Topics: Animals; Carcinogens, Environmental; Diethylnitrosamine; Disease Models, Animal; Guidelines as Topic; Humans; Laboratory Animal Science; Liver Neoplasms, Experimental; Mice
PubMed: 25835739
DOI: 10.1177/0023677215570086 -
Arquivos de Gastroenterologia 2023•In this review, we described different murine models of carcinogenesis: classic models, new transgenic and combined models, that reproduce the key points for HCC and... (Review)
Review
•In this review, we described different murine models of carcinogenesis: classic models, new transgenic and combined models, that reproduce the key points for HCC and CCA genesis allowing a better understanding of its genetic physiopathological, and environmental abnormalities. •Each model has its advantages, disadvantages, similarities, and differences with the corresponding human disease and should be chosen according to the specificity of the study. Ultimately, those models can also be used for testing new anticancer therapeutic approaches. •Cholangiocarcinoma has been highlighted, with an increase in prevalence. This review has an important role in understanding the pathophysiology and the development of new drugs. Background - This manuscript provides an overview of liver carcinogenesis in murine models of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Objective - A review through MEDLINE and EMBASE was performed to assess articles until August 2022.Methods - Search was conducted of the entire electronic databases and the keywords used was HCC, CCA, carcinogenesis, animal models and liver. Articles exclusion was based on the lack of close relation to the subject. Carcinogenesis models of HCC include HCC induced by senescence in transgenic animals, HCC diet-induced, HCC induced by chemotoxicagents, xenograft, oncogenes, and HCC in transgenic animals inoculated with B and C virus. The models of CCA include the use of dimethylnitrosamine (DMN), diethylnitrosamine (DEN), thioacetamide (TAA), and carbon tetrachloride (CCl4). CCA murine models may also be induced by: CCA cells, genetic manipulation, Smad4, PTEN and p53 knockout, xenograft, and DEN-left median bile duct ligation. Results - In this review, we described different murine models of carcinogenesis that reproduce the key points for HCC and CCA genesis allowing a better understanding of its genetic, physiopathological, and environmental abnormalities. Conclusion - Each model has its advantages, disadvantages, similarities, and differences with the corresponding human disease and should be chosen according to the specificity of the study. Ultimately, those models can also be used for testing new anticancer therapeutic approaches.
Topics: Animals; Mice; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinogenesis; Carcinoma, Hepatocellular; Cholangiocarcinoma; Disease Models, Animal; Liver Neoplasms
PubMed: 37792769
DOI: 10.1590/S0004-2803.230302023-58 -
Cell Reports Apr 2023Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular...
Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we report that PPDPF is significantly downregulated in HCC and the decreased PPDPF expression indicates poor prognosis. In the dimethylnitrosamine (DEN)-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promotes hepatocarcinogenesis, and reintroduction of PPDPF into liver-specific Ppdpf knockout (LKO) mice inhibits the accelerated HCC development. Mechanistic study shows that PPDPF regulates nuclear factor κB (NF-κB) signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzes K63-linked ubiquitination of RIPK1 at K140. In addition, liver-specific overexpression of PPDPF activates NF-κB signaling and attenuates apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-κB signaling and provides a potential therapeutic candidate for HCC.
Topics: Animals; Mice; Carcinogenesis; Carcinoma, Hepatocellular; Liver Neoplasms; NF-kappa B; Ubiquitination
PubMed: 37027301
DOI: 10.1016/j.celrep.2023.112340 -
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 -
Arhiv Za Higijenu Rada I Toksikologiju Mar 2021In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received... (Review)
Review
In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: -nitrosodimethylamine (NDMA) and -nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives.
Topics: Carcinogens; Diethylnitrosamine; Dimethylnitrosamine; Drug Contamination; Humans; Nitrosamines
PubMed: 33787187
DOI: 10.2478/aiht-2021-72-3491 -
JAMA Jul 2021
Topics: Dimethylnitrosamine; Ranitidine; Water Pollutants, Chemical
PubMed: 34180953
DOI: 10.1001/jama.2021.10043 -
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 -
Nederlands Tijdschrift Voor Geneeskunde Mar 2019In early July 2018, it became known that a number of generic preparations containing the active substance valsartan could be carcinogenic. This news took caregivers and...
In early July 2018, it became known that a number of generic preparations containing the active substance valsartan could be carcinogenic. This news took caregivers and patients by surprise. Initially, a recall was initiated at the pharmacy level. A few weeks later, the recall was expanded to the patient level. The source of the contamination was a factory of the Chinese company Zhejiang Huahai Pharmaceutical, where the active ingredient valsartan is produced. It was found that batches from that factory had contained too high a concentration of N-nitrosodimethylamine since as early as 2012. The EMA estimates that if 5000 patients took the maximum dose of 320 mg of tainted valsartan tablets every day in the period from July 2012 to July 2018, there will be one extra case of cancer. The valsartan contamination raises the question of whether or not the Dutch authorities involved responded adequately. It has become clear from the contamination of valsartan that good and timely communication is important.
Topics: Antihypertensive Agents; Carcinogens; Dimethylnitrosamine; Drug Contamination; Drugs, Generic; Humans; Neoplasms; Valsartan
PubMed: 30945826
DOI: No ID Found -
Chemosphere Jan 2018This review summarizes major findings over the last decade related to N-Nitrosodimethylamine (NDMA) in water and wastewater. In particular, the review is focused on the... (Review)
Review
This review summarizes major findings over the last decade related to N-Nitrosodimethylamine (NDMA) in water and wastewater. In particular, the review is focused on the removal of NDMA and of its precursors by conventional and advanced water and wastewater treatment processes. New information regarding formation mechanisms and precursors are discussed as well. NDMA precursors are generally of anthropogenic origin and their main source in water have been recognized to be wastewater discharges. Chloramination is the most common process that results in formation of NDMA during water and wastewater treatment. However, ozonation of wastewater or highly contaminated surface water can also generate significant levels of NDMA. Thus, NDMA formation control and remediation has become of increasing interest, particularly during treatment of wastewater-impacted water and during potable reuse application. NDMA formation has also been associated with the use of quaternary amine-based coagulants and anion exchange resins. UV photolysis with UV fluence far higher than typical disinfection doses is generally considered the most efficient technology for NDMA mitigation. However, recent studies on the optimization of biological processes offer a potentially lower-energy solution. Options for NDMA control include attenuation of precursor materials through physical removal, biological treatment, and/or deactivation by application of oxidants. Nevertheless, NDMA precursor identification and removal can be challenging and additional research and optimization is needed. As municipal wastewater becomes increasingly used as a source water for drinking, NDMA formation and mitigation strategies will become increasingly more important. The following review provides a summary of the most recent information available.
Topics: Dimethylnitrosamine; Disinfection; Drinking Water; Oxidants; Wastewater; Water Pollutants, Chemical; Water Pollution, Chemical; Water Purification
PubMed: 29078192
DOI: 10.1016/j.chemosphere.2017.10.089 -
Journal of Pharmaceutical Sciences Sep 2023Most N-Nitrosamine compounds are found to be genotoxic in several animal species. Some are classified as probable or possible human carcinogens and very low acceptable... (Review)
Review
Most N-Nitrosamine compounds are found to be genotoxic in several animal species. Some are classified as probable or possible human carcinogens and very low acceptable daily intake has been established such as 96 ng/day for N-nitrosodimethylamine (NDMA) and 26.5 ng/N-nitrosodiethylamine (NDEA). The pharmaceutical industry has considered all processing areas for potential formation or contamination of N-nitrosamine. One risk is the potential contamination of nitrosamine during drug product blister packaging using lidding foils containing nitrocellulose, and different approaches have been used by pharmaceutical companies to evaluate and mitigate this risk. Herein we share a perspective from IQ Consortium N-nitrosamine Working Group on some of the approaches and corresponding results. From these assessments, it was concluded that the risk of nitrosamine contamination during blister packaging is negligible. The approaches shared in this perspective can be incorporated into risk assessment for nitrosamine contamination during drug product packaging at other pharmaceutical companies.
Topics: Animals; Humans; Nitrosamines; Blister; Dimethylnitrosamine; Drug Contamination; Product Packaging; Pharmaceutical Preparations
PubMed: 37478970
DOI: 10.1016/j.xphs.2023.07.014