N-Nitrosodiethylamine mechanistic data and risk assessment: Bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation

Verna, Lynne; Whysner, John; Williams, Gary M.

doi:10.1016/0163-7258(96)00062-9

Cited by 459 publications

(384 citation statements)

References 69 publications

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“…Hepatocytes, particularly those in the centrilobular region, metabolized DEN into an alkylating agent that, in turn, can induce DNA damage and mutations in hepatocytes (Verna et al, 1996). Simultaneously, DEN metabolites can generate reactive oxygen species (ROS) Schwabe and Brenner, 2006).…”

Section: Discussionmentioning

confidence: 99%

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

Wang

Nakamoto

et al. 2010

Oncogene

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Pim-3, a proto-oncogene with serine/threonine kinase activity, was enhanced in hepatocellular carcinoma (HCC) tissues. To address the roles of Pim-3 in HCC development, we prepared transgenic mice that express human Pim-3 selectively in liver. The mice were born at a Mendelian ratio, were fertile and did not exhibit any apparent pathological changes in the liver until 1 year after birth. Pim-3-transgenic mouse-derived hepatocytes exhibited accelerated cell cycle progression. The administration of a potent hepatocarcinogen, diethylnitrosamine (DEN), induced accelerated proliferation of liver cells in Pim-3 transgenic mice in the early phase, compared with that observed for wild-type mice. Treatment with DEN induced lipid droplet accumulation with increased proliferating cell numbers 6 months after the treatment. Eventually, wild-type mice developed HCC with a frequency of 40% until 10 month after the treatment. Lipid accumulation was accelerated in Pim-3 transgenic mice with higher proliferating cell numbers, compared with that observed for wild-type mice. Pim-3 transgenic mice developed HCC with a higher incidence (80%) and a heavier burden, together with enhanced intratumoral CD31-positive vascular areas, compared with that observed for wild-type mice. These observations indicate that Pim-3 alone cannot cause, but can accelerate HCC development when induced by a hepatocarcinogen, such as DEN.

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Section: Discussionmentioning

confidence: 99%

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

Wang

Nakamoto

et al. 2010

Oncogene

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“…Contrary to N-nitrosamides, N-nitrosodialkylamines require metabolic activation (-hydroxylation), mediated by cytochrome P450 enzymes, in order to induce DNA damage. N-diethylnitrosamine (DEN) is a genotoxic, carcinogenic nitrosamine having its place among N-nitrosodialkylamines (Dutra et al, 2007;Fausto and Campbell, 2010;Heindryckx et al, 2009;Inami et al, 2010;Verna et al, 1996). According to Inami et al (2010), spontaneous decomposition of -hydroxynitrosamines generates aldehydes and alkanediazohy-droxides, followed by the production of alkyldiazonium ions, which alkylate DNA bases.…”

Section: Introductionmentioning

confidence: 99%

N-diethylnitrosamine mouse hepatotoxicity: Time-related effects on histology and oxidative stress

Santos

Colaço

Costa

et al. 2014

Experimental and Toxicologic Pathology

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Animal models, namely mice, have been used to study chemically induced carcinogenesis due to their similarity to the histological and genetic features of human patients. Hepatocellular carcinoma (HCC) is a common malignancy with poor clinical outcome. The high incidence of HCC might be related to expo-sure to known risk factors, including carcinogenic compounds, such as N-nitrosamines, which cause DNA damage. N-nitrosamines affect cell mitochondrial metabolism, disturbing the balance between reactive oxygen species (ROS) and antioxidants, causing oxidative stress and DNA damage, potentially leading to carcinogenesis. This work addresses the progressive histological changes in the liver of N-diethylnitrosamine (DEN)-exposed mice and its correlation with oxidative stress.Male ICR mice were randomly divided into five DEN-exposed and five matched control groups. DEN was IP administered, once a week, for eight consecutive weeks.2 Samples were taken 18 h after the last DEN injection (8 weeks post-exposure). The following sampling occurred at weeks 15th, 22nd, 29th and 36th after the first DEN injection. DEN resulted in early toxic lesions and, from week 29 onwards, in progressive proliferative lesions. Between 15 and 29 weeks, DEN-exposed animals showed significant changes in hepatic antioxidant (glutathione, glutathione reductase, and catalase) status (p < 0.05) compared with controls. These results point to an association between increased DEN-induced oxidative stress and the early histopathological alterations, suggesting that DEN disrupted the antioxidant defense mechanism, thereby triggering liver carcinogenesis.

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“…Diethylnitrosamine (DEN) is a DNA alkylating and ROS inducing carcinogen that is widely used as a model to study the progression of HCC in rodents. 9,10 DEN treatment mimics the human disease by inducing DNA damage in proliferating hepatocytes of infant mice. 9 Increases in the generation of ROS and accumulation of DNA damage can stimulate an inflammatory response and hyperproliferation that helps drive tumour progression.…”

mentioning

confidence: 99%

“…9 Increases in the generation of ROS and accumulation of DNA damage can stimulate an inflammatory response and hyperproliferation that helps drive tumour progression. [7][8][9][10] It has increasingly been recognised that apoptosis and compensatory proliferation are crucial for progression of certain cancers including HCC. [11][12][13] While loss of apoptosis would indirectly favour proliferation, this is not universally true, for example loss of PUMA, or hepatocyte-specific deletion of Bid, impedes HCC by preventing compensatory proliferation.…”

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confidence: 99%

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

et al. 2016

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Aberrant cell death/survival has a critical role in the development of hepatocellular carcinoma (HCC). Caspase-2, a cell death protease, limits oxidative stress and chromosomal instability. To study its role in reactive oxygen species (ROS) and DNA damageinduced liver cancer, we assessed diethylnitrosamine (DEN)-mediated tumour development in caspase-2-deficient (Casp2 −/− ) mice. Following DEN injection in young animals, tumour development was monitored for 10 months. We found that DEN-treated Casp2 −/− mice have dramatically elevated tumour burden and accelerated tumour progression with increased incidence of HCC, accompanied by higher oxidative damage and inflammation. Furthermore, following acute DEN injection, liver injury, DNA damage, inflammatory cytokine release and hepatocyte proliferation were enhanced in mice lacking caspase-2. Our study demonstrates for the first time that caspase-2 limits the progression of tumourigenesis induced by an ROS producing and DNA damaging reagent. Our findings suggest that after initial DEN-induced DNA damage, caspase-2 may remove aberrant cells to limit liver damage and disease progression. We propose that Casp2 −/− mice, which are more susceptible to genomic instability, are limited in their ability to respond to DNA damage and thus carry more damaged cells resulting in accelerated tumourigenesis. The initiator caspase, caspase-2, has recently emerged as a tumour suppressor with loss of this protein being associated with increased lymphomagenesis in ATM-deficient mice and Eμ-Myc transgenic mice, and MMTV/c-neu-driven mammary carcinoma. 1-4 Caspase-2 has been shown to protect cells from oxidative stress, DNA damage and genomic instability, and caspase-2 deficiency is linked to chromosomal instability and aneuploidy. 1,5,6 However, currently little is known about the possible role of caspase-2 in carcinogenesis induced by ROS and DNA damage.Hepatocellular carcinoma (HCC) is among the most common cancers and is the second leading cause of cancer-related deaths worldwide. 7 Development of HCC is multifaceted progressing from DNA damage to dysplasia, adenoma development and malignant transformation of hepatocytes. 7,8 The major risk factors of HCC include viral hepatitis, excessive alcohol consumption, carcinogens and metabolic diseases. 7,8 Despite this, the molecular causes of the disease are relatively less understood. Diethylnitrosamine (DEN) is a DNA alkylating and ROS inducing carcinogen that is widely used as a model to study the progression of HCC in rodents. 9,10 DEN treatment mimics the human disease by inducing DNA damage in proliferating hepatocytes of infant mice. 9 Increases in the generation of ROS and accumulation of DNA damage can stimulate an inflammatory response and hyperproliferation that helps drive tumour progression. 7-10 It has increasingly been recognised that apoptosis and compensatory proliferation are crucial for progression of certain cancers including HCC. 11-13 While loss of apoptosis would indirectly favour proliferation, this is not universa...

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N-Nitrosodiethylamine mechanistic data and risk assessment: Bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation

Cited by 459 publications

References 69 publications

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver

N-diethylnitrosamine mouse hepatotoxicity: Time-related effects on histology and oxidative stress

Caspase-2 deficiency accelerates chemically induced liver cancer in mice

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