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

Abstract

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.

The Effects of Long-Term Chaetomellic Acid A Administration on Renal Function and Oxidative Stress in a Rat Model of Renal Mass Reduction

“…Assay was conducted as described by Paula Santos et al [23]. The reaction medium consisted of potassium phosphate buffer (50 mM KH 2 PO 4 pH 7.4) and H 2 O 2 (1 M) in a final volume of 1 ml.…”

“…The GR activity was performed according to Paula Santos et al [23] and Smith et al [24]. The reaction medium consisted of potassium phosphate buffer (100 mM KH 2 PO 4 and 0.5 mM EDTA, pH 7.4), 100 mM GSSG, and 10 mM NADPH.…”

Dietary restriction protects against diethylnitrosamine-induced hepatocellular tumorigenesis by restoring the disturbed gene expression profile

“…The diethylnitrosamine (DEN)-induced HCC in mouse is one of the most frequently used animal models in liver cancer researches89, which has a gene expression profile similar to human HCC10. The formation of alkyl DNA adducts, which causes genome instability, and eventually results in the transformation of preneoplastic or neoplastic cells, has been considered as the key event in DEN-mediated tumorigenesis111213.…”

Antihepatocarcinogenic activity of whey protein concentrate and lactoferrin in diethylnitrosamine‐treated male albino mice

“…DEN caused cellular oxidative stress and DNA damage through inhibiting the mitochondrial metabolism and augmenting the release of reactive oxygen and nitrogen species (ROS and RNS, respectively). Therefore, the generation and accumulation of free radicals by DEN played a major role in the development of HCC . In the current study, the concentration of liver nonenzymic antioxidants (GSH) and the activities of liver enzymic antioxidants (CAT, GPx, and SOD) decreased significantly in the DEN‐induced hepatocarcinogenic mice compared with the noncancerous control mice, which likely led to hepatic oxidative injury.…”

“…In the current study, the concentration of liver nonenzymic antioxidants (GSH) and the activities of liver enzymic antioxidants (CAT, GPx, and SOD) decreased significantly in the DEN‐induced hepatocarcinogenic mice compared with the noncancerous control mice, which likely led to hepatic oxidative injury. Other studies also reported the defects in hepatic antioxidant defense system of rodents due to the excessive production of ROS by DEN . ROS oxidizes cellular fatty acids, especially polyunsaturated fatty acids, and produces lipid peroxyl radicals.…”