Liver Diseases
George Feuer, Felix A. de la Iglesia in Molecular Biochemistry of Human Disease, 2020
In the progression of the cancer, one or more of the focal proliferations formed during promotion or selection may represent the sites where further changes can occur. Few cells proliferate without any apparent external influence. This rare event repeats itself until the malignant tumor develops. Subsequent sequences of progression in man include various types of precancerous lesions such as carcinoma in situ, atypical hyperplasia, and displasia.158,321,393 These lesions appear later than focal proliferations, and at present, we do not know how these lesions relate to each other. Precancerous or cancerous lesions can arise in the area of focal proliferation in the liver of experimental animals and in many sites in humans.595 Many chemicals can induce hyperplastic nodules which are further transformed to malignant lesions. These chemicals include diethylnitrosamine, 3ˊ-methyl-4ˊ-dimethylaminoazobenzene, aramite, and ethionine.147,209,455,524
Quick Methods: Structure-Activity Relationships and Short-Term Bioassay
Samuel C. Morris in Cancer Risk Assessment, 2020
Short-term in vivo bioassays take advantage of model systems which have a high background cancer rate, and thus a presumed high sensitivity to cancer induction. This leads, however, to the possibility that the effect being measured may be a decrease in latent period rather than an increase in tumor incidence. Other-short term in vivo assays (de Serres and Matsushima) include: (1) the well-known mouse skin model, widely used for initiation-promotion experiments. Tumorigenic effects can be detected in as little as 10 weeks in this test. (2) Breast cancer induction in female Sprague-Dawley rats. An injected carcinogen produces a high incidence of multiple mammary tumors in 9 months. (3) A rat liver initiation-promotion assay. One group of rats are used to test cancer promotion properties of a chemical. They are given a dose of diethylnitrosamine (DEN) to initiate hepatocarcinogenesis, and then given the test chemical. A second group of rats tests for initiation. They are injected with NaCl instead of DEN, followed by the test chemical. The third group of rats serves as the control; they are given only DEN. The livers of all three groups are assayed after eight weeks. Of the 18 known hepatocarcinogens, 16 scored positive for promotion; 8 known nonhepatocarcinogens scored negative.
Long-Term Effects: Cancer
Ernest L. Abel in Smoking and Reproduction: An Annotated Bibliography, 2017
17.f.5. Diwan, B. A. and Meier, H., Transplacental carcinogenic effects of diethylnitrosamine in mice, Naturwissenschaften, 63, 487—488, 1976. Diethylnitro-samine, a substance occurring in tobacco smoke, was injected into pregnant mice. Offspring exposed on gestation day 14 did not develop tumors. A total of 2 out of 20 offspring exposed on gestation day 15 developed lymphoid leukemia. Administration on gestation day 16 or later resulted in an increased incidence of tumors of 24% when exposure occurred on gestation day 16, 73% when exposure occurred on gestation day 17, and 87% when exposure occurred on gestation day 18. Offspring exposed on gestation day 18 lived for 41.7 weeks compared to 56.7 weeks for controls.
Re-evaluation of the anticarcinogenic effect of metformin in a chemically-induced hepatocellular carcinoma model not associated with diabetes
Published in Egyptian Journal of Basic and Applied Sciences, 2022
Fatima A. M. El-Deeb, Yomna I. Mahmoud, Nagwa H. A. Hassan
Diethylnitrosamine (DEN) was purchased from Sigma-Aldrich (0.95 g/ml; Sigma N0258-1 G; St. Louis, MO, USA). Carbon tetrachloride was obtained from Research Lab (Serial# 02076; Batch# 02076170415). Metformin hydrochloride (Glucophage® 1000 mg, equivalent to 780 mg of metformin) was bought from Minapharm (10th of Ramadan, Egypt). Kits for determining serum alanine aminotransferase (ALT; catalog # 41280), aspartate aminotransferase (AST; catalog # 41264), and albumin (ALB; catalog # 1001291) were purchased from SPINREACT, S.A./S.A.U. (Ctra. Santa. Coloma, Spain). Alkaline phosphatase (ALP; catalog # 214002) kit was from SPECTRUM Diagnostics (Cairo, Egypt). Bilirubin (Bil; catalog # 235672), and lactate dehydrogenase (LDH; catalog # 197000) kits were from ABCAM (United Kingdom). Mouse alpha- fetoprotein (AFP) ELISA kit was from CUSABIO (Catalog # CSP- E08282m; San Diego, CA, USA).
The human organic cation transporter OCT1 and its role as a target for drug responses
Published in Drug Metabolism Reviews, 2019
Nicolas Brosseau, Dindial Ramotar
Deletion of the OCT1 gene in mice resulted in the upregulation of the related transporter genes OCT2 and OCT3, suggesting that these later two genes may function to compensate for the loss of OCT1 (Chen L et al. 2014). Likewise, deletion of the OCT3 gene leads to the increased expression of the OCT1 gene (Vollmar et al. 2017). Despite the upregulation of the OCT1 gene in the Oct3-/- null mice, these animals are predisposed to hepatocarcinogenesis (Vollmar et al. 2017). In this Oct3-/- mouse model, OCT1 levels were increased in the tissue surrounding the hepatocellular carcinoma, while it remains uninduced in the tumor (Vollmar et al. 2017). The reason for the differential tissue regulation of the OCT1 gene in the Oct3-/- null mice is not clear, although it could be due to increase methylation at the promoter from the initial exposure to diethylnitrosamine used for inducing liver tumors (Vollmar et al. 2017). From these observations, two points can be raised (i) diethylnitrosamine is a potential substrate for OCT1, and (ii) sorafenib would be ineffective to suppress the hepatocellular carcinoma growth in the Oct3-/- mice due to the OCT1 downregulation (Vollmar et al. 2017).
Protective effect of rosemary (Rosmarinus officinalis) against diethylnitrosamine-induced renal injury in rats
Published in Biomarkers, 2020
Naglaa H. M. Hassanen, Abdelgawad Fahmi, Engy Shams-Eldin, Mariam Abdur-Rahman
The kidney contains many xenobiotic metabolising enzymes and plays a central role in metabolising drugs and foreign compounds in the body. Kidney diseases represent a worldwide public health issue and can range from mild infection to dangerous kidney failure (Nasri and Rafieian-Kopaeil 2014). Kidneys receive approximately 25% of the cardiac output, and renal tubules have a high tendency for drug uptake via transporter proteins or endocytosis. This can result in high intracellular levels of various drugs and substances that to be metabolised, leading to formation of reactive oxygen species (ROS) and toxic metabolites (Perazella 2009). Excessive ROS production and oxidative stress have been demonstrated to play a role in drug-induced renal damage and tubular necrosis (Lopez-Novoa et al.2011, Abd El-Twab et al.2016). N-nitrosamines are chemical compounds produced by reactions of nitrosating agents and organic amines (Rostkowska et al.1998). High concentration of nitrosamines has been reported in processed meat due to the addition of nitrite to prevent the growth of Clostridium botulinum (Cho and Bratzler 1970). Diethylnitrosamine (DEN) is a potent carcinogenic compound found in soybean, cheese, tobacco smoke, processed meats and a wide variety of dietary prroducts (Verna et al.1996). DEN metabolism generates high levels of ROS leading to mutagenicity and carcinogenesis (Deng et al.2019). Therefore, inhiition of ROS generation can protect against DEN-induced cellular and tissue damage.
Related Knowledge Centers
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