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Quick Methods: Structure-Activity Relationships and Short-Term Bioassay
Published in Samuel C. Morris, 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.
Biochemical Aspects of Fatty Liver
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Dimethylnitrosamine and diethylnitrosamine are also powerful alkylating, carcinogenic, and steatogenic substances. Fatty liver is evident in this case 5–6 h after treatment with 30–50 mg/kg b.w.t. Both substances are activated by the enzymes of the SER (Brouwers and Emmelot, 1960; Kawanishi et al., 1985; Magee, 1971). Induction of such enzyme by previous treatments strongly increases toxicity (Garner and McLean, 1969; Seawright and McLean, 1967), whereas previous feeding a protein-deficient diet results both in decrease in cytochrome P450 and in toxicity (McLean and McLean, 1969; Menzel et al., 1982).
Metabolism of Chemical Carcinogens by Intestinal Tissue
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
Several N-nitrosamines were also metabolized by human colon into metabolites which associate with DNA (Table 1, Figure 1). The highest level of modification occurred with dimethylnitrosamine (DMNA).50 Only the tissues that exhibit a high level of binding of DMNA also bound detectable amounts of diethylnitrosamine or N-nitro-sopyrrolidine.50 However, these N-nitrosamines were metabolized as indicated by binding to cellular proteins and formation of CO2. Two other nitrosamines, N-nitrosopi-perazine and N-nitrosopiperidine, were also metabolized in colon as measured by the same criteria.50 A positive correlation between the amount of 14COz formed after incubation with DMNA for 24 hr and the level of radioactivity associated with DNA was observed in human colon. Most of the alkylation of DNA with DMNA occurred at the phosphate groups, but some alkylation was also observed at the O6 and 7 positions of guanine50 (Figure 2).
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.
Quercetin and naringenin abate diethylnitrosamine/acetylaminofluorene-induced hepatocarcinogenesis in Wistar rats: the roles of oxidative stress, inflammation and cell apoptosis
Published in Drug and Chemical Toxicology, 2022
Osama M. Ahmed, Adel A. Ahmed, Hanaa I. Fahim, Mohamed Y. Zaky
Diethylnitrosamine (DEN) is an established well known hepatocarcinogenic and hepatotoxic agent in experimental animals as well as human (Arboatti et al. 2018). It is existing in cosmetics, pharmaceutical agents, water, tobacco smoke, agricultural chemicals and cured and fried meals (Dar et al. 2019). DEN has been used to initiate the liver cancer either alone or in combination with other carcinogens such as 2-acetylaminofluorene (2AAF) which acts as promoter for carcinogenesis (Lto et al. 2003). Oxidative stress and inflammation play an important role in the progress of carcinogenesis (Ahmed 2016).
Differential changes in the pharmacokinetics of doxorubicin in diethylnitrosamine-induced hepatocarcinoma model rats
Published in Xenobiotica, 2020
Jie Pan, Yuan Lu, Shuai Zhang, Yueting Li, Jia Sun, Hua Chunhua Liu, Zipeng Gong, Jing Huang, Chuang Cao, Yonglin Wang, Yongjun Li, Ting Liu
Diethylnitrosamine (DEN) is a well-known chemical agent and has a potent hepatocarcinogenic effect. As DEN-induced HCC is similar to human HCC, and is highly successful and reproducible (Travis et al., 1991), the DEN-induced HCC rat model is widely used in preclinical studies. In the present research, in order to determine the effect of HCC on the pharmacokinetics of DOX and its possible underlying molecular mechanisms, the pharmacokinetics of DOX were investigated, the expression of drug-metabolic enzymes (cbr1) and transporters (p-gp and slc22a16) involved in DOX metabolism and transport were evaluated.