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Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Hydrazine and its alkylated derivatives are carcinogens; liver is one of the primary target organs. Some hydrazines occur naturally in mushrooms. Procarbazine is a hydrazine derivative used as an antitumor agent. A series of oxidation steps results in the formation of carcinogenic electrophiles (Kadlubar and Hammons, 1987). Dimethylhydrazine and procarbazine have been the prototype agents for the study of the biotransformation of this chemical class. Azodialkanes are the first oxidation products formed. This pathway appears to be mediated by the CYP2B gene family and by monoamine oxidase. Initial oxidation by FMO results in a monoalkylated derivative and an aldehyde. Additional oxidations to azoxydialkanes and diazenes are separate bioactivation pathways. The electrophilic diazenes result from further oxidations of the primary oxidation products by P450, peroxidases and FMO. Formation of azoxydialkanes from the azodialkanes requires the sequential action of P450. N-Oxidation is catalyzed by CYP2C6 and CYP1A1. Next, α-carbon oxidation similar to that for nitrosamine bioactivation appears to be necessary for formation of the ultimate carcinogenic metabolite of azoxydialkanes, methylazoxymethanol (MAM) from DMH. CYP2E1 may catalyze this reaction. From MAM, the methyldiazonium ion, which is the same putative carcinogenic electrophilic as for nitrosamines, can form spontaneously or from catalysis by choline or alcohol dehydrogenase.
Experimental Colon Carcinogens and Their Mode of Action
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
John H. Weisburger, Emerich S. Fiala
AOM has the same organ and species specificity as the parent compound DMH but is not used in research as frequently as the latter because it is more expensive and not as widely available commercially. Nonetheless, it would seem to be a preferred agent since the effective dosage is lower than with dimethylhydrazine, and it is an easily formulated, water-soluble, chemically stable compound.109
Chemopreventive Potential of Myrtenal against Nitrosamine-Initiated, Radiation-Promoted Rat Bladder Carcinogenesis
Published in Nutrition and Cancer, 2022
Mostafa A. Farrag, Magda K. Ezz, Nashwa K. Ibrahim, Emad K. Ahmed
In the present study, administration of myrtenal to animals of the induction group caused a significant down-regulation in the expression of COX-2, NF-κB and STAT3. These effects could be ascribed to the documented antitumor and antiproliferative activities of myrtenal. Babu et al (10) has reported the antineoplastic potential of myrtenal on suppressing diethylnitrosamine-induced hepatocellular carcinoma in rats and the tumor preventive power of myrtenal was attributed to its ability to reduce the levels and activities of phase I hepatic drug metabolizing enzymes (cyto p450, cyto b5, CPR, CBR), decrease microsomal lipid peroxidation and simultaneously increase phase II enzymes (GST) as well as preventing the carcinogen-induced upregulation of TNF-α. Moreover, the antitumor efficacy of myrtenal against dimethylhydrazine-induced colon cancer was also reported in Wistar rats(46). Monoterpenes, by virtue of their isoprenoid structure, have been demonstrated previously to inhibit the propagation of carcinogenic processes. The mechanism of action involves preventing carcinogens from interacting with DNA through modulating carcinogen metabolism to less damaging end products, hence prevents the dissemination of initiated cells during the initiation phase of carcinogenesis (47). It also involves the inhibition of post-translational modification of cellular critical proteins involved in the regulation of signal transduction and gene expression (46).
Methanolic Extract of Muntingia Calabura L. Mitigates 1,2-Dimethyl Hydrazine Induced Colon Carcinogenesis in Wistar Rats
Published in Nutrition and Cancer, 2021
Ninan Jisha, A. Vysakh, V. Vijeesh, P. S. Anand, M. S. Latha
1,2-Dimethyl hydrazine (DMH) is a colon specific carcinogen widely used in experimental animals to induce colorectal tumors (5). DMH induced CRC emanates from various molecular and histopathological alterations in the colonic epithelium like the development of aberrant crypt foci (ACF) and mucin depleted foci (MDF) (6). ACF and MDF are the preneoplastic leisions that may contribute to the progression of colonic epithelial transformation into colorectal carcinoma which are considered as the early biomarkers of CRC (7, 8). The DMH is metabolized initially in the liver and transported to colon as glucoronide conjugates via bile or blood (9, 10) and further degraded into azomethane. The azoxymethane generated from azomethane by the process of oxidation (N-oxidation) undergoes hydroxylation to form methylazoxymethanol (an unstable compound) which readily generates a highly reactive electrophilic methyl diazonium ion. This process causes the release of methyl free radicals meanwhile in the presence of metal ions, DMH causes the generation of hydroxyl radical or hydrogen peroxide which evokes oxidative stress as a result of the imbalance between the ROS and endogenous antioxidants (11, 12). Oxidative stress further progresses to inflammation which finally promotes CRC.
The germ-free mice monocolonization with Bacteroides fragilis improves azoxymethane/dextran sulfate sodium induced colitis-associated colorectal cancer
Published in Immunopharmacology and Immunotoxicology, 2019
Yen-Peng Lee, Chien-Chao Chiu, Tien-Jen Lin, Shao-Wen Hung, Wen-Ching Huang, Ching-Feng Chiu, Yen-Te Huang, Yi-Hsun Chen, Ter-Hsin Chen, Hsiao-Li Chuang
The colorectal cancer (CRC) is one of most common malignant neoplasms in western and Asian countries. Environmental and genetic factors influence the development of CRC, and inflammation is a critical hallmark of cancer that may arise from a variety of factors. Additionally, inflammatory bowel disease (IBD), in particular ulcerative colitis, represents a separate entity in which the risk of CRC is increased. The incidence of CRC in IBD patients, such as colitis-associated colorectal cancer (CAC), has been reported to be up to 60% higher than the general population [1]. In order to investigate the molecular pathogenesis of CRC in IBD patients, recent studies have reported that the combination of dextran sulfate sodium (DSS) with azoxymethane (AOM) as a model of CAC, which has gained popularity for its reproducibility, potency, low cost, and ease of use [2,3]. AOM has been found to be more potent and stable in solution than 1,2-dimethylhydrazine (DMH). While tumor development in other models generally requires several months, mice injected with AOM and subsequently treated with DSS develop adequate tumors in as little as 7–10 weeks [2].