Experimental Colon Carcinogens and Their Mode of Action
Herman Autrup, Gary M. Williams in Experimental Colon Carcinogenesis, 2019
Sequential chemical oxidation of DMH in the laboratory can produce AOM and MAM. Since these chemical reactions are entirely analogous to the transformations occurring in vivo, they are described here in some detail. 1,2-Dimethylhydrazine is readily oxidized either by oxygen in the presence of metal ion catalysts60 or by chemical oxidants such as mercuric oxide,61 to azomethane, a poisonous and explosive gas. Further chemical oxidation converts azomethane to azoxymethane in high yield.61 Interestingly, azoxymethane is also produced during the chemical oxidation of methylam-ine.62 Related model compounds such as phenylethylamine can be converted biochemically to the corresponding azoxy compound.63 Azoxymethane is a more powerful carcinogen than 1,2-dimethylhydrazine, and its organospecificity is essentially identical.1,6,64–66 Bromination of azoxymethane and subsequent reaction with silver acetate produces methylazoxymethyl acetate,61 again a powerful carcinogen with much the same organospecificity as its chemical precursors.8,9 Methylazoxymethyl acetate, a stable liquid, is easily hydrolyzed by various esterases67–69 to the relatively unstable methylazoxymethanol. The latter may also be obtained by hydrolysis of cycasin with β-glucosidase.9
Xenobiotic Biotransformation
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in 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.
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].
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).
Augmentation of diethylnitrosamine–induced early stages of rat hepatocarcinogenesis by 1,2-dimethylhydrazine
Published in Drug and Chemical Toxicology, 2019
Charatda Punvittayagul, Arpamas Chariyakornkul, Teera Chewonarin, Kanokwan Jarukamjorn, Rawiwan Wongpoomchai
DEN, 3, 3′-diaminobenzidine tetrahydrochloride hydrate, glutathione reduced form, UDP-glucuronic acid and cytochrome c Type IV were purchased from Sigma Aldrich (St. Louis, MO). 1,2-Dimethylhydrazine dihydrochloride was obtained from TCI (Tokyo, Japan). Methylene blue was purchased from Merck (Darmstadt, Germany). Rabbit polyclonal antibodies against rat CYP1A1, CYP2B1, CYP2C11, CYP2E1, CYP3A2 and NADPH: cytochrome P450 reductase were kindly provided by Prof. Dr. Yoshihiko Funae, School of Medicine, Osaka City University, Osaka, Japan. GST-A and UGT1A antibodies were obtained from Alpha Diagnostic Intl., Inc. (San Antonio, TX) and Cell Signaling Technology, Inc. (Beverly, MA), respectively. Anti-rat GST-placental form was obtained from MBL (Nagoya, Japan). A Vectastrain ABC kit was obtained from Vector Laboratories, Inc. (Burlingame, CA). All other chemicals were of analytical grade.
Related Knowledge Centers
- Methyl Group
- Unsymmetrical Dimethylhydrazine
- Symmetrical Dimethylhydrazine
- Monomethylhydrazine