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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
Sugimura’s group discovered that the surface of fried fish and fried meat contains powerful mutagens.185,186 The mutagenic activity characteristically is in the form of frameshift mutagens in the Ames Salmonella test system with biochemical activation. The several mutagens thus far identified are ortho-methyl substituted heterocyclic amines which structurally mimic 3,2′-dimethyl-4-aminobiphenyl, discussed above. Weisburger has proposed that these kinds of compounds may be important in the etiology of cancer of the colon, breast, and prostate that are seen to a greater extent in populations typically consuming fried meats.187 The model compound 3,2′-dimethyl-4-aminobiphenyl does induce cancer of the colon, breast, and prostate in rats.188 Because of the difficulty of chemically synthesizing large amounts of IQ and related compounds, they have not yet been tested in appropriate animal models to establish whether they could or could not induce cancer in these target organs. A beginning has been made in delineating the metabolism of these agents. As is true with the homocyclic analog, N-oxidation appears to be a primary activation pathway towards metabolic, and probably carcinogenic, intermediates.189–192
Organic Chemicals
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Other existing aromatic amines include 4-aminodiphenyl, 2,3,4-aminopyridines, quinolines, azaarenes, and nitroso compounds. These can be quite toxic and have adverse effects on the chemically sensitive. Each will be discussed separately.
Etiology and Pathogenesis of Bladder Cancer
Published in George T. Bryan, Samuel M. Cohen, The Pathology of Bladder Cancer, 2017
The urinary bladder was among the first visceral organs for which specific chemicals were proposed as etiologic agents of human cancer.12 In 1895, the German clinician Rehn19 reported that workers employed in the dyestuffs industry were at increased risk of bladder cancer development. This report was followed over the next 50 years by many reports of other investigators in several countries who identified similar clusterings of industrial exposures to arylamines and the development of bladder cancer in exposed workmen.20 A major and significant epidemiologic study was reported in 1954 by Case and associates,21 who demonstrated that dyestuff workers were at a 10- to 80-fold increased risk of dying from bladder cancer. The magnitude of risk varied with the particular arylamine handled and with the duration and intensity of exposures. In selected exposure circumstances, as many as 100% of exposed workers developed bladder cancer.20 Benzidine and 2-naphthylamine were implicated as especially potent human bladder carcinogens.20,21 1-Naphthylamine was associated with a low risk of bladder carcinogenesis possibly due to contamination with 2-naphthylamine.20,21 In 1955, data were presented by clinical investigators that workers exposed to 4-aminobiphenyl were at increased risk of bladder cancer formation.22 Thus, by the mid-1950s conclusive evidence was available implicating at least three industrial arylamines as potent human bladder carcinogens.4,8,10,14,20 With these data, several industrialized countries took steps to limit or abolish manufacture of these chemicals.4,20 At that time it was believed generally that no more than 1% of human urothelial neoplasms were etiologically related to exposures to one or more of these chemicals.20 Thus, studies by clinicians concerned about causes of bladder cancer in their patients developed important leads for other investigators.
A comprehensive review of cytochrome P450 2E1 for xenobiotic metabolism
Published in Drug Metabolism Reviews, 2019
Jingxuan Chen, Sibo Jiang, Jin Wang, Jwala Renukuntla, Suman Sirimulla, Jianjun Chen
4-Aminobiphenyl, a trace component of cigarette smoke and hair dyes, manifests its toxic effects after bioactivation (Wang et al. 2015a, 2015b). The traditional model of aminobiphenyl carcinogenesis has shown that the chemical is oxidized, esterified, and then spontaneously hydrolyzed, producing a highly reactive nitrenium ion (Chen et al. 2005). The metabolite further contributes to the DNA-adducts formation and thus initiates liver tumor growth in mice. Both CYP2E1 and CYP1A2 are responsible for N-hydroxylation of aminobiphenyl, the first step in the bioactivation of aminobiphenyl (Wang et al. 2015a, 2015b). Interestingly, postnatal exposure of mice to aminobiphenyl causes a higher incidence of liver tumors in males than in females. However, no correlation was found between sex or CYP1A2 function and the corresponding damage of DNA; yet sex-differences in CYP2E1-dependent oxidative stress and antioxidant response to the substrate contribute to the observed sex difference in tumor incidence (Wang et al. 2015b).
Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Sonali Kurup, Bradley McAllister, Pavlina Liskova, Trusha Mistry, Anthony Fanizza, Dan Stanford, Jolanta Slawska, Ulrich Keller, Alexander Hoellein
Compound 16 was synthesised as described for 1 with 4-aminobiphenyl and was obtained as a white solid (89%); TLC Rf 0.65 (CH2Cl2/CH3OH, 10:1); 1H NMR (400 MHz, DMSO-d6) δ 6.84 (d, J = 4 Hz, 1 H), 7.25–7.31 (m, 2 H), 7.42 (d, J = 8 Hz, 2 H), 7.64–7.66 (m, 4 H), 8.01 (d, J = 8 Hz, 2 H), 8.32 (s, 1 H), 9.47 (s, 1 H); 13C NMR (400 MHz DMSO-d6) δ153.79, 151.27, 151.03, 140.39, 140.35, 134.10, 129.32, 127.23, 127.14, 126.58, 122.78, 120.99, 104.26, 99.34; HRMS (ESI) (M + H)+: Calcd for C18H15N4m/z = 287.1218, found m/z = 287.5214.
The Activity of Class I-IV Alcohol Dehydrogenase Isoenzymes and Aldehyde Dehydrogenase in Bladder Cancer Cells
Published in Cancer Investigation, 2018
Karolina Orywal, Wojciech Jelski, Tadeusz Werel, Maciej Szmitkowski
Globally, bladder cancer is the 10th most common malignancy with highest incidence rates reported in Europe, North America, and Australia (1). Tobacco smoking, long-term exposure to industrial aromatic amines and amides (e.g. 4-aminobiphenyl, benzidine, 2-naphthylamine) are found to be important risk factors for bladder cancer (2). Although several epidemiologic studies have been conducted to investigate the association between alcohol consumption and bladder cancer risk, the issue remains still unclear. No significant relationship was found in most studies but the results of European countries investigations found suggestive evidence for an increased risk of bladder cancer for current-drinkers vs. nondrinkers (3).