DMBA carcinogen

Among the chemical carcinogens, dimethylbenzanthracene (DMBA) is one that is widely used in experimental studies. A large body of literature gathered over several decades exists from studies of DMBA carcinogenicity in fish (see review 13). 

Methylcholanthrene (3-MC) is a potent carcinogen, intermediate in activity between DMBA and BP (27,77). It was first prepared in 1925 by Wieland from desoxycholic acid (89). Biological studies have tentatively identified the 9,10-dihydrodiol (24a) and/or its 1- or 2-hydroxy derivatives (24b and 24c) and the corresponding diol and triol epoxides (25 -c) as the proximate and ultimate carcinogenic forms, respectively, of 3-MC (90-93). 

The mechanism of carcinogenesis by PAHs is believed to involve alkylation of an informational macromolecule in a critical, but at present unknown, manner. Such an interaction with a protein has been modelled by alkylation of a peptide this showed a conformational change occurred on alkylation. It has not yet been possible to study the structure of DNA alkylated by an activated carcinogen this is because DNA is a fiber and the structural order in it is not sufficient for a crystal structure determination. However the crystal structures of some alkylated portions of nucleic acids are described, particularly some nucleosides alkylated by chloromethyl derivatives of DMBA. In crystals of these alkylation products the PAH portion of the adduct shows a tendency to lie between the bases of other nucleoside... 

Figure 2. Views of some carcinogenic molecules showing K- and bay- regions. Views are given of BP (I), DMBA (II), 3-methyl-cholanthrene (III), ll-methyl-15,16-dihydrocyclopenta[a]phen-anthracene (VII) and 5-methylchrysene (VIII). These and all subsequent ball-and-stick diagrams were drawn using the computer program VIEW (141).

The mode of action of this carcinogen is believed to involve epoxidation of a double bond (49), as indicated in Figure 3 in this Figure the similarities of the shapes, and particularly of the sites of activation of aflatoxin, BP and DMBA are demonstrated. Aflatoxin has functional groups at each end of the molecule, unlike an activated PAH which has functional groups only at one end of the molecule. 

At first three K-region oxides were studied, those of DMBA (XI), BP (XII) and phenanthrene, the non-carcinogenic parent (XIII) the structures are shown in Figure 8. These epoxides, which were considered very reactive, were found to remain stable both in air and in the X-ray beam when in the crystalline state (82, 83). 

In addition to influencing hydrocarbon metabolite-DNA reactions, the physical binding properties of hydrocarbon metabolites covalently bound to DNA may also be important to carcinogenic activity. The covalent binding of ultimate carcinogens derived from BP and DMBA to DNA produces adducts with tt binding properties similar to those of naturally occurring nucleotides. These adducts... 

Phenol has been tested in animals for carcinogenicity by the oral and dermal routes, but results are equivocal. In a chronic NCI cancer bioassay (NCI 1980), a significant incidence of tumors (pheochro-mocytomas of the adrenal gland, leukemia, or lymphomas) occurred only in male rats exposed to the lowest dose level (2,500 ppm, 277 mg/kg/day) of phenol but not in male or female mice or male rats exposed to a higher dose level (5,000 ppm, 624 mg/kg/day). Since tumors occurred only in males in one of the two species tested, and since a positive dose-response relationship was not established, this study does not provide sufficient evidence to conclude that phenol is carcinogenic when administered by the oral route. Dermal application of phenol has been shown to result in tumors in mice phenol is a tumor promoter when it is applied after the application of the tumor initiator DMBA (Boutwell and Bosch 1959 Salaman and Glendenning 1957 Wynder and Hoffmann 1961). However, this effect occurs at dose levels of phenol that produce severe skin... 

Goerttler, K. and Laehrke, H. (1976). "Diaplacental carcinogenesis initiation with the carcinogens dimethyl-benzanthracene (DMBA) and urethane during fetal life and postnatal promotion with the phorbol ester TPA in a modified 2-stage BerenblumyMottram experiment, Virch. Arch. Path. Anat. HistoL 372,29. 

Indeed, in the experiment described above with the carcinogen DMBA, the production of papillomas in mice shows a sigmoid dose-response curve when plotted against the concentration of TPA. The dose-response curve for the interaction between the TPA and its receptor mirrors this dose-response curve almost exactly. 

The anti-carcinogenic effects of resveratrol were also tested in vivo, by examination of mammary glands of mice treated with DMBA and TPA. A dose-dependent reduction in the formation of tumors was observed when the mice were treated with resveratrol. Resveratrol is present in high concentrations in the skins of grapes (50-100 pg/g) and, consequently, in red wine (1.5-3 mg/1). Based on these experiments, the consumption of grapes and grape products appears to have beneficial effects. 

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