Article

7,12-Dimethylbenz[a]anthracene induces oxidative DNA modification in vivo

Department of Environmental Medicine, New York University Medical Center, New York, NY 10016-6451, USA.
Free Radical Biology and Medicine (Impact Factor: 5.71). 10/1995; 19(3):373-80. DOI: 10.1016/0891-5849(95)00046-Z
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ABSTRACT Initiation and promotion are major stages in the multistage carcinogenesis process. Formation of initiating carcinogen-DNA base adducts leads to heritable genetic changes, but the tumor-promoting events induced by complete carcinogens have not, as yet, been elucidated. Oxidant production and oxidative DNA damage induced by phorbol esters (i.e., 12-O-tetradecanoyl-phorbol-13-acetate) are associated with tumor promotion, while antioxidants and inhibitors of oxidative DNA damage suppress promotion and carcinogenesis. Our goal was to establish whether a carcinogen that requires oxidative metabolism for its activity can also induce oxidant production and DNA base oxidation. We found that topical treatment of SENCAR mice with 7,12-dimethylbenz[a]anthracene, which induces tumors in 40-50% of the mice, also causes hydrogen peroxide production and formation of oxidized bases (i.e., 8-hydroxyl-2'-deoxyguanosine and 5-hydroxymethyl-2'-deoxyuridine) in epidermal DNA. The levels of oxidized bases were of comparable magnitude to those mediated by the potent tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. The oxidized bases persisted over several weeks in epidermal DNA. These oxidative events appear to be temporally associated with inflammatory responses that include edema and polymorphonuclear leukocyte infiltration, which remained elevated over longer periods of time and at higher levels than those induced by phorbol ester. Because these processes are usually associated with tumor promotion, our results support the conjecture that oxidative events may be involved in what is operationally referred to as the tumor promotion process by 7,12-dimethylbenz[a]anthracene.

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    • "During metabolic activation of DMBA to diol epoxide an overproduction of reactive oxygen species occurs causing oxidative damage to DNA (Ray and Husain, 2002; Frenkel et al., 1995). "
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    Toxicology Letters 11/2013; 224(2). DOI:10.1016/j.toxlet.2013.10.012 · 3.36 Impact Factor
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    • "Hence, we have just initiated a comprehensive repetition of DMBA/TPA treatment where we will have a representative sample of animals from different stages following the application of this carcinogen in order to answer this question through quantification of apoptosis and senescence of Spalax skin and muscle tissue at the area of the carcinogen application. Furthermore, considering the high tolerance of Spalax to oxidative stress and the fact that DMBA is metabolized among others into ROS that cause oxidative DNA damage in the skin [31], the above experiment will allow us to compare the ROS levels upon DMBA application in Spalax and mice. "
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    • "Arsenite can act as a co-carcinogen with UV light in a mouse skin model (Rossman et al., 2001a). Chemicals possessing tumor initiating and/or enhancing properties, such as 7,12-dimethyl benz[a]anthracene (DMBA), 12-O- tetradecanoylphorbol-13-acetate (TPA), and UV radiation commonly induce chronic inflammation and oxidative stress (Wei and Frenkel, 1993; Frenkel et al., 1995; Soriani et al., 1999). It is thought that inflammatory reactions, characterized by the modulation of various cytokines and other inflammatory factors, may play an important role during the process of carcinogenesis [reviewed in (Frenkel, 1992; Shacter and Weitzman, 2002)]. "
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