Xenobiotics adduct formation with DNA

Rahimtula, M., Washington, W., Gregory, B. and O Brien, P.J. (1985). Xenobiotic Adduct Formation with DNA or GSH Following Oxidation by Lipid Peroxide or H202-Peroxidase. 

Prostaglandin synthetase, peroxidase or lipid peroxidation have been shown to oxidise arylamine xenobiotics to reactive species that bind extensively to DNA. The binding could be an initial event in the toxic or carcinogenic process. Evidence is presented that cation radicals are involved in the formation of the various oxidation products and DNA adduct formation with the carcinogen aminofluorene. Furthermore methylaminoazobenzene (butter yellow) was found to form the same major GSH adduct as is formed in vivo. 

The pollutant (xenobiotic) forms a stable covalent bond with its target. Examples include the phosphorylation of cholinesterases by the oxon forms of OPs, the formation of DNA adducts by the reactive epoxides of benzo[a] pyrene and other PAHs, and the binding of organomercury compounds to... 

Figure 13.8. GST may enhance the toxicity of xenobiotics. Ethylene dibromide is a substrate of GST (theta and others) to be converted to l-bromo-2-.S -glutathionyl ethane, which facilitates spontaneous formation of the episulfonium ion. The episulfonium ion attacks the N7 position of guanine and causes DNA adduct formation. GST pi Ilel05 to Val polymorphism, causing increased GSTpi activity, appears to correlate with higher testicular and bladder cancer. This may also be involved in GSTpi-mediated activation of unidentified xenobiotics. (Adapted from Henderson et al. Proc. Natl. Acad. Sci. USA 95, 5275-5280,1998.)...

---