Mechanisms of Mutagenicity of DNA Adducts Derived from Alkyl and Vinyl Halides

Many small alkyl and vinyl halides are used on a large scale in industrial settings, and most are potentially capable of causing cancer. In general these compounds cause mutations, after activation by various metabolic pathways. In many cases oxidation by cytochrome P450 enzymes results in the formation of electrophiles that bind DNA ; however, sometimes activation is the result of enzymatic conjugation with glutathione (GSH). The adducts derived from vinyl chloride (via 2-chlorooxirane) are best characterized and include N7-(2-oxoethyl) guanine, 1, N6-etheno (ε) adenine, 5, 6, 7, 9-tetrahydro-7-hydroxy-9-oxoimidazo [1, 2-a] purine, 3, N4-ε-cytosine, N2, 3-ε-guanine, and 1, N2-ε-guanine. All of the ε adducts are capable of miscoding in various situations, and the extent of misincorporation seems to vary with the polymerase. Monoalkyl halides react directly with DNA, and evidence exists for the importance of O6-alkyl guanines and O2- and O4-alkyl thymidines in miscoding. Several of the vinyl and alkyl halides can be activated to electrophiles by enzymatic GSH conjugation. This group includes polyhalogenated olefins, which appear to yield N-acyl-modified DNA adducts and their derivatives. GSH conjugation with 1, 2-dihaloalkanes yields half-mustards, which form episulfonium ions due to anchimeric assistance. Known DNA adducts derived from 1, 2-dibromoethane include S-[2-(N7-guanyl) ethyl] GSH, S-[2-(N1-adenyl) ethyl] GSH, S-[2-(N2-guanyl) ethyl] GSH, and S-[2-(O6-guanyl) ethyl] GSH. One of the guanyl adducts appears to be responsible for the GC to AT transitions observed in several different systems. The activation of dihalomethanes (e.g. CH2Cl2) is also understood in terms of GSH conjugation, which yields S-[1-(N2-guanyl) methyl] GSH. This type of activation scheme may also apply with CHCl3.