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730470 
Journal Article 
Mechanisms of mutagenicity of DNA adducts derived from alkyl and vinyl halides 
Guengerich, FP 
1997 
Eisei Kagaku / Journal of Hygienic Chemistry
ISSN: 0013-273X 
43 
69-82 
English 
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 O^6-alkyl guanines and O^2- and O^4-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. CH_2Cl_2) 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 CHCl_3. 
DNA adduct; halogenated hydrocarbon; mutagenesis; glutathione; vinyl chloride; cytochrome P450