DNA ADDUCT FORMATION BY ALLYL GLYCIDYL ETHER

Glycidyl ethers are reactive epoxides used as components of a variety of epoxy materials, These compounds are known to cause allergic reacti ons, but since they are generally also genotoxic it would be of intere st to evaluate the risk for induction of such effects, Reaction produc ts of allyl glycidyl ether with nucleic acid components were therefore studied, Adduct standards of expected major products in DNA were prep ared and assigned to N-7-guanine, N-1- and N-3-adenine and N-3-cytosin e, The adducts were characterized by UV spectroscopy, and the adduct t o N-1-adenine also by mass spectrometry and nuclear magnetic resonance spectroscopy, In analogy with the formation of corresponding reaction products of other simple epoxides the N-1-adenine adduct rearranged i n a base catalysed reaction to N-6 and the N-3-cytosine adduct deamina ted to form the corresponding N-3-uracil adduct, For allyl glycidyl et her these further reactions of the N-1-adenine and N-3-cytosine adduct s were, however, slower than has been observed for corresponding produ cts of other epoxides, but faster than for methylated and ethylated pr oducts, In double-stranded salmon testis DNA treated in vitro with all yl glycidyl ether, the major product was found at N-7-guanine, followe d by those at N-1-adenine, N-3-adenine and N-3-cytosine (including N-3 -uracil). A minor amount of an N-6-adenine adduct was also detected, b ut only after 48 h of reaction, In single-stranded DNA the yield of th e N-1-adenine adduct was increased to about the level of the N-7-guani ne adduct, The level of the N-3-cytosine adduct was also considerably higher in single-stranded DNA and was the third largest adduct, The re activity of N-3-adenine was decreased in single-stranded DNA and since other adducts increased the relative yield of this adduct was very lo w, The N-7-guanine and N-3-adenine adducts were lost from DNA as a con sequence of depurination with half-lives in double-stranded DNA at 37 degrees C and pH 7.4 of 38 and 20 h, respectively, The rates of losses (due to depurination or rearrangement) of initially formed adducts in DNA increased in the order N-1-adenine < N-7-guanine approximate to N -3-cytosine < N-3-adenine and were faster in single- than in double-st randed DNA, Taking only the rate of formation and chemical stability i nto consideration, the adducts with N-1-adenine and N-7-guanine seem t o be the most promising candidates for monitoring allyl glycidyl ether exposures in vivo.