Formation of O6-ethylthioethylguanine in DNA by reaction with the sulfur mustard, chloroethyl sulfide, and its apparent lack of repair by O6-alkylguanine-DNA alkyltransferase.
The reactions of the monofunctional sulfur mustard, chloroethyl ethyl sulfide, with calf thymus DNA have been studied in vitro. In addition to extensive alkylation of the 7 position of guanine and the 3 position of adenine, approximately 0.1% of the total alkylation is on the O6 position of guanine. Since chloroethyl ethyl sulfide is a model for S-adenosylmethionine and for the reactive intermediates generated from glutathione by certain environmental agents, this result establishes a route by which these compounds could be mutagenic. A DNA substrate modified for repair studies has been produced by incubating calf thymus DNA with [14C]chloroethyl-labelled chloroethyl ethyl sulfide. This DNA contains 6 nmol/mg of alkylated products including 6 pmol/mg O6-ethylthioethylguanine. Incubation of this substrate with up to a 20-fold excess of mammalian O6-alkylguanine-DNA alkyltransferase has indicated that O6-ethylthioethylguanine is either not a substrate or a poor one for this DNA repair system.
D000225:Adenine / Q000378:metabolism; D000478:Alkylation; D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006147:Guanine / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism*; D009150:Mustard Compounds / Q000494:pharmacology*; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase
D009150:Mustard Compounds; D006147:Guanine; C031278:2-chloroethyl ethyl sulfide; D004247:DNA; C043642:O(6)-ethylthioethyldeoxyguanosine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D003849:Deoxyguanosine; D000225:Adenine; D009151:Mustard Gas