The relevance of DNA damage and repair to the vesicant action of sulfur mustard is supported by the observation that inhibitors of DNA repair significantly exacerbate skin injury.
Sulfur mustard at neutral pH alkylates purines, pyrimidines, nucleosides, and nucleotides, preferentially at N-7 of guanine and N-1 of adenine. Reactions with 0-6 and N-2 of guanine and N-6 of adenine have also been reported. The following products have been isolated from the reaction of sulfur mustard with DNA (5-18):
Sulfur mustard, because of its bifunctional nature, is more cytotoxic than is its monofunctional analogue. The molecular basis for this greater toxicity is the ability of sulfur mustard to form interstrand cross-links between guanines of the double helix, which prevents strand separation during replication. In addition, 7-alkylguanines and 3-alkyladenines of DNA are unstable and are released spontaneously from sulfur mustard-treated DNA at physiologic pH and temperature by cleavage of the N-9 glycosyl bond to give an apurinic site. Opening of the imidazole ring of this alkylated purine may also occur under physiologic conditions.
Although sulfur mustard also reacts with RNA, proteins, and phospholipids, the consensus of opinion has been for some time that it is the alkylation of DNA that is by far the most important of its actions. The interstrand DNA cross-link produced by bifunctional mustard com-