Sulfur-containing proreactive intermediates: hydrolysis and mutagenicity of halovinyl 2-nitrophenyl disulfides.
Chemical cleavage of the sulfur-sulfur bond in halovinyl and fluoroalkyl 2-nitrophenyl disulfides is expected to yield halovinyl and fluoroalkyl thiols identical to those formed by cysteine conjugate beta-lyase catalyzed cleavage of the corresponding cysteine S-conjugates. To study the potential use of disulfides as precursors for these thiols, whose transformation to acylating agents is most likely responsible for cysteine S-conjugate mutagenicity, we determined the mutagenicity of several halovinyl and fluoroalkyl 2-nitrophenyl disulfides and identified products formed by hydrolysis of these disulfides, 1,2,3,4,4-Pentachlorobutadienyl 2-nitrophenyl disulfide, 1,2,2-trichlorovinyl 2-nitrophenyl disulfide, 1-fluro-2,2-dichlorovinyl 2-nitrophenyl disulfide and 1,2-dichloro-3,3,3-trifluropropenyl 2-nitrophenyl disulfide were mutagenic in nitroreductase deficient strains of Salmonella typhimurium TA100; as haloalkyl cysteine S-conjugates, 1,1-difluoro-2,2-dichloroethyl 2-nitrophenyl disulfide and 1-chloro-1,2,2-trifluroethyl 2-nitrophenyl disulfide were not mutagenic. Hydrolysis of 1,2,3,4,4-pentachlorobutadienyl 2-nitrophenyl disulfide and 1,2,2-trifluorethyl 2-nitrophenyl disulfide in presence of diethylamine resulted in tetrachlorothiobutenoic acid diethylamide and chlorofluorothionoacetic acid diethylamide. The differences in mutagenicity between halovinyl and fluoroalkyl disulfides are most likely responsible to their different abilities to react with DNA-constituents. Products formed from the mutagenic 1,2,3,4,4-pentachlorobutadienyl 2-nitrophenyl disulfide modified 2'-deoxyguanosine-3'-monophosphate and DNA as detected by 32Phosphorus-postlabeling, whereas products formed from the nonmutagenic 1-chloro-1,2,2-trifluoroethyl 2-nitrophenyl disulfide did not result in detectable 2'-deoxyguanosine-3'-monophosphate and DNA modification.
Müller
D A
DA
Institut für Toxikologie, Universität Würzburg, F.R.G.
Urban
G
G
Dekant
W
W
D004247:DNA / Q000737:chemistry; D004249:DNA Damage; D003848:Deoxyguanine Nucleotides / Q000737:chemistry; D004220:Disulfides / Q000737:chemistry / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D006219:Halogens / Q000737:chemistry / Q000633:toxicity*; D006868:Hydrolysis; D009152:Mutagenicity Tests; D009153:Mutagens; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014753:Vinyl Compounds / Q000737:chemistry / Q000633:toxicity*
D003848:Deoxyguanine Nucleotides; D004220:Disulfides; D006219:Halogens; D009153:Mutagens; D011355:Prodrugs; D013438:Sulfhydryl Compounds; D014753:Vinyl Compounds; C007257:2'-deoxyguanosine 5'-phosphate; D004247:DNA