Additional pathways of S-conjugate formation during the interaction of thiols with nitrosoarenes bearing pi-donating substituents.
During the well-established reaction pathways of nitrosoarenes interacting with thiols, a reactive N-(thiol-S-yl)-arylamine cation was implicated in the so-called rearrangement reaction which transforms the semimercaptal to the sulfinamide. In the case of nitrosoarenes with pi-donating substituents, this cationic transition state includes resonance structures bearing the positive charge in 2 and 4 position, thereby facilitating the attack of nucleophiles to the aromatic ring. Investigating the reaction products of 4-nitrosophenetol and reduced glutathione in chemical systems and human red cells, some glutatione S-conjugates were detected other than the already known sulfenamide and sulfinamide. Three of them were separated by HPLC and identified by mass spectroscopy, 1H-NMR, and UV-visible spectroscopy, by determination of pKa values and chemical behavior. The hitherto unknown conjugates are 4-ethoxy-2-(glutathione-S-yl)-aniline, N-(4-ethoxyphenyl)-N'-(glutathione-S-yl)-benzoquinonediimine, and 4-amino-4'-ethoxy-2-(glutathione-S-yl)-diphenylamine. In preliminary experiments, some of these conjugates were shown to be highly active in producing ferrihemoglobin. Considerations on the formation pathways of these metabolites lend further support to the electrophilic N-(glutathione-S-yl)arylamine cation as a reactive intermediate that may be implicated in nitrosoarene toxicity.
Gallemann
D
D
Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Germany.
Eyer
P
P
D000595:Amino Acid Sequence; D002412:Cations; D004912:Erythrocytes / Q000378:metabolism*; D005019:Ethyl Ethers / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry*; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009603:Nitroso Compounds / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D002412:Cations; D005019:Ethyl Ethers; D009603:Nitroso Compounds; D013438:Sulfhydryl Compounds; D005978:Glutathione