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. 1994 Oct;102(Suppl 6):137–142. doi: 10.1289/ehp.94102s6137

Additional pathways of S-conjugate formation during the interaction of thiols with nitrosoarenes bearing pi-donating substituents.

D Gallemann 1, P Eyer 1
PMCID: PMC1566862  PMID: 7889836

Abstract

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.

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Selected References

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  1. Dölle B., Töpner W., Neumann H. G. Reaction of arylnitroso compounds with mercaptans. Xenobiotica. 1980 Jul-Aug;10(7-8):527–536. doi: 10.3109/00498258009033787. [DOI] [PubMed] [Google Scholar]
  2. Eckert K. G., Eyer P., Sonnenbichler J., Zetl I. Activation and detoxication of aminophenols. II. Synthesis and structural elucidation of various thiol addition products of 1,4-benzoquinoneimine and N-acetyl-1,4-benzoquinoneimine. Xenobiotica. 1990 Apr;20(4):333–350. doi: 10.3109/00498259009046851. [DOI] [PubMed] [Google Scholar]
  3. Ellis M. K., Hill S., Foster P. M. Reactions of nitrosonitrobenzenes with biological thiols: identification and reactivity of glutathion-S-yl conjugates. Chem Biol Interact. 1992 Apr 15;82(2):151–163. doi: 10.1016/0009-2797(92)90107-v. [DOI] [PubMed] [Google Scholar]
  4. Eyer P., Ascherl M. Reactions of para-substituted nitrosobenzenes with human hemoglobin. Biol Chem Hoppe Seyler. 1987 Mar;368(3):285–294. doi: 10.1515/bchm3.1987.368.1.285. [DOI] [PubMed] [Google Scholar]
  5. Eyer P., Hertle H., Kiese M., Klein G. Kinetics of ferrihemoglobin formation by some reducing agents, and the role of hydrogen peroxide. Mol Pharmacol. 1975 May;11(3):326–334. [PubMed] [Google Scholar]
  6. Eyer P. Reactions of nitrosobenzene with reduced glutathione. Chem Biol Interact. 1979 Feb;24(2):227–239. doi: 10.1016/0009-2797(79)90011-5. [DOI] [PubMed] [Google Scholar]
  7. Eyer P. Reactions of oxidatively activated arylamines with thiols: reaction mechanisms and biologic implications. An overview. Environ Health Perspect. 1994 Oct;102 (Suppl 6):123–132. doi: 10.1289/ehp.94102s6123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gallemann D., Eyer P. Effects of the phenacetin metabolite 4-nitrosophenetol on glycolysis and pentose phosphate pathway in human red cells. Biol Chem Hoppe Seyler. 1993 Jan;374(1):37–49. doi: 10.1515/bchm3.1993.374.1-6.37. [DOI] [PubMed] [Google Scholar]
  9. Gallemann D., Eyer P. Effects of the phenacetin metabolite 4-nitrosophenetol on the glutathione status and the transport of glutathione S-conjugates in human red cells. Biol Chem Hoppe Seyler. 1993 Jan;374(1):51–60. doi: 10.1515/bchm3.1993.374.1-6.51. [DOI] [PubMed] [Google Scholar]
  10. Klehr H., Eyer P., Schäfer W. Formation of 4-ethoxy-4'-nitrosodiphenylamine in the reaction of the phenacetin metabolite 4-nitrosophenetol with glutathione. Biol Chem Hoppe Seyler. 1987 Aug;368(8):895–902. doi: 10.1515/bchm3.1987.368.2.895. [DOI] [PubMed] [Google Scholar]
  11. Klehr H., Eyer P., Schäfer W. On the mechanism of reactions of nitrosoarenes with thiols. Formation of a common intermediate "semimercaptal". Biol Chem Hoppe Seyler. 1985 Aug;366(8):755–760. doi: 10.1515/bchm3.1985.366.2.755. [DOI] [PubMed] [Google Scholar]
  12. Maples K. R., Eyer P., Mason R. P. Aniline-, phenylhydroxylamine-, nitrosobenzene-, and nitrobenzene-induced hemoglobin thiyl free radical formation in vivo and in vitro. Mol Pharmacol. 1990 Feb;37(2):311–318. [PubMed] [Google Scholar]
  13. Mulder G. J., Kadlubar F. F., Mays J. B., Hinson J. A. Reaction of mutagenic phenacetin metabolites with glutathione and DNA. Possible implications for toxicity. Mol Pharmacol. 1984 Sep;26(2):342–347. [PubMed] [Google Scholar]
  14. Ross D., Larsson R., Norbeck K., Ryhage R., Moldéus P. Characterization and mechanism of formation of reactive products formed during peroxidase-catalyzed oxidation of p-phenetidine. Trapping of reactive species by reduced glutathione and butylated hydroxyanisole. Mol Pharmacol. 1985 Feb;27(2):277–286. [PubMed] [Google Scholar]

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