Reactions of oxidatively activated arylamines with thiols: reaction mechanisms and biologic implications. An overview.
Open Access
- 1 October 1994
- journal article
- review article
- Published by Environmental Health Perspectives in Environmental Health Perspectives
- Vol. 102 (suppl 6) , 123-132
- https://doi.org/10.1289/ehp.94102s6123
Abstract
Aromatic amines belong to a group of compounds that exert their toxic effects usually after oxidative biotransformation, primarily in the liver. In addition, aromatic amines also undergo extrahepatic activation to yield free arylaminyl radicals. The reactive intermediates are potential promutagens and procarcinogens, and responsible for target tissue toxicity. Since thiols react with these intermediates at high rates, it is of interest to know the underlying reaction mechanisms and the toxicologic implications. Phenoxyl radicals from aminophenols and aminyl radicals from phenylenediamines quickly disproportionate to quinone imines and quinone diimines. Depending on the structure, Michael addition or reduction reactions with thiols may prevail. Products of sequential oxidation/addition reactions (e.g., S-conjugates of aminophenols) are occasionally more toxic than the parent compounds because of their higher autoxidizability and their accumulation in the kidney. Even after covalent binding of quinone imines to protein SH groups, the resulting thioethers are able to autoxidize. The quinoid thioethers can then cross-link the protein by addition to neighboring nucleophiles. The reactions of nitrosoarenes with thiols yield a so-called "semimercaptal" from which various branching reactions detach, depending on substituents. Compounds with strong pi-donors, like 4-nitrosophenetol, give a resonance-stabilized N-(thiol-S-yl)-arylamine cation that may lead to bicyclic products, thioethers, and DNA adducts. Examples of toxicologic implications of the interactions of nitroso compounds with thiols are given for nitrosoimidazoles, heterocyclic nitroso compounds from protein pyrolysates, and nitrosoarenes. These data indicate that interactions of activated arylamines with thiols may not be regarded exclusively as detoxication reactions.Keywords
This publication has 93 references indexed in Scilit:
- Covalent binding of acetaminophen to mouse hemoglobin. Identification of major and minor adducts formed in vivo and implications for the nature of the arylating metabolitesPublished by Elsevier ,2002
- Reactions of the wurster's red radical cation with hemoglobin and glutathione during the cooxidation of N,N-dimethyl-p-phenlenediamine and oxyhemoglobin in human red cellsChemico-Biological Interactions, 1992
- Reactions of nitrosonitrobenzenes with biological thiols: Identification and reactivity of glutathion-S-yl conjugatesChemico-Biological Interactions, 1992
- Reactions of the Wurster's blue radical cation with thiols, and some properties of the reaction productsChemico-Biological Interactions, 1991
- Non-enzymatic glutathione conjugation of 2-nitroso-6-methyldipyrido [1,2-a: 3′,2′-d] imidazole (NOGluP-1) in vitro: N-hydroxy-sulfonamide, a new binding form of arylnitroso compounds and thiolsChemico-Biological Interactions, 1988
- On the Mechanism of Reactions of Nitrosoarenes with Thiols. Formation of a Common Intermediate “Semimercaptal”Biological Chemistry Hoppe-Seyler, 1985
- Thiyl radicals - formation during peroxidase-catalyzed metabolism of acetaminophen in the presence of thiolsBiochemical and Biophysical Research Communications, 1984
- Glutathione conjugation of arylnitroso compound: Detection and monitoring labile intermediates in situ inside a fast atom bombardment mass spectrometerBiochemical and Biophysical Research Communications, 1984
- Glutathione conjugates of misonidazoleBiochemical and Biophysical Research Communications, 1983
- Reactions of nitrosobenzene with reduced glutathioneChemico-Biological Interactions, 1979