Reactions of oxidatively activated arylamines with thiols: reaction mechanisms and biologic implications. An overview.

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 ic-donors, like 4-nitrosophenetol, give a resonance-stabilized N-lthiol-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. -Environ Health Perspect 102(Suppl 6): 123-132 (1994)

Enzymatic Reduction and Glutathione Conjugation of Benzoquinone Ansamycin Heat Shock Protein 90 Inhibitors: Relevance for Toxicity and Mechanism of Action

“…In reactions in phosphate buffer at pH 7.4 and room temperature using 5 mM reduced glutathione and 50 μM BA, approximately 45 μM of GMH 2 -SG conjugate was formed within 5 min which then slowly oxidized to GM-SG (Figure 5A). This indicates formation via a classic 1,4-reductive Michael addition generating the hydroquinone conjugate intermediates which are then oxidized to quinone conjugates (Monks and lau, 1992; Eyer, 1994). Under the same conditions, approximately 47 μM of 17DMAG-SG conjugate was formed within 4 hours while 17DMAGH 2 -SG was not detected (Figure 6A).…”

Metabolism and Biomarkers of Heterocyclic Aromatic Amines in Molecular Epidemiology Studies: Lessons Learned from Aromatic Amines

“…Reaction pathways of nitrosoarenes, nitroso-HAAs, or nitro-HAA intermediates with GSH and GSTs (393,419,420,429,430) .…”

“…The interaction of GSH or other thiols with arylnitroso compounds has been extensively examined. The reactions are complex and product formation is dependent on thiol concentration, pH, and substituent effects (419-421) . The initial product formed between the arylnitroso derivatives and GSH is a labile semimercaptal.…”

S-Nitrosoglutathione is a substrate for rat alcohol dehydrogenase class III isoenzyme

“…A similar product, called a ' semimercaptal ', has been considered to arise consequent to the reaction of glutathione with nitroso-arenes, the latter formed through the metabolic N-oxygenation of aromatic amines or the reduction of nitro aromatics [47][48][49]. The semimercaptal evidently has a transient existence, however, and spontaneously ' rearranges ' to a glutathione sulphinamide (shown to be a loss and subsequent addition of hydroxy moiety [48]). Glutathione sulphinamides are somewhat labile in mild acid and hydrolyse to glutathione sulphinic acid and an amine [47].…”