Studies on the mechanism of toxicity of acetaminophen. Synthesis and reactions of N-acetyl-2,6-dimethyl- and N-acetyl-3,5-dimethyl-p-benzoquinone imines

Fernando, C; Calder, I. C.; Ham, Kathryn N.

doi:10.1021/jm00185a001

Cited by 85 publications

(29 citation statements)

References 7 publications

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“…16 In contrast, N -acetyl-3,5-dimethyl- p -benzoquinone imine reacted with aniline to give the N -phenyl quinone imine, whereas the 2,6-isomer gave a tetrahedral adduct in which the acetamido group was retained. 17 In the present work, we looked for and found no evidence by mass spectrometry for 1,4--addition of N α -( t -Boc)lysine to 3,5-DMQI when forming 2a . 1,4-Addition is clearly not blocked by the methyl substituents, but it is directed toward the unsubstituted positions on the ring: we found that 3,5-DMQI reacts with N -acetylcysteine at the 2-position at much greater rates than the rate of transimination with N α -( t -Boc)lysine, and similarly, N -acetyl-3,5-dimethyl- p -benzoquinone imine readily forms a Michael product with ethanethiol.…”

mentioning

confidence: 65%

Transimination of Quinone Imines: A Mechanism for Embedding Exogenous Redox Activity into the Nucleosome

Seneviratne

Chao

et al. 2012

Chem. Res. Toxicol.

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Aminophenols can redox cycle through the corresponding quinone imines to generate ROS. The electrophilic quinone imine intermediate can react with protein thiols as a mechanism of immobilization in vivo. Here, we describe the previously unkown transimination of a quinone imine by lysine as an alternative anchoring mechanism. The redox properties of the condensation product remain largely unchanged because the only structural change to the redox nucleus is the addition of an alkyl substituent to the imine nitrogen. Transimination enables targeting of histone proteins since histones are lysine-rich but nearly devoid of cysteines. Consequently, quinone imines can be embedded in the nucleosome and may be expected to produce ROS in maximal proximity to the genome.

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mentioning

confidence: 65%

Transimination of Quinone Imines: A Mechanism for Embedding Exogenous Redox Activity into the Nucleosome

Seneviratne

Chao

et al. 2012

Chem. Res. Toxicol.

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“…It may result from the reaction of GSH with both the radical and the quinone diimine. In the latter case, ipso adduct formation is conceivable, as already discussed for other quinone imines (10)(11)(12). The situation in the former case is more puzzling.…”

Section: Environmental Health Perspectivesmentioning

confidence: 74%

“…With all three compounds, thioethers were produced, but significant amounts of GSSG were found only with NAPAP (21). The mechanism of GSSG formation has been attributed to intermediate ipso adducts which, after attack of a second GSH molecule, yield GSSG and NAPAP (10)(11)(12). During the reaction of the quinone imine of p-aminophenol with GSH, sequential oxidation/addition reactions occur as revealed by a variety of polysubstituted thioadducts.…”

Section: Quinone Iminesmentioning

confidence: 99%

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

Eyer

1994

Environ Health Perspect

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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)

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“…3',5'-Dimethylacetaminophen (3',5'-dimethyl-4'-hydroxyacetanilide) is reported to be of comparable toxicity to acetaminophen itself (18). 3',5'-Dimethylacetaminophen (3',5'-dimethyl-4'-hydroxyacetanilide) is reported to be of comparable toxicity to acetaminophen itself (18).…”

Section: As Shown In Eqs (3)-(5) This One-electron Pathway Is Formamentioning

confidence: 99%

“…The slow decay of the absorbance is probably due to hydrolysis of N-acetyl-3,5-dimethyl-p-benzoquinone imine(18). As one can see, varying the concentration of horseradish peroxidase from 0.5 ,ug/mL to 4.0 ,ug/mL results in a linear increase in the rate of N-acetyl-3,5-dimethyl-p-benzo-Third group of the ESR spectrum obtained from the 2H3-3',5'-dimethylacetaminophen phenoxyl free radical: (A) experimental conditions were: 10 mM 2H3-3',5'-dimethylacetaminophen, 10 mM H202, and 1.0 p.g/mL horseradish peroxidase in phosphate buffer, pH 7.4, under a nitrogen atmosphere; (B) computer simulation.…”

mentioning

confidence: 99%

Free-Radical Metabolites of Acetaminophen and a Dimethylated Derivative

Fischer¹,

West²,

Harman³

et al. 1985

Environmental Health Perspectives

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JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives. The oxidation of acetaminophen (4'-hydroxyacetanilide) to the corresponding N-acetyl-p-benzoquinone imines by plant and mammalian peroxidases is discussed. The acetaminophen free radical (N-acetyl-4aminophenoxyl) has been reported as an intermediate. It is very reactive and forms melanin-like polymeric products. Application of a fast-flow system makes it possible to detect the transient species and clearly distinguish it from persistent paramagnetic melanin polymers.A model system, leading to more stable metabolites, can be obtained by introduction of methyl groups next to the oxygen, 3',5'-dimethylacetaminophen (3',5'-dimethyl-4'-hydroxyacetanilide). The ESR spectrum of the free radical formed could be completely analyzed and confirmed by deuterium substitution. The data are consistent with the assignment to a phenoxyl free radical (N-acetyl-2,6-dimethyl-4-aminophenoxyl). Its formation is discussed in terms of substrate, hydrogen peroxide and enzyme concentration dependence. It is believed to be formed via a direct one-electron oxidation of 3',5'-dimethyl-4'-hydroxyacetanilide.The radical does not form polymers or react with nucleophiles. Its redox behavior is discussed. The possible reaction of these phenoxyl free radicals with oxygen is thought to be negligible. Acetaminophen (4'-hydroxyacetanilide) is a commonly used, mild analgesic drug which has gained acceptance as a salicylate (aspirin) substitute. Although it is considered safe in normal dosage, ingestion of large quantities of acetaminophen can result in hepatic necrosis and acute renal failure in man (1,2). This toxicity has been attributed to the formation of a highly reactive metabolic species, the N-acetyl-p-benzoquinone imine (3,4), which is thought to bind covalently to protein in vivo. Under therapeutic dose conditions, tissue glutathione appears to protect against hepatic damage by binding to the N-acetyl-p-benzoquinone imine, as evidenced by acetaminophen dose-dependent depletion of liver glutathione (5,6). When acetaminophen is present in excess, however, the glutathione levels are depleted, leading to covalent binding of the arylating metabolite to tissue macromolecules and hepatic cell death (6,7). Several mechanisms for N-acetyl-p-benzoquinone imine formation have been proposed. Metabolic activation might occur through N-oxidation of acetaminophen to N-hydroxyacetaminophen, followed by dehydration to the arylating N-acetyl-p-benzoquinone imine (8) [Eq.(1)].

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Studies on the mechanism of toxicity of acetaminophen. Synthesis and reactions of N-acetyl-2,6-dimethyl- and N-acetyl-3,5-dimethyl-p-benzoquinone imines

Cited by 85 publications

References 7 publications

Transimination of Quinone Imines: A Mechanism for Embedding Exogenous Redox Activity into the Nucleosome

Transimination of Quinone Imines: A Mechanism for Embedding Exogenous Redox Activity into the Nucleosome

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

Free-Radical Metabolites of Acetaminophen and a Dimethylated Derivative

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