Covalent binding of acetaminophen to mouse hemoglobin. Identification of major and minor adducts formed in vivo and implications for the nature of the arylating metabolites

Axworthy, Donald B.; Hoffmann, Kurt; Streeter, Anthony J.; Calleman, Carl Johan; Pascoe, Gary A.; Baillie, Thomas A.

doi:10.1016/0009-2797(88)90009-9

Cited by 48 publications

(35 citation statements)

References 23 publications

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“…The NAPQI-CPF adducts observed had slightly different product ion spectra and consequently suggested the formation of two isomers. Based on literature, we assume that the major peak is most likely the 3Ј-NAPQI-S-CPF adduct because several studies have shown that conjugation of thiols to NAPQI predominantly takes place at the 3Ј position of NAPQI (Hoffmann et al, 1985;Axworthy et al, 1988;Pumford et al, 1997;Chen et al, 1999). As the minor NAPQI-CPF adduct, two different products can be considered: a thioether ipso adduct and a 2Ј-NAPQI-S-CPF adduct.…”

Section: Lc/tandem Ms Detection Of Apap-albumin Adductsmentioning

confidence: 99%

“…Previous methods that have been used to investigate covalent binding of APAP to proteins in vivo include several immunoassays (Roberts et al, 1987;Bartolone et al, 1988;Matthews et al, 1996;James et al, 2001) and the use of radiolabeled APAP (Axworthy et al, 1988;Zhou et al, 1996;Qiu et al, 1998). Still, these methods often lack the necessary sensitivity when concerning human serum samples (Zhou, 2003) quantify covalent protein binding of APAP.…”

Section: Adductmentioning

confidence: 99%

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Liquid Chromatography/Tandem Mass Spectrometry Detection of Covalent Binding of Acetaminophen to Human Serum Albumin

Damsten¹,

Commandeur²,

Fidder³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Covalent binding of reactive electrophilic intermediates to proteins is considered to play an important role in the processes leading to adverse drug reactions and idiosyncratic drug reactions. Consequently, both for the discovery and the development of new drugs, there is a great interest in sensitive methodologies that enable the detection of covalent binding of drugs and drug candidates in vivo. In this work, we present a strategy for the generation and analysis of drug adducts to human serum albumin. Our methodology is based on the isolation of albumin from blood, its digestion to peptides by pronase E, and the sensitive detection of adducts to the characteristic cysteine-proline-phenylalanine (CPF) tripeptide by liquid chromatography/tandem mass spectrometry. We chose acetaminophen (APAP) as a model compound because this drug is known to induce covalent binding to proteins when bioactivated by cytochromes P450 to its reactive N-acetyl-p-benzoquinoneimine metabolite. First, by microsomal incubations of APAP in presence of CPF and/or intact albumin, in vitro reference adducts were generated to determine the mass spectrometric characteristics of the expected CPF adducts and to confirm their formation on pronase E digestion of the alkylated protein. When applying this methodology to albumin isolated from blood of patients exposed to APAP, we were indeed able to detect the corresponding CPF adducts. Therefore, this strategy could be seen as a potential biomonitoring tool to detect in vivo reactive intermediates of drugs and drug candidates, e.g., in the preclinical and clinical development phase.

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Section: Lc/tandem Ms Detection Of Apap-albumin Adductsmentioning

confidence: 99%

Section: Adductmentioning

confidence: 99%

Liquid Chromatography/Tandem Mass Spectrometry Detection of Covalent Binding of Acetaminophen to Human Serum Albumin

Damsten¹,

Commandeur²,

Fidder³

et al. 2007

Drug Metab Dispos

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“…[2] Additionally, an in-vivo murine study demonstrated NAPQI's permeation of erythrocytes with arylation and covalent binding of hemoglobin, while an in-vitro study of human erythrocytes show that NAPQI interferes with actin/spectrin and thereby damages erythrocyte membrane and cytoskeletal integrity. [3,4] We postulate that such effects will be more pronounced in individuals with G6PDD and could precipitate hemolytic crisis in patients with severe variants. Furthermore, cases of mild hemolysis may go clinically unrecognized in patients with less severe variants.…”

mentioning

confidence: 98%

Hemolytic crisis following acetaminophen overdose in a patient with G6PD deficiency

Rickner

Cao

Simpson

2016

Clinical Toxicology

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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: 73%

“…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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Covalent binding of acetaminophen to mouse hemoglobin. Identification of major and minor adducts formed in vivo and implications for the nature of the arylating metabolites

Cited by 48 publications

References 23 publications

Liquid Chromatography/Tandem Mass Spectrometry Detection of Covalent Binding of Acetaminophen to Human Serum Albumin

Liquid Chromatography/Tandem Mass Spectrometry Detection of Covalent Binding of Acetaminophen to Human Serum Albumin

Hemolytic crisis following acetaminophen overdose in a patient with G6PD deficiency

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

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