Reaction of acetaldehyde with hemoglobin.

George, Richard C. San; Hoberman, Henry D.

doi:10.1016/s0021-9258(19)62688-8

Cited by 98 publications

(13 citation statements)

References 32 publications

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“…These observations suggest that the mechanism of hepatic GSH depletion involves the reaction of the ethanol metabolite acetaldehyde with the GSH breakdown product Cys-Gly to yield 2-(methylthiazolidine-4-carbonyl)glycine derivative (Scheme ). ,, The thiazolidine conjugate has been detected in rat bile after chronic ethanol treatment, which incidentally led to high systemic acetaldehyde concentrations (∼50 μM), comparable to the values (∼100 μM) observed in some Japanese alcoholic patients. , Administration of large doses of l -cysteine or the thiol-based chelator d -penicillamine effectively protects ethanol-treated rats against acetaldehyde toxicity with the concomitant formation of the anticipated cyclized condensation product between d -penicillamine and acetaldehyde. − Nonenzymatic conjugation of acetaldehyde with a free α-amino terminus, ε-amine side groups of lysine residues, and sulfhydryl groups in proteins (e.g., hemoglobin and serum albumin) have been reported in vitro and in vivo in alcoholics. − Conjugates of acetaldehyde with proteins trigger the generation of antibodies against de novo acetaldehyde epitopes. , Quantification of acetaldehyde–protein conjugates, directly or via their antibodies, has been used to evaluate chronic alcohol intake. ,, …”

Section: Adverse Drug Reactions Linked To Iminium/aldehyde Formationmentioning

confidence: 94%

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Kalgutkar

2016

Chem. Res. Toxicol.

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Soft electrophiles (e.g., epoxides, quinones, quinone-imines, quinone-methides, etc.) generated via the oxidative bioactivation of phenyl, phenolic, amino-, and alkylphenolic substituents can be trapped with nucleophiles of comparable softness (e.g., glutathione or cysteine) in reactive metabolite screens. In contrast, hard nucleophiles such as cyanide and amines are frequently utilized to trap hard electrophiles (e.g., iminiums and aldehydes) that result from the oxidative bioactivation of cyclic (or acylic) amines and primary alcohols. In some instances, soft sulfydryl nucleophiles have also been utilized to trap aldehydes to yield cyclized thiazolidine adducts. Case studies where hard electrophiles are thought to be responsible for cytochrome P450 inactivation, genotoxicity, and/or target organ toxicity in animals have been presented. The association of hard electrophiles with immune-mediated idiosyncratic adverse drug reactions is less clear given the paucity of available examples and the fact that several marketed drugs containing cyclic amine motifs can generate hard electrophiles via α-carbon ring oxidation. This perspective examines available data associating toxicity with the formation of hard electrophilic intermediates from small molecule drugs/drug candidates. Pragmatic risk mitigation strategies around unwarranted idiosyncratic toxicity risks with drug candidates that generate hard electrophiles are also discussed against the backdrop of marketed agents that possess analogous cyclic amine framework.

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Section: Adverse Drug Reactions Linked To Iminium/aldehyde Formationmentioning

confidence: 94%

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Kalgutkar

2016

Chem. Res. Toxicol.

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“…Analysis of samples incubated with acetaldehyde showed that diastereoisomers of imidazolidinone adducts had been formed. This structure was originally suggested by San George and Hoberman (15) to arise as a result of spontaneous rearrangement of the unstable Schiff base. We have also developed an HPLC-MS method to mea-sure simultaneously the stable imidazolidinone adducts of the Rand β-terminals of human globin.…”

Section: Discussionmentioning

confidence: 89%

“…There have been a number of reports which show that acetaldehyde forms stable and unstable adducts with hemoglobin and other proteins (13,14) which could be used as biomarkers of exposure. The main groups on proteins which have been identified as target sites for adduction with acetaldehyde are R-amino groups (15), -amino groups (16), and thiol groups (17). In the case of hemoglobin, several types of adducts have been identified that are due to modification by acetaldehyde.…”

Section: Introductionmentioning

confidence: 99%

Stable Acetaldehyde−Protein Adducts as Biomarkers of Alcohol Exposure

Birt

Shuker

Farmer

1998

Chem. Res. Toxicol.

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The consumption of alcoholic beverages has been associated with increased risks of a number of chronic disorders including cancers. It is still not clear whether ethyl alcohol or other components such as metabolites are directly involved in the carcinogenic process or whether the effects are due to the modulation of metabolism of other carcinogens. At present, there is no good biomarker of alcohol intake, particularly at low or moderate levels of consumption. A number of studies have shown the ability of the major metabolite acetaldehyde to react with proteins in vitro to give stable and unstable adducts. The interaction of acetaldehyde with model peptides, which correspond to N-terminal globin sequences, was studied. The major stable adduct was identified by mass spectrometry and NMR as a diastereoisomeric mixture of imidazolidinones. This is believed to be formed by reaction and cyclization of the initial Schiff base adduct with the N-terminal valine. Incubation of human globin with acetaldehyde (0-2 mM) yielded products which were identified as the N-terminal adducts by electrospray ionization mass spectrometry (ESI-MS) of proteolytic digests. The specificity and sensitivity of the analysis was improved by the use of on-line HPLC-ESI-MS. Tryptic digests of the modified globin which contained both the N-terminal acetaldehyde adducts of alpha-globin (heptapeptide) and beta-globin (octapeptide) were resolved. These results suggest that analysis of stable imidazolidinone adducts is a promising approach to estimation of alcohol exposure.

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“…o-Hydroxycarbonyl compounds, such as glycolaldehyde, give rise to stable 2-oxoalkylamines through Amadori rearrangement of initially formed Schiff-bases (31), and in the reduction of these amines 2-hydroxyalkylamines are formed. Schiff-bases may also rearrange to stable cyclic imidazolidinone derivatives that are not reducible (32).…”

Section: Reactivity Of Aldehydesmentioning

confidence: 99%

Adducted Proteins for Identification of Endogenous Electrophiles

Törnqvist¹,

Kautiainen²

1993

Environmental Health Perspectives

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Chemically reactive compounds in tissues can be monitored through their products of reaction with biomacromolecules. For the purpose of in vivo dose monitoring, hemoglobin (Hb) has been preferred to DNA because of its well-defined life span and more facile chemical identification of adducts. Through the N-alkyl Edman method, adducts to the N-terminals (valines) of the globin chains are measured mass spectrometrically with high sensitivity. In studies of low molecular weight adducts from occupational exposures or tobacco smoke, background levels were found in nonexposed control persons. In some cases the origin of these adducts could be determined. For instance, the 2-hydroxyethyl adduct has been shown to originate from ethylene oxide, a metabolite of endogenously produced ethene. The measured level, about 20 pmole/g globin, agrees well with the ethylene oxide dose calculated from expired ethene. Animal studies indicate contributions from the intestinal flora and dietary factors. An average background level of about 200 pmole/g globin of methylvaline has been observed in unexposed humans. From reaction-kinetic studies of S-adenosylmethionine (SAM), it has been shown that the background mainly originates from SAM. In twin studies, a genetic influence on the level has been shown. Furthermore, a contribution from tobacco smoking to the level was demonstrated in these studies. Certain aldehydes, e.g., malonaldehyde, have been shown to be related to dietary factors and lipid peroxidation. These studies show the usefulness of the method in a search for reactive compounds in the body, with the ultimate goal of assessing the total genotoxic load.

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Reaction of acetaldehyde with hemoglobin.

Cited by 98 publications

References 32 publications

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Stable Acetaldehyde−Protein Adducts as Biomarkers of Alcohol Exposure

Adducted Proteins for Identification of Endogenous Electrophiles

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