50700-49-7Relevant articles and documents
Covalent protein modification by reactive drug metabolites using online electrochemistry/liquid chromatography/mass spectrometry
Lohmann, Wiebke,Hayen, Heiko,Karst, Uwe
, p. 9714 - 9719 (2008)
We present a rapid and convenient method to perform and evaluate the covalent protein binding of reactive phase I metabolites. The oxidative metabolism of the drugs paracetamol, amodiaquine, and clozapine is simulated in an electrochemical (EC) flow-through cell, which is coupled online to an LC/MS system. Adduct formation of the reactive metabolites with the proteins β-lactoglobulin A and human serum albumin proceeds in a reaction coil between EC cell and injection system of the HPLC system. The formed drug-protein adducts are characterized with online time-of-flight mass spectrometry, and the modification site is localized using FTICR-mass spectrometry. Due to its simple setup, easy handling, and short analysis times, the method provides an interesting tool for the rapid risk assessment of covalent protein binding as well as for the synthesis of covalent drug-protein adducts in high purity and high yield.
Acetaminophen binds to mouse hepatic and renal DNA at human therapeutic doses
Rogers, Lynette K.,Moorthy, Bhagavatula,Smith, Charles V.
, p. 470 - 476 (1997)
Alkylation of DNA by acetaminophen metabolites has been reported previously, but has received little attention, and the biological impact of this alkylation is essentially unknown. In the present study, apparent covalent binding of acetaminophen metabolites to DNA in male ICR mice was observed at levels of 2.0 ± 0.4 to 18.5 ± 5.5 pmol of acetaminophen/mg of DNA in liver and 0.6 ± 0.1 to 26.9 ± 2.6 pmol of acetaminophen/mg of DNA in kidney with doses ranging from 10 to 400 mg/kg. Investigations of the reaction of [3H]-N-acetyl-p-benzoquinone imine (NAPQI) or [ring-14C]NAPQI with DNA in vitro yielded low levels of DNA alkylation. Greater apparent binding of [3H]NAPQI to DNA occurred in reactions containing nuclear proteins, such as by using chromatin or whole nuclei. The binding of NAPQI to purified DNA also was enhanced by the presence of 0.1 mM cysteine, but not by 1.0 mM cysteine. Increased binding of NAPQI to DNA in the presence of cysteine or nuclear protein is in contrast to the effects of alternate sulfhydryls on the binding of NAPQI to proteins, which implies that the mechanisms responsible for binding to DNA may be different than the mechanisms that mediate alkylation of protein. The alkylation of DNA by [ring-14C]NAPQI was enhanced markedly at buffer pH 2O2. Measurable binding was obtained in all systems, but HRP and H2O2 produced binding levels 200-fold greater than was observed with the microsomal systems. The 32P-postlabeling of DNA from acetaminophen-treated mice, and of DNA reacted with acetaminophen, HRP, and H2O2, produced unique spots that were not identical. The present data further support the hypothesis that acetaminophen metabolites bind covalently to DNA and demonstrate that this apparent binding is observed in experimental animals in vivo at doses that mimic therapeutic doses in humans.
Synthesis, decomposition kinetics, and preliminary toxicological studies of pure N-acetyl-p-benzoquinone imine, a proposed toxic metabolite of acetaminophen
Dahlin,Nelson
, p. 885 - 886 (1982)
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Ni2P Nanosheets: A High Catalytic Activity Platform for Electrochemical Detection of Acetaminophen
Bai, Liwei,Cao, Xiaowei,Jia, Jianfeng,Jiang, Yimin,Liu, Guoqin,Liu, Xuebo,Lu, Wenbo,Wei, Ming,Wu, Haishun
, p. 1849 - 1854 (2021)
Accurate determination of acetaminophen concentration is essential for studying the metabolic status of acetaminophen in clinical practice. In this study, nickel phosphide was used for electrochemical detection of acetaminophen for the first time. An electrochemical acetaminophen sensor based on Ni2P nanosheets was successfully constructed and the sensor showed many convincing properties: (a) a good linear range (0.5 μmol/L—4.5 mmol/L); (b) a moderate sensitivity (131.1 μA·mmol–1·L·cm–2); (c) a low detection limit (0.107 μmol/L). In addition, the sensor also showed excellent selectivity, robust stability and reliable repeatability. Further experiments demonstrate that the prepared sensor can be used for quantitative detection of acetaminophen in commercial medical drugs.
Metabolites of acetaminophen trigger Ca2+ release from liver microsomes
Stoyanovsky, Detcho A.,Cederbaum, Arthur I.
, p. 23 - 29 (1999)
Release of mitochondrial calcium is believed to play a key role in the toxicity of acetaminophen in biological systems. Elevated cytosolic Ca2+ may also result from activation of calcium releasing channels. The major metabolites of acetaminophen, benzoquinone imine and 1,4-benzoquinone, induced Ca2+ release in isolated rat liver microsomes. The 1,4-benzoquinone-induced release of calcium was suppressed by ryanodine and fully inhibited by reduced glutathione. Concentrations of 1,4-benzoquinone that induced Ca2+ release did not affect the activity of the microsomal Ca2+, Mg2+-APTase. The binding of [3H]ryanodine to liver microsomes, however, was significantly decreased by 1,4-benzoquinone, suggesting a direct interaction of this metabolite with the ryanodine-binding protein (ryanodine receptor). These results suggest that cellular Ca2+ levels may be elevated by acetaminophen by pathways involving, in part, activation of Ca2+ releasing channels such as the ryanodine receptor. Copyright (C) 1999 Elsevier Science Ireland Ltd.
Rat liver microsomal cytochrome P450-dependent oxidation of 3,5-disubstituted analogues of paracetamol
Bessems,Te Koppele,Van Dijk,Van Stee,Commandeur,Vermeulen
, p. 647 - 666 (1996)
1. The cytochrome P450-dependent binding of paracetamol and a series of 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -C(H)3, -C2H5, -iC3H7) have been determined with β-naphthoflavone (βNF)-induced rat liver microsomes and produced reverse type I spectral changes. K(s,app) varied from 0.14 mM for 3,5-diiC3H7-paracetamol to 2.8 mM for paracetamol. 2. All seven analogues underwent rat liver microsomal cytochrome P450-dependent oxidation, as reflected by the formation of GSSG in the presence of GSH. The GSSG-formation was increased in all cases upon pretreatment of rats by β-naphthoflavone (βNF) and was generally decreased upon pretreatment by phenobarbital (PB). 3. Rat liver microsomal cytochrome P450 as well as horseradish peroxidase catalysed the formation of 3,5-disubstituted NAPQI analogues from the corresponding parent compounds, as identified by UV-spectrophotometry of the NAPQI analogues and by GC/MS detection of the following GSH-conjugates: 2-glutathione-S-yl-3,5-dimethyl-1,4-dihydroxybenzene, 2-glutathione-S-yl-3,5-dichloro-paracetamol, and 2-glutathione-S-yl-3,5-dibromo-paracetamol. 4. In liver microsomal (βNF-induced) incubations, apparent K(m) values, as determined for the cytochrome P450 catalysis-dependent oxidation of GSH, for seven 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -CH3, -C2H5, iC3H7) varied from 0.07 to 0.64 mM. Paracetamol exhibited an apparent K(m) of 0.73 mM. Apparent V(max) values for the cytochrome P450 catalysis dependent oxidation of GSH varied from 0.66 nmol min-1 mg-1 protein for paracetamol to 3.0 nmol min-1 mg-1 protein for 3,5-dimethyl-paracetamol.
MWCNT-CTAB modified glassy carbon electrode as a sensor for the determination of paracetamol
Gowda, Jayant I.,Gunjiganvi, Danavva G.,Sunagar, Nagaveni B.,Bhat, Manjushree N.,Nandibewoor, Sharanappa T.
, p. 49045 - 49053 (2015)
An electrochemical sensor for the sensitive detection of paracetamol (PCM) was developed by constructing a glassy carbon electrode (GCE) modified with multiwalled carbon nanotube-cetyltrimethyl ammonium bromide (MWCNT-CTAB). Modification improves the redox kinetics of PCM with increased current intensity. A similar modification at CTAB modified GCE did not result in an impressive charge transfer. The detection limit of PCM was determined from a differential pulse voltammetric (DPV) study and found to be 4.82 × 10-9 M with a linear dynamic range of 4.0 × 10-7 M to 4.0 × 10-6 M. The interference studies showed that the modified electrode exhibits excellent selectivity in the presence of a large excess of interferents and the response is fast, stable, reliable, resistant to biofouling and can be applied for real sample analysis in medical, pharmaceutical and biotechnological sectors. Kinetic parameters were determined using electrochemical approaches. The practical analytical application of this electrode was demonstrated by measurement of the PCM content in a PYREMOL 650 tablet and real sample analysis.
Kinetic insights on the oxidation of acetaminophen and caffeine by a Mn(IV)3 complex
Das, Ranendu Sekhar,Singh, Bula
, p. 565 - 573 (2021/09/09)
The kinetics of the oxidation reactions of APAP and Cafn by a Mn(IV)-oxidant, [MnIV3(μ-O)4(phen)4(H2O)2]4+ (1) has been studied at room temperature. Under the acidic reaction condition ([H+] = 0.2–1.0?M), both APAP and Cafn exist in equilibrium with their conjugate acids APAPH+ and CafnH+ and each of the species acts as the potential reductants. Kinetic observations reveal that the observed rate constant, ko, values increase with the increase in media acidity and the ionic strength, I. The second-order rate-constant values for oxidizing the protonated forms of the two reductants (APAPH+ and CafnH+) were evaluated to be 6.04 ± 0.29 and 0.18 ± 0.01?M?1?s?1, respectively. Overall, under acid media, Mn(IV)-complex efficiently oxidizes APAP to a mixture of benzoquinone and acetamide (or, to quinone oxime and acetic acid) and Cafn to 1,3,7-trimethyluric acid.
