50700-49-7Relevant academic research and scientific papers
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.
Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes
Cheng, Dan,Xu, Wang,Yuan, Lin,Zhang, Xiaobing
, p. 7693 - 7700 (2017)
Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO-) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction-based fluorescent probes (Naph-ONOO- and Rhod-ONOO-) for ONOO- through a novel and universally applicable mechanism: ONOO--mediated deprotection of α-keto caged fluorophores. Among them, Rhod-ONOO- can selectively accumulate and react in mitochondria, one of the main sources of ONOO-, with a substantial lower nanomolar sensitivity of 43 nM. The superior selectivity and sensitivity of two probes enable real-time imaging of peroxynitrite generation in lipopolysaccharide-stimulated live cells, with a remarkable difference from cells doped with other interfering reactive oxygen species, in either one- or two-photon imaging modes. More importantly, we elucidated the drug-induced hepatotoxicity pathway with Rhod-ONOO- and revealed that CYP450/CYP2E1-mediated enzymatic metabolism of acetaminophen leads to ONOO- generation in liver cells. This is the first time to showcase the drug-induced hepatotoxicity pathways by use of a small-molecule fluorescent probe. We hence conclude that fluorescent probes can engender a deeper understanding of reactive species and their pathological revelations. The reaction-based fluorescent probes will be a potentially useful chemical tool to assay drug-induced hepatotoxicity.
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.
Electrochemical performance of a new imidazolium ionic liquid crystal and carbon paste composite electrode for the sensitive detection of paracetamol
Khan, Rajkumar,Mangaiyarkarasi, R.,Pratibha, R.,Premlatha, S.,Umadevi, S.
, (2020)
A new ionic liquid crystal (ILC) bearing a biphenyl core and a terminal imidazolium moiety was synthesized which exhibited two enantiotropic smectic A mesophases having a wide phase range. Interestingly one of these mesophases exhibited the features of a biaxial phase. A composite electrode containing the synthesized ILC and carbon paste (CP) was fabricated and employed for the successful electrochemical detection of a clinically important analgesic drug, paracetamol. The ILC-CP composite electrode displayed an enhanced current response due to a versatile combination of properties namely, good ionic conductivity, increased edge-site defects and excellent electrocatalytic activity. The composite electrode responded quickly upon addition of paracetamol and the peak current of anodic oxidation enhanced at lower over potential compared to the carbon paste electrode (CPE). Differential pulse voltammetric (DPV) experiments for the detection of paracetamol yielded acceptable linear range from 0 to 120 μM with a good detection limit of 2.8 μM. Interference test results showed anti-interfering ability in presence of a mixture of interferents. The electrode stability was evaluated from DPV current response and 92.6% current was retained after one month which revealed the excellent stability. The electrode was successfully applied for the direct determination of paracetamol in pharmaceutical formulations.
Selective determination of paracetamol and acetylsalicylic acid on electrode modified with a mixed-valent film of ruthenium oxide-ruthenium cyanide
Shaidarova,Gedmina,Chelnokova,Budnikov
, p. 620 - 627 (2011)
Catalytic activity exhibited by a mixed-valent film of ruthenium oxideruthenium cyanide deposited on the surface of a glassy-carbon electrode in electrooxidation of paracetamol and acetylsalicylic acid was used to develop a high-sensitivity selective method for determination of these compounds in the case of their joint presence under flow-injection conditions.
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.
Monitoring analgesic drug using sensing method based on nanocomposite
Narang, Jagriti,Malhotra, Nitesh,Singh, Sandeep,Singh, Gajendra,Pundir
, p. 2396 - 2404 (2015)
This paper reports a rapid, reliable and sensitive electrochemical method for the determination of acetaminophen, a safe analgesic drug. Most methods currently used for therapeutic drug monitoring require a pre-treatment of the sample. Biosensors avoid this kind of drawbacks. A horseradish peroxidase (HRP) was immobilized using core-shell ZrO@Fe3O4 nanoparticles on chitosan hybrid film electrodeposited on the surface of an Au electrode. The surface functionalization of core-shell ZrO@Fe3O4NPs on a chitosan hybrid film was characterized by cyclic voltammetry (CV), scanning electron microscopy (SEM), and electrochemical impedance spectroscopy (EIS). The experimental variables that can affect the acetaminophen amperometric response, such as the pH, temperature and applied potential, have been optimized to perform a selective determination of acetaminophen. An average limit of detection of 0.01 μM (S/N = 3) was obtained. The biosensor was finally applied to the determination of acetaminophen in complex matrices, such as pharmaceutical 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.
Facile and clean electrochemical synthesis of new acetaminophen derivatives through electrochemical oxidation of acetaminophen in the presence of thiouracil derivatives
Asghari, Alireza,Ameri, Mohsen,Taghipour, Samira,Ghaderi, Omid
, p. 163 - 172 (2017)
The electrochemical oxidation of acetaminophen (1a) is carried out in the presence of thiouracil derivatives (3a–c), as nucleophiles, in an acetate buffer solution (0.15 M, pH 5) mixed with Dimethylformamide (DMF) using cyclic voltammetry and coulometry under a constant potential. The results obtained indicate that N-acetyl-p-benzoquinone-imine derived from acetaminophen participates in a 1,4-Michael-type addition reaction with thiouracils to form the corresponding acetaminophen derivatives (4a–c) in good yields and with high purities using a facile, catalyst-free, and one-pot electrochemical method using three carbon electrodes in an undivided cell under mild conditions. The products obtained were characterized after purification by IR, 1H NMR, and 13C NMR spectroscopies, and by the elemental analysis method.
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.
