The antithrombotics of the tetrahydrothienopyridine series, clopidogrel and prasugrel, are prodrugs that must be metabolized in two steps to become pharmacologically active. The first step is the formation of a thiolactone metabolite. The second step is a cytochrome P450 (P450)-dependent oxidation of this thiolactone resulting in the formation of a sulfenic acid that is eventually reduced into the corresponding active thiol. It has been postulated that the sulfenic acid metabolite resulted from a nucleophilic attack of water on a highly reactive thiolactone sulfoxide derived from P450-dependent oxidation of the thiolactone primary metabolite. The data described in the present article are in complete agreement with this proposition as they show that it was possible to trap these thiolactone sulfoxides by a series of nucleophiles such as amines, thiols, or cyclopentane-1,3-dione (CPDH), an equivalent of dimedone that is used as a sulfenic acid trapping agent. HPLC-MS studies showed that various bis-adducts having incorporated two nucleophile molecules were formed in these reactions. One of them that resulted from the oxidation of 2-oxo-prasugrel by human liver microsomes in the presence of ethanolamine and CPDH was isolated and completely characterized by (1)H and (13)C NMR spectroscopy in addition to MS and MS(2) spectrometry. All metabolites derived from an attack of H2O or an amine at the CO carbon of the intermediate thiolactone sulfoxide existed as a mixture of two diastereomers having a cis configuration of the double bond, whereas those formed in the presence of thiols appeared as a mixture of four diastereomers with a cis or trans configuration of the double bond. This led us to propose tentative mechanisms for the previously reported formation of trans isomers of the active thiol metabolite of clopidogrel upon microsomal metabolism of this antithrombotic in the presence of thiols. The results described in this article showed that thiolactone sulfoxides are formed as reactive metabolites during the metabolism of clopidogrel and prasugrel and are able to react as bis-electrophiles with a variety of nucleophiles. The possible implications of the formation of these reactive metabolites in the pharmacological and/or secondary toxic effects of these drugs remain to be studied.
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FEBS Lett
April 2023
Department of Chemistry, Indian Institute of Technology Kharagpur, India.
Of the proteinaceous β-sheet-rich amyloid fibrillar structures, the Aβ peptide, a component of the full-length Aβ involved in Alzheimer's disease, has similar toxicity to the parent peptide. In this study, the effects of homocysteine thiolactone (HCTL) and hydrogen peroxide (H O ) on the conformation and fibrillation propensity of the Aβ peptide were investigated. Both HCTL and H O induced amino acid modifications along with alteration in aggregation propensity.
View Article and Find Full Text PDFEcotoxicol Environ Saf
August 2021
National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, Zhejiang, China. Electronic address:
Acrylamide classified as a probable carcinogen to humans is a high production volume chemical in industrial applications released to aquatic and environmental ecosystems, and also widely found in the thermal processing of starch-rich foods. To gain insight into the urinary metabolomics that may induce physiological responses stimulated by acrylamide, rats were orally administered with a single dose of C-acrylamide (10 mg/kg bw) in the treatment group and urine samples were continuously collected every 2 h during the first 18 h and every 3 h during the period from 18 h to 36 h. A reliable nontargeted screening method for the analysis of urinary metabolomics in rats was developed using ultra-high performance liquid chromatography coupled to quadrupole-Orbitrap high-resolution mass spectrometry.
View Article and Find Full Text PDFPLoS One
October 2017
ChemCom S.A., Brussels, Belgium.
T2R38 has been shown to be a specific bacterial detector implicated in innate immune defense mechanism of human upper airway. Several clinical studies have demonstrated that this receptor is associated with the development of chronic rhinosinusitis (CRS). T2R38 was previously reported to bind to homoserine lactones (HSL), quorum sensing molecules specific of Pseudomonas Aeruginosa and other gram negative species.
View Article and Find Full Text PDFChem Res Toxicol
June 2015
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, Sorbonne Paris Cité, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France.
The antithrombotics of the tetrahydrothienopyridine series, clopidogrel and prasugrel, are prodrugs that must be metabolized in two steps to become pharmacologically active. The first step is the formation of a thiolactone metabolite. The second step is a further oxidation with the formation of a thiolactone sulfoxide whose hydrolytic opening leads to a sulfenic acid that is eventually reduced into the corresponding active cis thiol.
View Article and Find Full Text PDFJ Phys Chem A
December 2013
Department of Chemistry, Portland State University, Portland, Oregon 97207-0751, United States.
The kinetics of N-acetyl homocysteine thiolactone (NAHT) oxidation by aqueous iodine and iodate were studied by spectrophotometric techniques. The iodate-NAHT reaction is slow and results in the formation of N-acetyl homocysteine thiolactone sulfoxide as the sole product (NAHTSO). The stoichiometry of the reaction was deduced as: IO3(-) + 3NAHT → I(-) + 3NAHTSO (S1).
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