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Metabolism of Strained Rings: Glutathione -transferase-Catalyzed Formation of a Glutathione-Conjugated Spiro-azetidine without Prior Bioactivation.
Drug Metab Dispos
November 2019
Drug Metabolism and Pharmacokinetics, Research and Early Development Cardiovascular, Renal and Metabolism (X.-Q.L., E.-H.B., L.W.), Hit Discovery, Discovery Sciences (M.A.H.), and Medicinal Chemistry, Early Respiratory, Inflammation and Autoimmunity (G.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; and Department of Chemistry, Virginia Tech, Blacksburg, Virginia (N.C.J.)
AZD1979 [(3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone] is a melanin-concentrating hormone receptor 1 antagonist designed for the treatment of obesity. In this study, metabolite profiles of AZD1979 in human hepatocytes revealed a series of glutathione-related metabolites, including the glutathionyl, cysteinyl, cysteinylglycinyl, and mercapturic acid conjugates.
View Article and Find Full Text PDFTrypanothione: a unique bis-glutathionyl derivative in trypanosomatids.
Biochim Biophys Acta
May 2013
Institut Pasteur de Montevideo, Montevideo, Uruguay.
Background: Trypanosomatids are early-diverging eukaryotes devoid of the major disulfide reductases - glutathione reductase and thioredoxin reductase - that control thiol-redox homeostasis in most organisms. These protozoans have evolved a unique thiol-redox system centered on trypanothione, a bis-glutathionyl conjugate of spermidine. Notably, the trypanothione system is capable to sustain several cellular functions mediated by thiol-dependent (redox) processes.
View Article and Find Full Text PDFFormation, reactivity, and antiplatelet activity of mixed disulfide conjugates of clopidogrel.
Mol Pharmacol
April 2013
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-5632, USA.
In this work, we investigated the formation, reactivity, and antiplatelet activity of various mixed disulfide conjugates of clopidogrel. Our results showed that the production of the active metabolite (AM) from 2-oxoclopidogrel by human liver microsomes (HLMs) is greatly affected by the thiol reductants used. Among the 10 thiol compounds tested, glutathione (GSH) is most efficient in producing the AM at a rate of 167 pmoles AM/min/mg HLM.
View Article and Find Full Text PDFFormation of the thiol conjugates and active metabolite of clopidogrel by human liver microsomes.
Mol Pharmacol
August 2012
Department of Pharmacology, University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-5632, USA.
We reported previously the formation of a glutathionyl conjugate of the active metabolite (AM) of clopidogrel and the covalent modification of a cysteinyl residue of human cytochrome P450 2B6 in a reconstituted system (Mol Pharmacol 80:839-847, 2011). In this work, we extended our studies of the metabolism of clopidogrel to human liver microsomes in the presence of four reductants, namely, GSH, l-Cys, N-acetyl-l-cysteine (NAC), and ascorbic acid. Our results demonstrated that formation of the AM was greatly affected by the reductant used and the relative amounts of the AM formed were increased in the following order: NAC (17%) < l-Cys (53%) < ascorbic acid (61%) < GSH (100%).
View Article and Find Full Text PDFSynthesis, quantification, characterization, and signaling properties of glutathionyl conjugates of enals.
Methods Enzymol
October 2010
Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky, USA.
Oxidation of lipids generates large quantities of highly reactive alpha,beta-unsaturated aldehydes (enals). Enals and their protein adducts accumulate in the tissues of several pathologies. In vitro, low concentrations of enals such as HNE (4-hydroxy trans-2-nonenal) affect cell signaling whereas high concentrations of enals are cytotoxic.
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