| Glutathione S-transferase catalyzed desulfonylation of a sulfonylfuropyridine. | |
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MedLine Citation:
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PMID: 19797605 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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MRL-1, a cannabinoid receptor-1 inverse agonist, was a member of a lead candidate series for the treatment of obesity. In rats, MRL-1 is eliminated mainly via metabolism, followed by excretion of the metabolites into bile. The major metabolite M1, a glutathione conjugate of MRL-1, was isolated and characterized by liquid chromatography/mass spectrometry and NMR spectroscopic methods. The data suggest that the t-butylsulfonyl group at C-2 of furopyridine was displaced by the glutathionyl group. In vitro experiments using rat and monkey liver microsomes in the presence of reduced glutathione (GSH) showed that the formation of M1 was independent of NADPH and molecular oxygen, suggesting that this reaction was not mediated by an oxidative reaction and a glutathione S-transferase (GST) was likely involved in catalyzing this reaction. Furthermore, a rat hepatic GST was capable of catalyzing the conversion of MRL-1 to M1 in the presence of GSH. When a close analog of MRL-1, a p-chlorobenzenesulfonyl furopyridine derivative (MRL-2), was incubated with rat liver microsomes in the presence of GSH, p-chlorobenzene sulfinic acid (M2) was also identified as a product in addition to the expected M1. Based on these data, a mechanism is proposed involving direct nucleophilic addition of GSH to sulfonylfuropyridine, resulting in an unstable adduct that spontaneously decomposes to form M1 and M2. |
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Authors:
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Thomas J Bateman; John S Debenham; Christina Madsen-Duggan; Richard B Toupence; Thomas F Walsh; Quang Truong; Scott A Bradley; George A Doss; Sanjeev Kumar; Vijay Bhasker G Reddy |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 38 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2009-12-16 Completed Date: 2010-03-19 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 108-14 Citation Subset: IM |
Affiliation:
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Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, Rahway, New Jersey, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bile / chemistry Biocatalysis* Biotransformation / physiology Chromatography, Liquid Cytosol / metabolism Dogs Glutathione / metabolism Glutathione Transferase / metabolism* Haplorhini Humans Liver / enzymology Magnetic Resonance Spectroscopy Male Microsomes, Liver / enzymology Molecular Structure NADP / metabolism Pyridines / metabolism, pharmacokinetics* Rats Rats, Sprague-Dawley Receptor, Cannabinoid, CB1 / antagonists & inhibitors Species Specificity Sulfur Compounds / metabolism, pharmacokinetics* Tandem Mass Spectrometry |
| Chemical | |
Reg. No./Substance:
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0/Cnr1 protein, rat; 0/Pyridines; 0/Receptor, Cannabinoid, CB1; 0/Sulfur Compounds; 53-59-8/NADP; 70-18-8/Glutathione; EC 2.5.1.18/Glutathione Transferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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