TY - JOUR T1 - Glutathione <em>S</em>-Transferase Catalyzed Desulfonylation of a Sulfonylfuropyridine JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 108 LP - 114 DO - 10.1124/dmd.109.029801 VL - 38 IS - 1 AU - Thomas J. Bateman AU - John S. Debenham AU - Christina Madsen-Duggan AU - Richard B. Toupence AU - Thomas F. Walsh AU - Quang Truong AU - Scott A. Bradley AU - George A. Doss AU - Sanjeev Kumar AU - Vijay Bhasker G. Reddy Y1 - 2010/01/01 UR - http://dmd.aspetjournals.org/content/38/1/108.abstract N2 - 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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -