Exploration of in vitro pro-drug activation and futile cycling by glutathione S-transferases: thiol ester hydrolysis and inhibitor maturation

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• 作者：Ibarra ; Catherine ; Grillo ; Mark P. ; Lo Bello ; Mario ; Nucettelli ; Marzia ; Bammler ; Theo K. ; et. al.
• 关键词：Enzyme inhibitors ; Glutathione pro-drugs ; Cancer chemotherapy ; Futile cycling ; Glutathione adducts
• 刊名：Archives of Biochemistry and Biophysics
• 出版年：2003
• 出版时间：June 15, 2003
• 年：2003
• 卷：414
• 期：2
• 页码：303-311
• 全文大小：189 K

文摘

In addition to glutathione (GSH) conjugating activity, glutathione S-transferases (GSTs) catalyze “reverse” reactions, such as the hydrolysis of GSH thiol esters. Reverse reactions are of interest as potential tumor-directed pro-drug activation strategies and as mechanisms for tissue redistribution of carboxylate-containing drugs. However, the mechanism and specificity of GST-mediated GSH thiol ester hydrolysis are uncharacterized. Here, the GSH thiol esters of ethacrynic acid (E-SG) and several nonsteroidal antiinflammatory agents have been tested as substrates with human GSTs. The catalytic hydrolysis of these thiol esters appears to be a general property of GSTs. The hydrolysis of the thiol ester of E-SG was studied further with GSTA1-1 and GSTP1-1, as a model pro-drug with several possible fates for the hydrolysis products: competitive inhibition, covalent enzyme adduction, and sequential metabolism. In contrast to hydrolysis rates, significant isoform-dependent differences in the subsequent fate of the products ethacrynic acid and GSH were observed. At low [E-SG], only the GSTP1-1 efficiently catalyzed sequential metabolism, via a dissociative mechanism.