Document Detail

Drug-S-acyl-glutathione Thioesters: Synthesis, Bioanalytical Properties, Chemical Reactivity, Biological Formation and Degradation.
MedLine Citation:
PMID:  20946099     Owner:  NLM     Status:  In-Data-Review    
Carboxylic acid-containing drugs can be metabolized to chemically-reactive acyl glucuronide, S-acyl-CoA thioester, and/or intermediate acyl-adenylate metabolites that are capable of transacylating the cysteinyl-thiol of glutathione (GSH) resulting in the formation of drug-S-acyl-GSH thioesters detected in-vivo in bile and in-vitro in hepatocytes. Authentic S-acyl-GSH thioesters of carboxylic acids can be readily synthesized by modifying the cysteinyl-thiol group of GSH with an applicable acylating reagent. Bionanalytical characterization of S-acyl-GSH derivatives has demonstrated enhanced extraction efficiency from biological samples when formic acid is included in appropriate extraction solvents, and that tandem mass spectrometry of S-acyl-GSH conjugates results in fragmentation producing a common MH+-147 Da product ion. Chemical reactivity comparisons have shown that S-acyl-CoA thioester and acyl-adenylate conjugates are more reactive than their corresponding 1-β-O-acyl glucuronides toward the transacylation of GSH forming S-acyl-GSH thioesters. S-Acyl-GSH thioester derivatives are also chemically-reactive electrophiles capable of transacylating biological nucleophiles. Glutathione S-transferases (GSTs) weakly catalyze S-acyl-GSH conjugate formation from S-acyl-CoA, acyl-adenylate, and 1-β-O-acyl glucuronide substrates; however purified-GSTs have also been shown to hydrolyze S-acyl-GSH thioesters. Mechanistic in vitro studies in hepatocytes have revealed the primary importance of the S-acyl-CoA formation pathway leading to S-acyl-GSH-adduct formation. In addition to being hydrolytically-unstable in hepatocytes and plasma, S-acyl-GSH thioesters undergo γ-glutamyltranspeptidase-mediated cleavage of the γ-glutamyl-group leading to N-acyl-cysteinylglycine amide-linked products. In summary, S-acyl GSH thioesters are indicators of reactive transacylating metabolite formation produced from the biotransformation of carboxylic acids, but since they are also chemically-reactive, perhaps these derivatives can contribute to covalent binding to tissue proteins and potential toxicity.
Mark P Grillo
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Current drug metabolism     Volume:  12     ISSN:  1875-5453     ISO Abbreviation:  Curr. Drug Metab.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-05-03     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100960533     Medline TA:  Curr Drug Metab     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  229-44     Citation Subset:  IM    
Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, CA 94080, USA.
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