Structure-activity relationships for substrates and inhibitors of mammalian liver microsomal carboxylesterases

Tien L. Huang, Takahiro Shiotsuki, Tamon Uematsu, Babak Borhan, Qing X. Li, Bruce D. Hammock

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Purpose. Carboxylesterases are important in the detoxification of drugs, pesticides and other xenobiotics. This study was to evaluate a series of substrates and inhibitors for characterizing these enzymes. Methods. A series of novel aliphatic esters and thioesters were used in spectral assays to monitor human, murine and porcine esterases. A series of transition state mimics were evaluated as selective esterase inhibitors. Results. Several α-alkyl thioacetothioates were found to be ~ 2 to 11-fold superior to commonly used substrates for monitoring carboxylesterase activity. Insertion of a heteroatom in the acid portion of these esters in the β or γ position relative to the carbonyl had a dramatic effect on enzyme activity with S or O substituents often improving the k(CAT)/KM) ratio of the substrate and N decreasing it. Several α,α'-bis-(2-oxo-3,3,3-trifluoropropylthio)alkanes proved to be potent selective transition state mimics of the esterase activity with IC50's from 10-5 to 10-9M. Conclusions. This library of substrates and inhibitors are useful research tools for characterizing the numerous isozymes of carboxylesterases present in mammalian tissues.

Original languageEnglish (US)
Pages (from-to)1495-1500
Number of pages6
JournalPharmaceutical Research
Volume13
Issue number10
DOIs
StatePublished - 1996

Keywords

  • Carboxylesterase
  • Mammalian liver
  • Structure-activity relationship
  • Thioester substrate
  • Trifluoromethylketone inhibitors

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

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