Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate

Albert L. Shroads, Taimour Langaee, Bonnie S. Coats, Tracie L. Kurtz, John R. Bullock, David Weithorn, Yan Gong, David A. Wagner, David A. Ostrov, Julie A. Johnson, Peter W. Stacpoole

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Dichloroacetate (DCA), a chemical relevant to environmental science and allopathic medicine, is dehalogenated by the bifunctional enzyme glutathione transferase zeta (GSTz1)/maleylacetoacetate isomerase (MAAI), the penultimate enzyme in the phenylalanine/tyrosine catabolic pathway. The authors postulated that polymorphisms in GSTz1/MAAI modify the toxicokinetics of DCA. GSTz1/MAAI haplotype significantly affected the kinetics and biotransformation of 1,2-13C-DCA when it was administered at either environmentally (μg/kg/d) or clinically (mg/kg/d) relevant doses. GSTz1/MAAI haplotype also influenced the urinary accumulation of potentially toxic tyrosine metabolites. Atomic modeling revealed that GSTz1/MAAI variants associated with the slowest rates of DCA metabolism induced structural changes in the enzyme homodimer, predicting protein instability or abnormal protein-protein interactions. Knowledge of the GSTz1/MAAI haplotype can be used prospectively to identify individuals at potential risk of DCA's adverse side effects from environmental or clinical exposure or who may exhibit aberrant amino acid metabolism in response to dietary protein.

Original languageEnglish (US)
Pages (from-to)837-849
Number of pages13
JournalJournal of Clinical Pharmacology
Volume52
Issue number6
DOIs
StatePublished - Jun 2012
Externally publishedYes

Keywords

  • dichloroacetate
  • glutathione transferase zeta
  • maleylacetoacetate isomerase
  • pharmacogenetics
  • toxicogenetics
  • tyrosine metabolism

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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