title: Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate.
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.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Albert L
authors.initials: AL
authors.lastname: Shroads
authors.forename: Taimour
authors.initials: T
authors.lastname: Langaee
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Coats
authors.forename: Tracie L
authors.initials: TL
authors.lastname: Kurtz
authors.forename: John R
authors.initials: JR
authors.lastname: Bullock
authors.forename: David
authors.initials: D
authors.lastname: Weithorn
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: David A
authors.initials: DA
authors.lastname: Wagner
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Peter W
authors.initials: PW
authors.lastname: Stacpoole
mesh_terms: D000096:Acetone / Q000031:analogs & derivatives / Q000652:urine; D000328:Adult; D019943:Amino Acid Substitution; D003999:Dichloroacetic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity; D004795:Enzyme Stability / Q000187:drug effects; D005260:Female; D005431:Florida; D056726:Genetic Association Studies; D005982:Glutathione Transferase / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008297:Male; D008298:Maleates / Q000652:urine; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D014443:Tyrosine / Q000031:analogs & derivatives / Q000652:urine; D055815:Young Adult
chemical_list: D004785:Environmental Pollutants; D008298:Maleates; C460372:maleylacetone; D000096:Acetone; D014443:Tyrosine; D003999:Dichloroacetic Acid; C407705:GSTZ1 protein, human; D005982:Glutathione Transferase