title: Haplotype variations in glutathione transferase zeta 1 influence the kinetics and dynamics of chronic dichloroacetate in children.
abstract: Dichloroacetate (DCA) is biotransformed by glutathione transferase zeta 1 (GSTZ1), a bifunctional enzyme that, as maleylacetoacetate isomerase (MAAI), catalyzes the penultimate step in tyrosine catabolism. DCA inhibits GSTZ1/MAAI, leading to delayed plasma drug clearance and to accumulation of potentially toxic tyrosine intermediates. Haplotype variability in GSTZ1 influences short-term DCA kinetics in healthy adults, but the impact of genotype in children treated chronically with DCA is unknown. Drug kinetics was studied in 17 children and adolescents with congenital mitochondrial diseases administered 1,2-(13) C-DCA. Plasma drug half-life and trough levels varied 3-6-fold, depending on GSTZ1/MAAI haplotype and correlated directly with urinary maleylacetone, a substrate for MAAI. However, chronic DCA exposure did not lead to progressive accumulation of plasma drug concentration; instead, kinetics parameters plateaued, consistent with the hypothesis that equipoise is established between the inhibitory effect of DCA on GSTZ1/MAAI and new enzyme synthesis. GSTZ1/MAAI haplotype variability affects DCA kinetics and biotransformation. However, these differences appear to be stable in most individuals and are not associated with DCA plasma accumulation or drug-associated toxicity in young children.
authors: Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
authors: A L
authors: AL
authors: Shroads
authors: B S
authors: BS
authors: Coats
authors: C W
authors: CW
authors: McDonough
authors: T
authors: T
authors: Langaee
authors: P W
authors: PW
authors: Stacpoole
mesh_terms: D000096:Acetone / Q000031:analogs & derivatives / Q000652:urine; D000293:Adolescent; D000328:Adult; D000622:Aminolevulinic Acid / Q000652:urine; D002648:Child; D002675:Child, Preschool; D003999:Dichloroacetic Acid / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004311:Double-Blind Method; D005260:Female; D030342:Genetic Diseases, Inborn / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007700:Kinetics; D008297:Male; D008298:Maleates / Q000652:urine; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D014443:Tyrosine / Q000378:metabolism; D055815:Young Adult
chemical_list: D008298:Maleates; C460372:maleylacetone; D000096:Acetone; D014443:Tyrosine; D000622:Aminolevulinic Acid; D003999:Dichloroacetic Acid; C407705:GSTZ1 protein, human; D005982:Glutathione Transferase
keywords: congenital lactic acidosis; dichloroacetate; glutathione transferase zeta 1; maleylacetoacetate isomerase; mitochondrial disease; pharmacogenetics; pharmacokinetics; tyrosine