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.

Keywords: congenital lactic acidosis; dichloroacetate; glutathione transferase zeta 1; maleylacetoacetate isomerase; mitochondrial disease; pharmacogenetics; pharmacokinetics; tyrosine.

© 2014, The American College of Clinical Pharmacology.

Figures

Fig. 1

Site of action and biotransformation of DCA. Panel A: The pyruvate dehydrogenase complex (PDC) irreversibly oxidizes pyruvate to acetyl CoA, thereby linking cytoplasmic glycolysis to the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Pyruvate dehydrogenase kinase (PDK) reversibly inhibits PDC activity by phosphorylation, whereas, pyruvate dehydrogenase phosphatase (PDP) restores PDC activity via dephosphorylation. DCA inhibits PDK, thereby maintaining PDC in its catalytically active form. Panel B: DCA is dehalogenated by GSTZ1 to glyoxylate, upon which the xenobiotic enters the general carbon pool of the host. The same enzyme, as MAAI, catalyzes the penultimate step in the phenylalanine/tyrosine catabolic pathway, isomerizing maleylacetoacetate and maleylacetone to fumarylacetoacetate and fumarylacetone, respectively.

Fig. 2

1, 2-13C-DCA trough levels as a function of duration of drug exposure in 6 selected subjects with differing GSTZ1/MAAI haplotypes. See Table 1 for further patient characteristics.