title: Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1.
abstract: Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism-based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects.
authors: Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States. Electronic address: mojames@ufl.edu.
authors: Margaret O
authors: MO
authors: James
authors: Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors: Stephan C
authors: SC
authors: Jahn
authors: Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors: Guo
authors: G
authors: Zhong
authors: Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors: Marci G
authors: MG
authors: Smeltz
authors: Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, United States.
authors: Zhiwei
authors: Z
authors: Hu
authors: Department of Medicine, University of Florida, Gainesville, FL 32610-0226, United States; Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, United States.
authors: Peter W
authors: PW
authors: Stacpoole
mesh_terms: D000818:Animals; D003999:Dichloroacetic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D028361:Mitochondrial Diseases / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; C407705:GSTZ1 protein, human; D005982:Glutathione Transferase; D017346:Protein Serine-Threonine Kinases
keywords: Dichloroacetate; GSTZ1; Inhibition of metabolism; Pharmacogenetics; Pharmacokinetics; Pyruvate dehydrogenase kinase