title: Pharmacogenetic considerations with dichloroacetate dosing.
abstract: The investigational drug dichloroacetate (DCA) is a metabolic regulator that has been successfully used to treat acquired and congenital metabolic diseases and, recently, solid tumors. Its clinical use has revealed challenges in selecting appropriate doses. Chronic administration of DCA leads to inhibition of DCA metabolism and potential accumulation to levels that result in side effects. This is because conversion of DCA to glyoxylate is catalyzed by one enzyme, glutathione transferase zeta 1 (GSTZ1-1), which is inactivated by DCA. SNPs in the GSTZ1 gene result in expression of polymorphic variants of the enzyme that differ in activity and rates of inactivation by DCA under physiological conditions: these properties lead to considerable variation between people in the pharmacokinetics of DCA.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610-0485, USA.
authors.forename: Margaret O
authors.initials: MO
authors.lastname: James
authors.affiliation: Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610-0485, USA.|Department of Biochemistry & Molecular Biology, University of Florida, Gainesville, FL 32610-0485, USA.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Stacpoole
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001711:Biotransformation; D002712:Chlorides / Q000494:pharmacology; D003999:Dichloroacetic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008659:Metabolic Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000009:adverse effects; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D002712:Chlorides; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; C407705:GSTZ1 protein, human; D005982:Glutathione Transferase; D017346:Protein Serine-Threonine Kinases
keywords: GSTZ1; dichloroacetate; pharmacogenetics