Wagner DA, Ostrov DA, Johnson JA, Stacpoole PW, unpublished observations). Using 1,2-13C-DCA, several researchers were able to clearly segregate “slow” and “fast” metabolizers of DCA, based on GSTz1/MAAI (Shroads AL, Langaee T, Coats BS, Kurtz TL, Bullock JR, Weithorn D, Gong Y, Wagner DA, Ostrov DA, Johnson JA, Stacpoole PW, unpublished observations). Those who metab- olized DCA slowly showed markedly delayed plasma clearance and biotransformation, increased excretion of unmetabolized drug [see Supplemental Material, Figure 3 (doi:10.1289/ ehp.1002554)], and increased urinary accumu- lation of maleylacetone and δ-aminolevulinate. Atomic modeling of the effect of GSTz1/MAAI polymorphism showed that variants associated with slow DCA metabolism induced structural changes in the enzyme homodimer leading to protein instability or abnormal protein– protein interactions. These data suggest that GSTz1/MAAI haplotype may predict, at least in part, the toxicogenetics of DCA. Moreover, such information may be used prospectively to adjust dosing and mitigate the risk of adverse events from DCA. Despite the potential toxicity of DCA, its therapeutic potential continues to be investigated. Its principal site of pharma- codynamic action is the mitochondrial pyruvate dehydrogenase (PDH) complex (Stacpoole 1989), a gatekeeper enzyme for regulating carbohydrate fuel metabolism in cells [see Supplemental Material, Figure 4 (doi:10.1289/ehp.1002554)]. Under aerobic conditions, PDH catalyzes the rate-determining step in glucose oxidation by irreversibly decarboxylating pyruvate to acetyl coenzyme A, thereby “priming” the Krebs cycle with glucose carbon. In addition, both the PDH- catalyzed reaction and several enzymes of the Krebs cycle generate reducing equivalents in the forms of nicotine adenine dinucleotide and flavin adenine dinucleotide that are used by the respiratory chain for the reduc- tion of molecular oxygen to water and for ATP synthesis from ADP. PDH is revers- ibly phosphorylated and inactivated by a family of PDH kinase (PDK) isoforms that exhibit variable tissue expression (Sugden and Holness 2003). DCA exerts differential inhibition on PDKs to maintain PDH in its unphosphorylated, catalytically active form and exerts greatest inhibition (Ki = 0.2 mM) (Bowker-Kinley et al. 1998) toward the ubiq- uitously expressed PDK2. Because pyruvate is in equilibrium with lactate, it follows that acquired or congenital deficiencies of PDH may lead to mitochondrial energy failure and lactate accumulation. Accordingly, DCA has been used to improve mitochondrial energet- ics and to mitigate tissue or systemic lactic acidosis (see Stacpoole et al. 1992, 2006 and references therein). Invoking the same site and mechanism of action described above, several laboratories have reported DCA’s selective proapoptotic and antiproliferative effects when administered in vitro to a variety of cultured human tumor cells or to human tumors implanted into immunocompromised rodents (reviewed by Michelakis et al. 2008). The rationale for considering DCA as an anticancer drug is predicted on the well-established finding that solid tumors derive most of their energy from glycolysis, rather than through mito- chondrial oxidative phosphorylation, even in the presence of adequate oxygen availability. This phenomenon is called the Warburg effect and is now known to be a consequence of the combined transactivation of glucose membrane transporters, glycolytic enzymes, and PDK (Vander Heiden et al. 2009). Consequently, PDH activity and oxidative phosphorylation are inhibited in most can- cers. By inhibiting PDK in tumor cells, DCA stimulates PDH and oxidative phosphoryla- tion, decreases tumor lactate concentration, and initiates a caspase-mediated chain of reactions leading to apoptosis of tumor, but not of host, cells (Bonnet et al. 2007) [see Supplemental Material, Text G (doi:10.1289/ ehp.1002554)]. Primary arterial hypertension repre- sents another neoplastic (but nonmalignant) condition in which mitochondrial dysfunc- tion and hyperproliferation of cells lining the pulmonary vasculature lead to increased pulmonary vascular resistance, failure of the right ventricle of the heart, and premature death. In animal models of primary arterial hypertension, DCA has been shown to pre- vent or reverse mitochondrial damage and cellular proliferation, improve lung function, and increase survival by its ability to stimu- late oxidative phosphorylation and induce apoptosis in proliferating cells (Bonnet et al. 2006; McMurtry et al. 2004; Michelakis et al. 2002). Results from clinical trials of DCA in this disease have not yet been reported [see Supplemental Material, Text H (doi:10.1289/ ehp.1002554)]. What are important areas of future research? Few chemicals have integrated the disciplines of environmental science and clinical research as effectively as DCA. Recent studies investigating the toxicogenetics of this compound when administered as a drug have important implications for human popu- lations chronically exposed to environmen- tally relevant concentrations. The findings are particularly germane to persons in con- tact with water sources contaminated with TCE or other industrial solvents or who are administered drugs that may be biotrans- formed to DCA (reviewed by Stacpoole et al. 1998b). The recent discovery of a mitochon- drial GSTz1/MAAI (Li et al. 2011) indicates Environmental Health Perspectives • volume 119 | number 2 | February 2011 The dichloroacetate dilemma that both the biotransformation of DCA and the site of its major pharmacodynamic action, the PDH complex, occur within the matrix of this organelle. This finding raises intriguing questions about whether the stim- ulation of PDH activity and, subsequently, the respiratory chain by DCA could generate sufficient amounts of reactive oxygen spe- cies to cause oxidative damage to mitochon- drial GSTz1/MAAI and further impair DCA metabolism. New epidemiological research on DCA should focus more selectively on populations that may be predisposed to DCA-associated health complications because of age or geno- type. For example, individuals with an inborn error of the phenylalanine and tyrosine cata- bolic pathway could suffer additional adverse consequences when exposed to clinically, and perhaps even environmentally, relevant doses of DCA. Individually, these diseases are rare. However, perhaps the most common of these conditions, hyperphenylalaninemia (which includes phenylketonuria), has a worldwide annual incidence that varies widely from approximately 3 to > 300 per million births (Scriver et al. 2001). Another popu- lation at potential risk is persons prone to hyperoxaluria. For example, primary hyper- oxaluria has a prevalence of > 1 per 10,000 persons and may cause widespread calcium oxalate crystal deposition (Danpure 2001). Such individuals could be at heightened risk for developing calcium oxalate deposits were they to receive clinical doses of DCA over long periods of time. Likewise, humans who metabolize DCA slowly may also be genetically predisposed to exhibit reduced flux through the phenylala- nine and tyrosine catabolic pathway. Chronic consumption of a high-protein diet by such individuals could lead to an accumulation of toxic tyrosine intermediates, with adverse consequences for hepatic, neurological, and other organ system failure. Testing this pos- tulate could involve studies of stable isotope amino acid kinetics in relation to GSTz1/ MAAI haplotype. Finally, careful consid- eration must be given to age and genotype when conducting future treatment-oriented research with DCA, particularly cancer trials involving adults. DCA has so far been proven to be neither a major environmental health hazard nor a panacea for human ills. Future clinical and environmental research on this unusual mole- cule should be focused increasingly on under- standing its impact on biological processes in discrete subpopulations of humans with known GSTz1/MAAI genotype. We continue to move incrementally, but steadily, from puzzled observations about the pharmacology of DCA to established conclusions about its effect on human health. 157