For several years we have researched the kinetics, metabolism and human toxicology of dichloroacetate (DCA), a potentially harmful metabolite of trichloroethylene (TCE). This new proposal continues this research and also integrates it with new human studies of chloral hydrate (CH), which is both a primary metabolite of TCE and a precursor of DCA. Indeed, recent advances in our understanding of the mechanisms of DCA and CH biotransformation in vivo provide new insight into the possible causes of the adverse effects of chronic DCA and CH exposure in humans. Specifically, we have discovered that 1) children metabolize CH to DCA, 2) CH and DCA alter each other's clearance in vivo, 3) DCA is dechlorinated to glyoxylate, 4) dechlorination is mediated by hepatic maleylacetoacetate isomerase (MAAI), an enzyme of tyrosine catabolism, 5) DCA inhibits MAAI expression in animals causing, buildup of potentially toxic tyrosine intermediates, and 6) these metabolites may be responsible for DCA (and CH) toxicity. Humans exhibit polymorphisms of MAAI that may possess different kinetic properties toward DCA. In turn, human haplotype variability may influence DCA's kinetics and toxicology. These hypotheses will be tested by accomplishing the following Specific Aims:
Specific Aim 1 : Quantify the influence of DCA, at exposure levels ranging from environmental (mu g/kg/d) to clinical (mg/kg/d), on human liver MAAI and tyrosine catabolism.
This aim tests the hypotheses that 1) there is a dose-dependent effect of DCA on human hepatocellular tyrosine metabolism in general and on the accumulation of potentially hepatotoxic tyrosine intermediates in particular, 2) DCA inhibits hepatic MAAI expression in vivo in humans in a dose-dependent manner and 3) DCA, tyrosine and/or their metabolites form adducts with MAAI.
Specific Aim 2 : Establish the relationship between human MAAI haplotype and DCA and tyrosine metabolism.
This aim tests the postulates that MAAI haplotype determines, and thus can predict, 1) dose-dependent DCA kinetics and biotransformation and 2) DCA's effects on tyrosine metabolism.
Specific Aim 3 : Determine the in vivo kinetics and biotransformation of CH in healthy adults and the influence of CH and DCA on each other's metabolism.
This specific aim will examine three postulates 1) CH is-metabolized in adults to DCA, 2) CH, via DCA formation, inhibits its own metabolism and that of tyrosine and 3) these effects are dependent upon exposure level but not upon gender.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES014617-04S2
Application #
7848483
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Balshaw, David M
Project Start
2006-04-18
Project End
2012-02-28
Budget Start
2009-06-01
Budget End
2012-02-28
Support Year
4
Fiscal Year
2009
Total Cost
$15,341
Indirect Cost
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Mangal, Naveen; James, Margaret O; Stacpoole, Peter W et al. (2018) Model Informed Dose Optimization of Dichloroacetate for the Treatment of Congenital Lactic Acidosis in Children. J Clin Pharmacol 58:212-220
Shroads, Albert L; Langaee, Taimour; Coats, Bonnie S et al. (2012) Human polymorphisms in the glutathione transferase zeta 1/maleylacetoacetate isomerase gene influence the toxicokinetics of dichloroacetate. J Clin Pharmacol 52:837-49
Li, Wenjun; Gu, Yuan; James, Margaret O et al. (2012) Prenatal and postnatal expression of glutathione transferase ? 1 in human liver and the roles of haplotype and subject age in determining activity with dichloroacetate. Drug Metab Dispos 40:232-9
Stacpoole, Peter W (2011) The dichloroacetate dilemma: environmental hazard versus therapeutic goldmine--both or neither? Environ Health Perspect 119:155-8
Li, Wenjun; James, Margaret O; McKenzie, Sarah C et al. (2011) Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione transferase zeta 1. J Pharmacol Exp Ther 336:87-94
Stacpoole, Peter W; Kurtz, Tracie L; Han, Zongchao et al. (2008) Role of dichloroacetate in the treatment of genetic mitochondrial diseases. Adv Drug Deliv Rev 60:1478-87
Shroads, Albert L; Guo, Xu; Dixit, Vaishali et al. (2008) Age-dependent kinetics and metabolism of dichloroacetate: possible relevance to toxicity. J Pharmacol Exp Ther 324:1163-71