title: Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans.
abstract: BACKGROUND
  Chloral hydrate (CH), a sedative and metabolite of the environmental contaminant trichloroethylene, is metabolized to trichloroacetic acid, trichloroethanol, and possibly dichloroacetate (DCA). DCA is further metabolized by glutathione transferase zeta 1 (GSTZ1), which is identical to maleylacetoacetate isomerase (MAAI), the penultimate enzyme in tyrosine catabolism. DCA inhibits its own metabolism through depletion/inactivation of GSTZ1/MAAI with repeated exposure, resulting in lower plasma clearance of the drug and the accumulation of the urinary biomarker maleylacetone (MA), a metabolite of tyrosine. It is unknown if GSTZ1/MAAI may participate in the metabolism of CH or any of its metabolites and, therefore, affect tyrosine catabolism. Stable isotopes were utilized to determine the biotransformation of CH, the kinetics of its major metabolites, and the influence, if any, of GSTZ1/MAAI.
  
  
  METHODS
  Eight healthy volunteers (ages 21-40 years) received a dose of 1 g of CH (clinical dose) or 1.5 μg/kg (environmental) for five consecutive days. Plasma and urinary samples were analyzed by gas chromatography-mass spectrometry.
  
  
  RESULTS
  Plasma DCA (1.2-2.4 μg/mL), metabolized from CH, was measured on the fifth day of the 1 g/day CH dosage but was undetectable in plasma at environmentally relevant doses. Pharmacokinetic measurements from CH metabolites did not differ between slow and fast GSTZ1 haplotypes. Urinary MA levels increased from undetectable to 0.2-0.7 μg/g creatinine with repeated CH clinical dose exposure. Kinetic modeling of a clinical dose of 25 mg/kg DCA administered after 5 days of 1 g/day CH closely resembled DCA kinetics obtained in previously naïve individuals.
  
  
  CONCLUSIONS
  These data indicate that the amount of DCA produced from clinically relevant doses of CH, although insufficient to alter DCA kinetics, is sufficient to inhibit MAAI and tyrosine catabolism, as evidenced by the accumulation of urinary MA.
authors.forename: Albert L
authors.initials: AL
authors.lastname: Shroads
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Coats
authors.forename: Taimour
authors.initials: T
authors.lastname: Langaee
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Shuster
authors.forename: Peter W
authors.initials: PW
authors.lastname: Stacpoole
mesh_terms: D000096:Acetone / Q000031:analogs & derivatives / Q000652:urine; D000328:Adult; D015415:Biomarkers / Q000652:urine; D002697:Chloral Hydrate / Q000378:metabolism*; D003999:Dichloroacetic Acid / Q000378:metabolism*; D005260:Female; D005982:Glutathione Transferase / Q000502:physiology; D064368:Healthy Volunteers; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism*; D008297:Male; D008298:Maleates / Q000652:urine; D014443:Tyrosine / Q000378:metabolism*; D055815:Young Adult; D019745:cis-trans-Isomerases / Q000037:antagonists & inhibitors* / Q000652:urine
chemical_list: D015415:Biomarkers; D006993:Hypnotics and Sedatives; D008298:Maleates; C460372:maleylacetone; D000096:Acetone; D002697:Chloral Hydrate; D014443:Tyrosine; D003999:Dichloroacetic Acid; C407705:GSTZ1 protein, human; D005982:Glutathione Transferase; D019745:cis-trans-Isomerases; C021531:maleylacetoacetate isomerase