Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans
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Albert L. Shroads
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.
Acknowledgments
We thank Ms. Candy Caputo for editorial assistance. This work was supported in part by the National Institutes of Health National Center for Advancing Translational Sciences Clinical and Translational Science Award to the University of Florida UL1 TR000064 and National Institutes of Health National Environmental Health Sciences TCE/Health Effects of Chlorinated Compounds grant P42 ES07375.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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©2015 by De Gruyter
Articles in the same Issue
- Frontmatter
- Editorial
- From DMDI “Drug Metabolism and Drug Interactions” to DMPT “Drug Metabolism and Personalized Therapy”
- Review
- Clinical drug-drug interactions: focus on venlafaxine
- Reviews in Population Pharmacogenomics
- Pharmacogenetics in Central American healthy volunteers: interethnic variability
- Genomic biomarkers related to drug response in Venezuelan populations
- Originial Articles
- No effect of CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) on lipid-lowering response to statins in Greek patients with primary hypercholesterolemia
- Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans
- Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects
- Minor contribution of biliary excretion in lithium elimination in rats
- Case Report
- Fatal hyperkalemia following succinylcholine administration in a child on oral propranolol
Articles in the same Issue
- Frontmatter
- Editorial
- From DMDI “Drug Metabolism and Drug Interactions” to DMPT “Drug Metabolism and Personalized Therapy”
- Review
- Clinical drug-drug interactions: focus on venlafaxine
- Reviews in Population Pharmacogenomics
- Pharmacogenetics in Central American healthy volunteers: interethnic variability
- Genomic biomarkers related to drug response in Venezuelan populations
- Originial Articles
- No effect of CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) on lipid-lowering response to statins in Greek patients with primary hypercholesterolemia
- Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans
- Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects
- Minor contribution of biliary excretion in lithium elimination in rats
- Case Report
- Fatal hyperkalemia following succinylcholine administration in a child on oral propranolol
