Pharmacologic or genetic ablation of maleylacetoacetate isomerase increases levels of toxic tyrosine catabolites in rodents

Ammini, Chandramohan V.; Fernández-Cañón, José Manuel; Shroads, Albert L.; Cornett, Rachel; Cheung, Jang; James, Margaret O.; Henderson, George N.; Grompe, Markus; Stacpoole, Peter W.

doi:10.1016/j.bcp.2003.07.002

Cited by 29 publications

(21 citation statements)

References 33 publications

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“…In contrast, MAAI activity in this bifunctional enzyme appeared to be inactivated, as evidenced by accumulation of MA during CH exposure. Nevertheless, urinary MA concentrations found in this study are quite small in comparison with the levels found in MAAI-knockout mice [25], in patients with hereditary tyrosinemia type I [16], or in subjects chronically treated with DCA.…”

Section: Discussioncontrasting

confidence: 61%

Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans

Shroads¹,

Coats²,

Langaee³

et al. 2014

Drug Metabolism and Personalized Therapy

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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.

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Section: Discussioncontrasting

confidence: 61%

Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans

Shroads¹,

Coats²,

Langaee³

et al. 2014

Drug Metabolism and Personalized Therapy

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“…DCA pharmacokinetics also have been examined in Gstz1 −/− mice; as expected, unchanged DCA was detected at high concentrations in the plasma and urine (Ammini, et al, 2003). The Gstz1 knockout mice excreted high levels of maleylacetone, fumarylacetone and succinylacetone in urine, while wild type mice did not excrete fumarylacetone or succinylacetone, and excreted much lower levels of maleylacetone.…”

Section: Toxicities Associated With Chronic Dca Administrationmentioning

confidence: 74%

“…Despite producing changes in GSTZ1 activity and protein expression, DCA did not affect steady state mRNA levels (Ammini, et al, 2003). The loss of function of this enzyme was proposed to occur post-translationally from adduct formation that leads to protein loss (Anderson, et al, 1999; Tzeng, et al, 2000).…”

Section: Inactivation Of Gstz1 By Dcamentioning

confidence: 99%

“…Mice with deletion of the Gstz1 gene have been generated to investigate the likely symptoms and severity of abnormalities that might be associated with loss of the GSTZ1 enzyme (Ammini, et al, 2003; Fernandez-Canon, et al, 2002; Lim, et al, 2004). One study reported that mice with the Gstz1 gene knocked out appeared normal unless stressed with a diet high in homogentisic acid, tyrosine or phenylalanine, which caused renal and hepatic failure thought to be due to build-up of maleylacetoacetate and maleylacetone (Fernandez-Canon, et al, 2002).…”

Section: Toxicities Associated With Chronic Dca Administrationmentioning

confidence: 99%

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Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

James

Jahn

Zhong

et al. 2017

Pharmacology & Therapeutics

103

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Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism-based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects.

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“…A trace amount of DCA can also be reductively dechlorinated to monochloroacetate in the blood (Shroads et al, 2008). In vivo exposure to DCA causes a dose-and duration-dependent reduction in hepatic GSTZ1 expression and activity (Cornett et al, 1999;Ammini et al, 2003). Accordingly, DCA exhibits reduced plasma clearance and prolonged elimination half-life after repeated exposure .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1

Li¹,

James²,

McKenzie³

et al. 2010

J Pharmacol Exp Ther

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Dichloroacetate (DCA) is a potential environmental hazard and an investigational drug. Repeated doses of DCA result in reduced drug clearance, probably through inhibition of glutathione transferase 1 (GSTZ1), a cytosolic enzyme that converts DCA to glyoxylate. DCA is known to be taken up by mitochondria, where it inhibits pyruvate dehydrogenase kinase, its major pharmacodynamic target. We tested the hypothesis that the mitochondrion was also a site of DCA biotransformation. Immunoreactive GSTZ1 was detected in liver mitochondria from humans and rats, and its identity was confirmed by liquid chromatography/tandem mass spectrometry analysis of the tryptic peptides. Study of rat submitochondrial fractions revealed GSTZ1 to be localized in the mitochondrial matrix. The specific activity of GSTZ1-catalyzed dechlorination of DCA was 2.5-to 3-fold higher in cytosol than in whole mitochondria and was directly proportional to GSTZ1 protein expression in the two compartments. Rat mitochondrial GSTZ1 had a 2.5-fold higher App K m for glutathione than cytosolic GSTZ1, whereas the App K m values for DCA were identical. Rats administered DCA at a dose of 500 mg/kg/day for 8 weeks showed reduced hepatic GSTZ1 activity and expression of ϳ10% of control levels in both cytosol and mitochondria. We conclude that the mitochondrion is a novel site of DCA biotransformation catalyzed by GSTZ1, an enzyme colocalized in cytosol and mitochondrial matrix.

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Pharmacologic or genetic ablation of maleylacetoacetate isomerase increases levels of toxic tyrosine catabolites in rodents

Cited by 29 publications

References 33 publications

Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans

Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1

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