Unified gas chromatographic?mass spectrometric method for quantitating tyrosine metabolites in urine and plasma

Shroads, Albert L.; Henderson, George N.; Cheung, Jang; James, Margaret O.; Stacpoole, Peter W.

doi:10.1016/j.jchromb.2004.05.005

Cited by 28 publications

(25 citation statements)

References 17 publications

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“…We purchased sodium 1,2-[ 13 C]DCA (99% pure) from Cambridge Isotopes Laboratories (Andover, MA). We verified the purity of the compound by gas chromatographic-mass spectrometric (GC-MS) analysis (Shroads et al, 2004), and we found that it contained Ͻ0.1% of […”

Section: Methodsmentioning

confidence: 99%

“…Analysis by mass spectrometry can readily distinguish the different isotopes of DCA and its metabolites, and it can also discriminate between the endogenous levels of glyoxylate and oxalate from their concentrations due to DCA administration (Shroads et al, 2004). We collected blood on day 5 at 0, 10, 20, and 40 min and 1, 2, 4, 6, 8, 10, and 12 h after 1,2-[ 13 C]DCA administration, and we immediately centrifuged the whole blood at 500g to isolate the plasma.…”

Section: Methodsmentioning

confidence: 99%

“…We measured 1,2-[ 12 C]DCA and 1,2-[ 13 C]DCA by GC-MS after derivatization in plasma and urine to their methyl esters with 12% boron trifluoride in methanol and subsequent extraction with methylene chloride (Shroads et al, 2004). We prepared calibration standards daily by adding varying amounts of [ 12 C]DCA and [ 13 C]DCA to fresh-frozen human plasma and derivitizing and analyzing as described above.…”

Section: Methodsmentioning

confidence: 99%

“…We used Zephyrhills Spring water for blank samples, and the water was found to be free of all analytes. We added the internal standard (50 g/ml 2-oxohexanoic acid) to all samples and standards before derivatization and extraction, and we analyzed them using an Agilent 5972 GC-MS (Agilent Technologies, Palo Alto, CA) under analytical conditions reported previously (Shroads et al, 2004). We determined the levels of both carbon-12 and carbon-13 isotopes of DCA, MCA, glyoxylate, and oxalate using this method.…”

Section: Methodsmentioning

confidence: 99%

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Age-Dependent Kinetics and Metabolism of Dichloroacetate: Possible Relevance to Toxicity

Shroads

Xu²,

Dixit³

et al. 2007

J Pharmacol Exp Ther

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Dichloroacetate (DCA) is an investigational drug for certain metabolic diseases. It is biotransformed principally by the -1 family isoform of glutathione transferase (GSTz1), also known as maleylacetoacetate isomerase (MAAI), which catalyzes the penultimate step in tyrosine catabolism. DCA causes a reversible peripheral neuropathy in several species, including humans. However, recent clinical trials indicate that adults are considerably more susceptible to this adverse effect than children. We evaluated the kinetics and biotransformation of DCA and its effects on tyrosine metabolism in nine patients treated for 6 months with 25 mg/kg/day and in rats treated for 5 days with 50 mg/kg/day. We also measured the activity and expression of hepatic GSTz1/MAAI. Chronic administration of DCA causes a striking age-dependent decrease in its plasma clearance and an increase in its plasma half-life in patients and rats. Urinary excretion of unchanged DCA in rats increases with age, whereas oxalate, an end product of DCA metabolism, shows the opposite trend. Low concentrations of monochloroacetate (MCA), which is known to be neurotoxic, increase as a function of age in the urine of dosed rats. MCA was detectable in plasma only of older animals. Hepatic GSTz1/MAAI-specific activity was inhibited equally by DCA treatment among all age groups, whereas plasma and urinary levels of maleylacetone, a natural substrate for this enzyme, increased with age. We conclude that age is an important variable in the in vivo metabolism and elimination of DCA and that it may account, in part, for the neurotoxicity of this compound in humans and other species.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Age-Dependent Kinetics and Metabolism of Dichloroacetate: Possible Relevance to Toxicity

Shroads

Xu²,

Dixit³

et al. 2007

J Pharmacol Exp Ther

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show abstract

“…DCA and MA were extracted with methylene chloride. The concentrations of DCA and MA were measured by gas chromatography-mass spectrometry Shroads et al, 2004), using a Hewlett Packard (Palo Alto, CA) 5890 Series II plus gas chromatograph and a 5972A Series mass selective detector.…”

Section: Downloaded Frommentioning

confidence: 99%

INHIBITION AND RECOVERY OF RAT HEPATIC GLUTATHIONES-TRANSFERASE ZETA AND ALTERATION OF TYROSINE METABOLISM FOLLOWING DICHLOROACETATE EXPOSURE AND WITHDRAWAL

Xu¹,

Dixit²,

Liu³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Dichloroacetate (DCA) is an investigational drug for certain metabolic disorders, a by-product of water chlorination and a metabolite of certain industrial solvents and drugs. DCA is biotransformed to glyoxylate by glutathione S-transferase zeta (GSTz1-1), which is identical to maleylacetoacetate isomerase, an enzyme of tyrosine catabolism. Clinically relevant doses of DCA (mg/kg/day) decrease the activity and expression of GSTz1-1, which alters tyrosine metabolism and may cause hepatic and neurological toxicity. The effect of environmental DCA doses (g/kg/day) on tyrosine metabolism and GSTz1-1 is unknown, as is the time course of recovery from perturbation following subchronic DCA administration. Male Sprague-Dawley rats (200 g) were exposed to 0 g, 2.5 g, 250 g, or 50 mg DCA/kg/day in drinking water for up to 12 weeks. Recovery was followed after the 8-week exposure. GSTz specific activity and protein expression (Western immunoblotting) were decreased in a dose-dependent manner by 12 weeks of exposure. Enzyme activity and expression decreased 95% after a 1-week administration of high-dose DCA. Eight weeks after cessation of high-dose DCA, GSTz activity had returned to control levels. At the 2.5 or 250 g/kg/day doses, enzyme activity also decreased after 8 weeks' exposure and returned to control levels 1 week after DCA was withdrawn. Urinary excretion of the tyrosine catabolite maleylacetone increased from undetectable amounts in control rats to 60 to 75 g/kg/24 h in animals exposed to 50 mg/kg/day DCA. The liver/body weight ratio increased in the high-dose group after 8 weeks of DCA. These studies demonstrate that short-term administration of DCA inhibits rat liver GSTz across the wide concentration range to which humans are exposed.

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Pharmacokinetics of Oral Dichloroacetate in Dogs

Maisenbacher

Shroads

Zhong

et al. 2013

J Biochem Mol Toxicol

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We characterized the pharmacokinetics and dynamics of dichloroacetate (DCA), an investigational drug for mitochondrial diseases, pulmonary arterial hypertension, and cancer. Adult Beagle dogs were orally administered 6.25 mg/kg q12h DCA for 4 weeks. Plasma kinetics was determined after 1, 14, and 28 days. The activity and expression of glutathione transferase zeta 1 (GSTZ1), which biotransforms DCA to glyoxylate, were determined from liver biopsies at baseline and after 27 days. Dogs demonstrate much slower clearance and greater inhibition of DCA metabolism and GSTZ1 activity and expression than rodents and most humans. Indeed, the plasma kinetics of DCA in dogs is similar to humans with GSTZ1 polymorphisms that confer exceptionally slow plasma clearance. Dogs may be a useful model to further investigate the toxicokinetics and therapeutic potential of DCA.

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Unified gas chromatographic?mass spectrometric method for quantitating tyrosine metabolites in urine and plasma

Cited by 28 publications

References 17 publications

Age-Dependent Kinetics and Metabolism of Dichloroacetate: Possible Relevance to Toxicity

Age-Dependent Kinetics and Metabolism of Dichloroacetate: Possible Relevance to Toxicity

INHIBITION AND RECOVERY OF RAT HEPATIC GLUTATHIONES-TRANSFERASE ZETA AND ALTERATION OF TYROSINE METABOLISM FOLLOWING DICHLOROACETATE EXPOSURE AND WITHDRAWAL

Pharmacokinetics of Oral Dichloroacetate in Dogs

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