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Rapid CommunicationAccelerated Communication

Glutathione-Dependent Conversion to Glyoxylate, a Major Pathway of Dichloroacetate Biotransformation in Hepatic Cytosol from Humans and Rats, is Reduced in Dichloroacetate-Treated Rats

M. O. James, R. Cornett, Z. Yan, G. N. Henderson and P. W. Stacpoole
Drug Metabolism and Disposition November 1997, 25 (11) 1223-1227;
M. O. James
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R. Cornett
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Z. Yan
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G. N. Henderson
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P. W. Stacpoole
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Abstract

Although it has been postulated that glyoxylate is an intermediate in the biotransformation of DCA to oxalate, CO2, and glycine, there has been no positive identification of glyoxylate as a metabolite of DCA. We have demonstrated that a GSH-dependent pathway in dialyzed hepatic cytosol from rats and humans converts a mixture of 1-14C- and 1,2-13C-DCA to isotopically labeled glyoxylate. The reaction does not occur in the presence of NADPH or NADH or in the absence of GSH. The identity of the glyoxylate was demonstrated by HPLC with radiochemical detection and confirmed by GC/MS of the methylated glyoxylate, which showed the13C-labeled product. The apparentKm for GSH was 0.075 mM in rat hepatic cytosol. Pretreatment of rats with NaDCA, 50 mg/kg, p.o. (by mouth) for 2 days prior to preparation of hepatic cytosol on the third day affected the cytosolic metabolism of DCA. With 0.2 mM DCA as substrate, in the presence of 1 mM GSH, control rats formed 1.45 ± 0.13 nmol glyoxylate/min/mg cytosolic protein, whereas the rate in DCA-treated rats was 0.45 ± 0.10 nmol glyoxylate/min/mg protein (mean ± SD, N = 4 in each group). The mechanism of this reduction in the rate of DCA biotransformation in DCA-treated rats is unknown but is consistent with in vivo observations that the elimination of DCA from plasma of humans and rats is slowed by prior administration of DCA.

Footnotes

  • Send reprint requests to: Dr. Margaret O. James, Department of Medicinal Chemistry, P.O. Box 100485, College of Pharmacy, University of Florida, Gainesville FL 32610-0485

  • ↵1 Present address: American Cyanamid, Princeton, NJ.

  • This work was supported in part by the US Public Health Service, National Institutes of Health, grants ES -07375 and ES-07355. Portions of this work were presented at the Society of Toxicology Annual Meetings at Baltimore, MD, March 1995 and Cincinnati, OH, March, 1997.

  • ↵3 James, M.O., K.U.M.M. Jayanti, G.N. Henderson, et al., in preparation.

  • ↵4 Stacpoole, P.W., Z. Yan, G.N. Henderson, et. al., unpublished studies, 1996–1997.

  • Abbreviations used are::
    DCA
    dichloroacetic acid
    GSH
    glutathione
    HEPES
    4-(2-hydroxyethyl)-1piperazineethane-sulfonic acid
    GST
    glutathione-S-transferase
    CDNB
    1-chloro-2,4-dinitrobenzene
    • Received June 18, 1997.
    • Accepted July 8, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 11
1 Nov 1997
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Rapid CommunicationAccelerated Communication

Glutathione-Dependent Conversion to Glyoxylate, a Major Pathway of Dichloroacetate Biotransformation in Hepatic Cytosol from Humans and Rats, is Reduced in Dichloroacetate-Treated Rats

M. O. James, R. Cornett, Z. Yan, G. N. Henderson and P. W. Stacpoole
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1223-1227;

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Rapid CommunicationAccelerated Communication

Glutathione-Dependent Conversion to Glyoxylate, a Major Pathway of Dichloroacetate Biotransformation in Hepatic Cytosol from Humans and Rats, is Reduced in Dichloroacetate-Treated Rats

M. O. James, R. Cornett, Z. Yan, G. N. Henderson and P. W. Stacpoole
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1223-1227;
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