RT Journal Article
SR Electronic
T1 Glutathione-Dependent Conversion to Glyoxylate, a Major Pathway of Dichloroacetate Biotransformation in Hepatic Cytosol from Humans and Rats, is Reduced in Dichloroacetate-Treated Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1223
OP 1227
VO 25
IS 11
A1 M. O. James
A1 R. Cornett
A1 Z. Yan
A1 G. N. Henderson
A1 P. W. Stacpoole
YR 1997
UL http://dmd.aspetjournals.org/content/25/11/1223.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics