Consequences of erythrocytic glutathione reductase deficiency.
We have used 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) as a selective and irreversible inhibitor of oxidized glutathione reductase (GSSG-R) to determine how human erythrocytes with various degrees of GSSG-R deficiency recover their reduced glutathione (GSH) after exposure to acetylphenylhydrazine or diamide. Pentose phosphate dehydrogenases and glutathione synthesis were not inhibited, de novo glutathione synthesis was negligible within the experimental time frame, and the reappearance of GSH was strictly under the control of GSSG-R. Results obtained with acetylphenylhydrazine or diamide were concordant. In red cells stressed by these reagents, GSSG-R deficiency began to impair the regeneration of GSH only after greater than 80% of the normal enzyme activity had been abolished. Thereafter GSH recovery deteriorated as drug-induced GSSG-R depression increased. Only erythrocytes that had been rendered almost totally GSSG-R deficient, that is, had lost greater than 90% of baseline activity, became functionally equivalent to GdA- glucose-6-phosphate dehydrogenase-deficient cells. The reserve capacity of GSSG-R in human erythrocytes is extremely large. Of all types of isolated GSSG-R "deficiencies" reported so far, only two can be considered pathogenically significant: the homozygous genetic defect found in a single family, and much more commonly, the acute pharmacologic phenocopy induced by BCNU.
D002330:Carmustine / Q000494:pharmacology; D003958:Diamide / Q000494:pharmacology; D004137:Dinitrochlorobenzene / Q000494:pharmacology; D004912:Erythrocytes / Q000201:enzymology*; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000201:enzymology; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000172:deficiency*; D006801:Humans; D010659:Phenylhydrazines / Q000494:pharmacology
D004137:Dinitrochlorobenzene; D010659:Phenylhydrazines; D003958:Diamide; C006384:N(1)-acetylphenylhydrazine; D005980:Glutathione Reductase; D005978:Glutathione; D002330:Carmustine