Syndromes with Increased Red Cell Glutathione (GSH)

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Abstract
GSH, the most abundant erythrocyte thiol, is synthesized from its constituent amino acids by two ATP-dependent enzymes present in the mature red cell. Its unusual γ-glutamyl linkage precludes degradation by any known red cell peptidase. The erythrocyte lacks a complete “γ-glutamyl cycle” as described by Meister. GSH has important enzymatic and non-enzymatic roles in oxidoreduction reactions. As the specific co-factor of gluta-thione peroxidase, it participates in the reduction of harmful organoperoxides. Oxidized glutathione is reconverted to GSH via NADPH-dependent, glutathione reductase. NADPH in the red cell is generated solely by the two dehydrogenases of the pentosephosphate shunt. Increased GSH concentrations are normally present in neonatal erythrocytes. For reasons not clear, they are an epiphenom-enon in inherited pyrimidine 5′-nucleotidase deficiency. Many syndromes of heterogeneous etiology having in common dyserythro-poietic anemia and ineffective erythropoiesis despite a cellular bone marrow also exhibit abnormally high concentrations of red cell GSH as one component of a constellation of metabolic abnormalities. In a single patient with the Lesch-Nyhan syndrome studied by us, erythrocyte GSH was increased. A kindred with dominantly transmitted (or possibly x-chromosome linked) hereditary hemolytic anemia in which the only thus far detected abnormality is increased red cell GSH has also been documented. The fundamental molecular lesion in this syndrome is unknown.