OXIDANT-INDUCED INJURY IN PYRUVATE KINASE (PK) DEFICIENT ERYTHROCYTES

Abstract

Oxidant-induced hemolysis, the hallmark of hexose monophosphate (HMP) shunt abnormalities/ generally is not appreciated in PK deficiency. In vitro, however, some patients with PK deficiency manifest oxidant sensitivity (increased sulfhemoglobin formation) in the presence of cyanide (CN) and ascorbate (Asc). The HMP shunt (glucose- 1-14C oxidation to 14CO2) of these PK deficient RBC's was stimulated by Asc to the same extent as were normal cells. CN enhanced the Asc-induced HMP stimulation in control cells, but inhibited the Asc effect in PK deficient RBC's. ATP was decreased significantly in PK deficient RBC's incubated with CN + Asc. Therapeutic salicylate levels (2 mM) also inhibited the Asc-induced HMP stimulation in PK deficient RBC's, but not in normal cells. These experiments suggest that inhibition of mitochondrial oxidative phosphorylation in PK deficient reticulocytes deprives these cells of adequate ATP for accelerated glucose phosphorylation in the presence of an oxidant stress. Certain drugs (salicylates) or prolonged stasis in a hypoxic splenic environment presumably could inhibit oxidative phosphorylation, impair the ability of PK deficient RBC's to detoxify oxidants produced by bacteria and macrophages during infection, and thereby induce oxidant cell injury. Furthermore, this partially may explain the exacerbation of hemolysis seen in PK deficiency during infection.