Relationships of Zinc, Copper, Cholesterol and Erythrocyte Oxidant Stress in Sickle Cell Anemia.

Abstract

The aims of the present studies were to define the nature and mechanism of interaction of erythrocyte oxidant stress, plasma cholesterol (P-C), erythrocyte membrane cholesterol (M-C), plasma zinc (Zn) and plasma copper (Cu) in sickle cell anemia (SCA) patients. In one study, cholesterol (C) uptake by sickle erythrocytes was determined and shown to be elevated relative to normal erythrocytes. This increased C uptake was probably not due to: (1) a cell age effect since G-6PD deficient erythrocytes enriched with young cells did not show an increased C uptake, or (2) a plasma effect since cross incubation of sickle erythrocytes in control plasma and control erythrocytes in sickle plasma produced no difference. Some defect of sickle erythrocytes must underlie the greater C uptake. Three studies tested the effect of variations in P-C and M-C on erythrocyte oxidant stress. The results showed that erythrocyte oxidant stress was decreased (1) in sickle and control erythrocytes with in vitro elevated M-C, (2) in erythrocytes from rats with higher endogenous P-C, and (3) in erythrocytes from rats with dietary-induced P-C. Five studies tested whether the mechanism of low P-C in SCA patients involves Cu-mediated oxidation of C to inhibitory oxysterols. The results showed that (1) in vivo oxidant stress in rats did not significantly lower P-C, (2) elevated dietary Cu in rats did not lower P-C of normal or hypercholesterolemic rats, (3) Zn supplementation in SCA patients led to a rise in P-C in only some patients, (4) in untreated SCA patients, there were no Cu- or erythrocyte oxidant stress-related C differences, and (5) oxysterols were not systematically elevated in SCA patients. The proposed mechanism of low P-C was unsupported. Relationships between Zn, Cu, C and erythrocyte oxidant stress may, nevertheless, exist as suggested by (1) the protective effect of elevated P-C or M-C against erythrocyte oxidant stress, (2) the rise in P-C in response to therapeutic Zn in some patients, (3) the association of Cu, measured as ceruloplasmin, with increased erythrocyte oxidant stress in untreated SCA patients and controls, and (4) the elevated oxysterols in one patient. Variations in these parameters may explain some of the clinical variability of sickle cell disease expression.