Hydroxyurea-induced oxidative damage of normal and sickle cell hemoglobins in vitro: amelioration by radical scavengers.

Hydroxyurea (HU) induces fetal hemoglobin (Hb F) production in patients with sickle cell anemia. The therapeutic dosage of HU used for Hb F induction often elicits myelosuppression, which becomes its major associated complication. We examined the effect of HU on hemoglobin modulation and the role of radical scavengers on these induced changes. In vitro exposure of human blood to various concentrations of HU at predetermined time intervals induced a progressive dose-dependent oxidation (MetHb formation) of both adult (Hb AA) and sickle (Hb SS) hemoglobins. The oxidative effect of HU on Hb SS was 3 times greater than its effect on Hb AA. Similar but less profound changes were observed in H2O2-treated samples. Hb F was, however, observed to be relatively resistant to HU-induced oxidative damage. A substantial protective effect of Hb by alpha-tocopherol, ascorbic acid, and D-mannitol was observed during pretreatment of Hb AA and Hb SS blood samples. Analyses of the hemoglobins and their globin chain components by high-performance liquid chromatography revealed a considerable protective effect by these free radical scavengers. These results indicate that the HU-induced damage of hemoglobin and their component globin chains can be reduced by radical scavengers.