Glutathione peroxidase (GPx) detoxifies H2O2 and lipid peroxides using reduced glutathione (GSH) as electron donor, generating oxidized glutathione (GSSG). Glutathione reductase restores GSH using NADPH. In G6PD deficiency, NADPH production is impaired, impairing GPx regeneration. A patient with G6PD deficiency takes primaquine (an oxidant drug) and develops hemolytic anemia. The RBC hemolysis is initiated by which molecular event?

• A Primaquine directly crosslinks spectrin proteins in the RBC cytoskeleton, causing membrane fragmentation
• B Primaquine inhibits ferrochelatase in G6PD-deficient RBCs, reducing heme synthesis and weakening the cell
• C Primaquine metabolites generate reactive oxygen species (H2O2, superoxide) that oxidize hemoglobin to Heinz bodies due to insufficient GPx regeneration ✓
• D Primaquine activates complement-mediated lysis of G6PD-deficient RBCs by exposing phosphatidylserine

Explanation

Primaquine and other oxidant drugs generate reactive oxygen species (H2O2, superoxide radicals) as metabolites. In G6PD-deficient RBCs, NADPH production via the HMP shunt is severely reduced. Without NADPH, glutathione reductase cannot regenerate GSH from GSSG. Low GSH means inadequate GPx activity, leaving H2O2 to accumulate. H2O2 oxidizes the ferrous iron (Fe2+) in hemoglobin to ferric (Fe3+), forming methemoglobin, and further oxidizes globin chains, creating denatured hemoglobin aggregates (Heinz bodies). Heinz bodies attach to the inner membrane, reducing RBC deformability, causing extravascular hemolysis ('bite cells' visible on peripheral smear as macrophages remove Heinz bodies). The hemolysis is primarily oxidative stress-mediated, not complement or cytoskeletal.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.