title: Understanding the mechanisms for metabolism-linked hemolytic toxicity of primaquine against glucose 6-phosphate dehydrogenase deficient human erythrocytes: evaluation of eryptotic pathway.
abstract: Therapeutic utility of primaquine, an 8-aminoquinoline antimalarial drug, has been limited due to its hemolytic toxicity in population with glucose 6-phosphate dehydrogenase deficiency. Recent investigations at our lab have shown that the metabolites generated through cytochrome P(450)-dependent metabolic reactions are responsible for hemotoxic effects of primaquine, which could be monitored with accumulation of methemoglobin and increased oxidative stress. The molecular markers for succeeding cascade of events associated with early clearance of the erythrocytes from the circulation were evaluated for understanding the mechanism for hemolytic toxicity of primaquine. Primaquine alone though did not induce noticeable methemoglobin accumulation, but produced significant oxidative stress, which was higher in G6PD-deficient than in normal erythrocytes. Primaquine, presumably through redox active hemotoxic metabolites generated in situ in human liver microsomal metabolism-linked assay, induced a dose-dependent methemoglobin accumulation and oxidative stress, which were almost similar in normal and G6PD-deficient erythrocytes. Primaquine alone or in presence of pooled human liver microsomes neither produced significant effect on intraerythrocytic calcium levels nor affected the phosphatidyl serine asymmetry of the normal and G6PD-deficient human erythrocytes as monitored flowcytometrically with Annexin V binding assay. The studies suggest that eryptosis mechanisms are not involved in accelerated removal of erythrocytes due to hemolytic toxicity of primaquine.
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS 38677, United States.
authors.forename: Shobana
authors.initials: S
authors.lastname: Ganesan
authors.forename: Narayan D
authors.initials: ND
authors.lastname: Chaurasiya
authors.forename: Rajnish
authors.initials: R
authors.lastname: Sahu
authors.forename: Larry A
authors.initials: LA
authors.lastname: Walker
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
mesh_terms: D017302:Annexins / Q000378:metabolism; D002118:Calcium / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects* / Q000201:enzymology; D005954:Glucosephosphate Dehydrogenase / Q000097:blood; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000097:blood* / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D008706:Methemoglobin / Q000032:analysis / Q000096:biosynthesis / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011319:Primaquine / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000097:blood
chemical_list: D017302:Annexins; D017382:Reactive Oxygen Species; D008706:Methemoglobin; D005954:Glucosephosphate Dehydrogenase; D011319:Primaquine; D002118:Calcium