Effect of quinone reductase 2 (NQO2) inhibitor melatonin on primaquine induced hemolysis

Abstract

The 8-aminoquinoline anti-malarial drug, primaquine (PQ) is the drug of choice for treatment for some forms of malaria. It has antihypnozoite activity against Plasmodium vivax and Plasmodium ovale and gametocytocidal activity against Plasmodium falciparum. Clinical use of PQ is limited due its hemolytic toxicity, especially in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Human erythrocytic NQO2 is the only protein target identified for PQ, and redox cycling of quinone metabolites has been implicated in hemotoxicity of PQ. Melatonin, a selective and potent inhibitor of NQO2, was tested for its effect on the hemolytic response to 5-hydroxy PQ (5-HPQ) and 6-methoxy-8-hydroxylaminoquinoline (MHQ), which are among the putative hemotoxic metabolites of PQ. An in vitro assay using normal and G6PD deficient human erythrocytes with accumulation of methemoglobin and generation of oxidative stress, as the markers of hemolysis, was employed. 5HPQ is a highly unstable compound, which is spontaneously converted to 5, 6-orthoquinone (5, 6-OQPQ). Melatonin synergistically increased the methemoglobin formation and reactive oxygen species (ROS) generation induced by 5-HPQ (5, 6-OQPQ) and MHQ. These results suggest a protective role of NQO2 in hemolytic toxicity of PQ. The precise interactions of these metabolites and others, along with PQ itself, with NQO2 should be further explored.