MECHANISM FOR DRUG-INDUCED METHEMOGLOBIN FORMATION : OXIDATION OF HUMAN OXYHEMOGLOBIN BY ETHOPROPAZINE

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The mechanism for oxidation of human oxyhemoglobin induced by ethopropazine was studied. The rate of methemoglobin formation followed second-order kinetics and became faster with an increase of pH. The methemoglobin formation was not inhibited by either catalase or superoxide dismutase. The increase of absorbance at 520 nm, which was attributed to the reduction of ferrocytochrome c, was not inhibited by superoxide dismutase. On the other hand, the decrease of absorbance at 550 nm which corresponded to the co-oxidation of ferrocytochrome c was inhibited by catalase. The oxidation of human oxyhemoglobin induced by ethopropazine seemed to occur through two electron reduction mechanism. In the initial step, a single electron transfers from ethopropazine to the bound dioxygen of oxyhemoglobin giving rise to (Fe^<2+>-OO^-) and a semiquinone free radical. In the second step, a single electron transfers from the iron atom to the bound dioxygen producing hydrogen peroxide and methemoglobin. The two electron transfer mechanism giving rise to hydrogen peroxide and methemoglobin seems to give an important implication to the drug-induced methemoglobin formation and hemolysis of erythrocyte.
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