Antimalarial quinones: redox potential dependence of methemoglobin formation and heme release in erythrocytes.

A number of quinones have been shown to be effective antimalarials. In addition some have been shown to have oxidant effects on glucose-6-phosphate dehydrogenase-deficient red cells. To clarify the mechanism of this oxidant effect and to determine whether it is a general property of antimalarial quinones, the effects of five compounds on red cells were studied. Two, 5-hydroxy-6-demethyl pentaquine (5H6DP) and menadione, caused marked methemoglobin production and the insertion of heme into the red-cell membrane. The other three, atovaquone, daphnetin, and menoctone, did not. The insertion of heme into membranes caused diminished deformability, and this might account for the hemolytic effects. Redox potentials of all five compounds were measured. The two quinones that caused heme release, menadione and 5H6DP, had redox potentials of -141 +/- 12 and -97 +/- 25 mV, respectively, which are similar to the reported redox potentials for hemoglobin. The other three quinones had redox potentials that were either significantly higher or lower. Thus only quinones of the appropriate redox potentials are likely to be toxic to red cells.