Methemoglobinemia caused by 8-aminoquinoline drugs: DFT calculations suggest an analogy to H4B's role in nitric oxide synthase.

We suggest a possible mechanism of how 8-aminoquinolines (8-AQ's) cause hemotoxicity by oxidizing hemoglobin to methemoglobin. In our DFT calculations, we found that 5-hydroxyprimaquine is able to donate an electron to O(2) to facilitate its conversion to H(2)O(2). Meanwhile, Fe(II) is oxidized to Fe(III) and methemoglobin is formed. In this mechanism, the 8-AQ drug plays a similar role as that of H(4)B in nitric oxide synthase. Furthermore, our study offers an approach to inform the design of less toxic antimalarial drugs.