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

Author
item LIU, HAINING - University Of Mississippi
item WALKER, LARRY - University Of Mississippi
item NANAYAKKARA, N.P. DHAMMIKA - University Of Mississippi
item DOERKSEN, ROBERT - University Of Mississippi

Submitted to: Journal of the American Chemical Society
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/4/2011
Publication Date: 1/18/2011
Citation: Liu, H., Walker, L.A., Nanayakkara, N., Doerksen, R.J. 2011. Methemoglobinemia caused by 8-aminoquinoline drugs: DFT calculations suggest an analogy to H4B's role in nitric oxide synthase. Journal of the American Chemical Society. 133:1172-1175.

Interpretive Summary: 8-aminoquinoline antimalarial drugs, such as primaquine, are able to cure liver stage malaria but can cause life-threatening damage to the blood of patients with a common genetic deficiency (G6PD). In this work we investigated the possibility that 5-hydroxyprimaquine causes this trouble by contributing to a change to hemoglobin, which normally carries oxygen in red blood cells, so that it cannot carry oxygen. We used computations, the results of which supported this hypothesis.

Technical Abstract: 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 O2 to facilitate its conversion to H2O2. 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 H4B in nitric oxide synthase. Furthermore, our study offers an approach to informthe design of less toxic antimalarial drugs.