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.
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, Mississippi 38677, United States.
Haining
H
Liu
Larry A
LA
Walker
N P Dhammika
NP
Nanayakkara
Robert J
RJ
Doerksen
D000634:Aminoquinolines / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism*; D000962:Antimalarials / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D008708:Methemoglobinemia / Q000139:chemically induced* / Q000201:enzymology; D008958:Models, Molecular; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011487:Protein Conformation; D011522:Protons; D011789:Quantum Theory
D000634:Aminoquinolines; D000962:Antimalarials; D006454:Hemoglobins; D011522:Protons; D001708:Biopterins; D019001:Nitric Oxide Synthase; C003402:sapropterin; C080436:8-aminoquinoline
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