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Hydroxylated metabolites of the antimalarial drug primaquine. Oxidation and redox cycling. J Biol Chem 1992 Apr 05;267(10):6848-54 PMID: 1313024

Pubmed ID

1313024

Abstract

Oxidation and redox cycling of the hydroxylated metabolites of the antimalarial drug primaquine (i.e. 5-hydroxyprimaquine, 5-hydroxydemethylprimaquine, and 5,6-dihydroxy-8-aminoquinoline) were studied. The three metabolites readily oxidized under physiological conditions, forming hydrogen peroxide and the corresponding quinone-imine derivatives as the main products. The latter compounds were characterized by visible, NMR, and infrared spectroscopy. Concomitant formation of drug-derived radicals and hydroxyl radicals was attested by direct and spin-trapping EPR experiments, respectively. The use of the spin stabilization method indicated that the radicals derived from 5-hydroxydemethylprimaquine and 5,6-dihydroxy-8-aminoquinoline are of the o-semiquinone type. Tentative structures are proposed for the radicals based on product identification and computer simulation of the experimental EPR spectra. The quinone-imines obtained from the reduced metabolites did not react at appreciable rates with NADPH but underwent redox cycling upon addition of ferredoxin:NADP+ oxidoreductase, forming hydrogen peroxide and hydroxyl radicals. The effect of antioxidant enzymes on hydroxyl radical yield obtained during oxidation and redox cycling indicates that the main route for hydroxyl radical formation is the metal ion-catalyzed reaction between the drug-derived radicals and hydrogen peroxide. Taken together, the results indicate that hydrogen peroxide is the potential toxic product formed from the primaquine metabolites.

Author List

Vásquez-Vivar J, Augusto O

Author

Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin

Scopus

2-s2.0-0026630568   65 Citations

MESH terms used to index this publication - Major topics in bold

Antimalarials
Cytochrome c Group
Electron Spin Resonance Spectroscopy
Free Radicals
Hydroxylation
Kinetics
NADP
Oxidation-Reduction
Oxygen
Primaquine
Spectrum Analysis