J. Vasquezvivar et O. Augusto, OXIDATIVE ACTIVITY OF PRIMAQUINE METABOLITES ON RAT ERYTHROCYTES IN-VITRO AND IN-VIVO, Biochemical pharmacology, 47(2), 1994, pp. 309-316
The oxidative activities of primaquine 6-methoxy-8-(4-amino-1-methylbu
tylamino)quinoline] and its metabolites, the quinone-imine derivatives
of 5-hydroxyprimaquine 6-methoxy-8-(4-amino-1-methylbutylamino)quinol
ine] and 5-hydroxydemethylprimaquine demethyl-8-(4-amino-1-methylbutyl
amino)quinoline], 6-methoxy-8-amino quinoline and hydrogen peroxide, w
ere studied on rat erythrocytes in vitro and in vivo. In both cases, t
he most effective metabolites in oxidizing hemoglobin and depleting no
n-protein sulfhydryl groups from erythrocytes were the quinone-imine d
erivatives of the ring-hydroxylated metabolites, 5-hydroxyprimaquine a
nd 5-hydroxydemethylprimaquine. The latter quinone-imines were shown b
y light absorption spectroscopy and oxygen consumption studies to be a
ble to oxidize purified rat hemoglobin to methemoglobin but to be unab
le to react directly with reduced glutathione. In agreement with these
results, no radical adduct was detected by electron paramagnetic reso
nance spectroscopy in incubations of rat erythrocytes with the quinone
-imines and the spin-trap 5,5-dimethyl-1-pyrroline-N-oxide; metabolite
-derived free radicals were detected instead. Taken together, the resu
lts suggest that 5-hydroxyprimaquine and 5-hydroxydemethylprimaquine a
re important metabolites in the expression of primaquine hemotoxicity,
in contrast to 6-methoxy-8-aminoquinoline. Additionally, the results
indicate that hydrogen peroxide is the ultimate oxidant formed from th
e ring-hydroxylated metabolites by redox-cycling of the corresponding
quinone-imine derivatives both in vitro and in vivo.