Selective toxicity of the antimalarial primaquine-evidence for both uncoupling and inhibitory effects of a metabolite on the energetics of mitochondria and its ATP synthase complex.

A methylene-linked dimeric metabolite of primaquine can exist as an oxidized form (PD(+)) or a reduced form (PDH). Using a rat liver mitochondrial preparation, low concentrations (E 50% = 12 µM) of PD(+) were found to act as a classical uncoupler of oxidative phosphorylation leading to a stimulation of mitochondrial respiration. At higher concentrations, PD(+) was found to inhibit a purified F1-ATPase preparation, while its effects on the complete ATP synthase complex (F0F1-ATPase) was bimodal. A working hypothesis relating F0F1-ATPase and glucose-6-phosphate dehydrogenase activity to the selective toxicity of primaquine on the malaria parasite and host is presented.