Xanthine oxidase inhibits growth of Plasmodium falciparum in human erythrocytes in vitro.
Malaria parasites, unable to synthesize purine de novo, use host-derived hypoxanthine preferentially as purine source. In a previous study (1990. J. Biol. Chem. 265:6562-6568), we noted that xanthine oxidase rapidly and completely depleted hypoxanthine in human erythrocytes, not by crossing the erythrocyte membrane, but rather by creating a concentration gradient which facilitated hypoxanthine efflux. We therefore investigated the ability of xanthine oxidase to inhibit growth of FCR-3, a chloroquine-resistant strain of Plasmodium falciparum in human erythrocytes in vitro. Parasites were cultured in human group O+ erythrocytes in medium supplemented, as required, with xanthine oxidase or chloroquine. Parasite viability was assessed by uptake of radiolabeled glycine and adenosine triphosphate-derived purine into protein and nucleic acid, respectively, by nucleic acid accumulation, by L-lactate production, and by microscopic appearance. On average, a 90% inhibition of growth was observed after 72 h of incubation in 20 mU/ml xanthine oxidase. Inhibition was notably greater than that exerted by 10(-7) M chloroquine (less than 10%) over a comparable period. The IC50 for xanthine oxidase was estimated at 0.2 mU/ml, compared to 1.5 x 10(-7) M for chloroquine. Inhibition was completely reversed by excess hypoxanthine, but was unaffected by oxygen radical scavengers, including superoxide dismutase and catalase. The data confirms that a supply of host-derived hypoxanthine is critical for nucleic acid synthesis in P. falciparum, and that depletion of erythrocyte hypoxanthine pools of chloroquine-resistant malaria infection in humans. of chloroquine-resistant malaria infection in humans.
Berman
P A
PA
Department of Chemical Pathology, University of Cape Town Medical School, Observatory, South Africa.
Human
L
L
Freese
J A
JA
D000818:Animals; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000469:parasitology*; D005998:Glycine / Q000378:metabolism; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011687:Purines / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000494:pharmacology* / Q000627:therapeutic use
D007042:Hypoxanthines; D011687:Purines; D019271:Hypoxanthine; D002738:Chloroquine; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D005998:Glycine