Favism: Divicine hemotoxicity in the rat

Favism is an acute hemolytic anemia known to occur in susceptible individua ls who ingest fava beans. Susceptibility to favism is conferred by a geneti c deficiency in erythrocytic glucose-6-phosphate dehydrogenase (G6PD) activ ity. Although the fava bean pyrimidine aglycones, divicine and isouramil, h ave been implicated in the onset of favism in humans, the lack of a well-de fined experimental animal model for favism has hampered progress in elucida ting the mechanism underlying hemotoxicity. We have examined whether a favi c-like response could be provoked in G6PD-normal rats treated with syntheti c divicine. Intraperitoneal administration of divicine to rats preloaded wi th Cr-51-tagged erythrocytes resulted in a severe, dose-dependent decrease in blood radioactivity (TD50 similar to 0.5 mmol/kg) within 24 h. The incre ased rate of removal of blood radioactivity was accompanied by a rapid decl ine in reduced glutathione levels in the blood, decreased hematocrits, mark ed hemoglobinuria, splenic enlargement, and reticulocytosis. In vitro expos ure of Cr-51-tagged red cells to divicine before their re-administration to isologous rats also resulted in a sharp, concentration-dependent decrease in erythrocyte survival in vivo (TC50 similar to 1.5 mM), and these divicin e-damaged red cells were removed from the circulation by the spleen. These data demonstrate that a favic response can be induced in G6PD-normal rats t reated with divicine, and that hemolytic activity can be reproduced in isol ated red cells under conditions that will allow a direct examination of the mechanism underlying this hemotoxicity.