Favism: divicine hemotoxicity in the rat.
Favism is an acute hemolytic anemia known to occur in susceptible individuals who ingest fava beans. Susceptibility to favism is conferred by a genetic deficiency in erythrocytic glucose-6-phosphate dehydrogenase (G6PD) activity. Although the fava bean pyrimidine aglycones, divicine and isouramil, have been implicated in the onset of favism in humans, the lack of a well-defined experimental animal model for favism has hampered progress in elucidating the mechanism underlying hemotoxicity. We have examined whether a favic-like response could be provoked in G6PD-normal rats treated with synthetic divicine. Intraperitoneal administration of divicine to rats preloaded with 51Cr-tagged erythrocytes resulted in a severe, dose-dependent decrease in blood radioactivity (TD50 approximately 0.5 mmol/kg) within 24 h. The increased rate of removal of blood radioactivity was accompanied by a rapid decline in reduced glutathione levels in the blood, decreased hematocrits, marked hemoglobinuria, splenic enlargement, and reticulocytosis. In vitro exposure of 51Cr-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 approximately 1.5 mM), and these divicine-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 treated with divicine, and that hemolytic activity can be reproduced in isolated red cells under conditions that will allow a direct examination of the mechanism underlying this hemotoxicity.
McMillan
D C
DC
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston 29425, USA. mcmilldc@musc.edu
Jollow
D J
DJ
D000818:Animals; D002857:Chromium / Q000097:blood / Q000652:urine; D002860:Chromium Radioisotopes; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000201:enzymology; D007887:Fabaceae; D005236:Favism / Q000097:blood / Q000139:chemically induced* / Q000201:enzymology; D005954:Glucosephosphate Dehydrogenase / Q000097:blood; D005978:Glutathione / Q000097:blood; D006454:Hemoglobins / Q000378:metabolism; D006461:Hemolysis; D007928:Lethal Dose 50; D008297:Male; D010946:Plants, Medicinal; D010947:Plants, Toxic / Q000633:toxicity; D011744:Pyrimidinones / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002860:Chromium Radioisotopes; D006454:Hemoglobins; D011744:Pyrimidinones; D002857:Chromium; C026511:divicine; D005954:Glucosephosphate Dehydrogenase; D005978:Glutathione