Cardiotoxic effects of 5-fluorouracil in the guinea pig.
In order to search into the underlying mechanisms of ECG changes suggestive of ischemia observed in humans and in rabbits after administration of 5-fluorouracil (5-FU), experiments were performed in anesthetized open-chest guinea pigs. The substance produced similar ECG changes in this species as well, after a rather long latent period of around 3 hours after intravenous administration. The incidence of ECG abnormality in animals given 60 mg/kg was 7/7, while that in animals given 30 mg/kg was 4/9. with 10-20 mg/kg, ECG changes were not observed during an experimental period as long as 5 hours. Associated with these ECG changes, a depletion of the high-energy phosphate compounds of the ventricular myocardium was observed. Analysis of tricarboxylic acid cycle (TCA cycle) intermediates revealed an accumulation of citrate within the myocardium, suggesting a malfunction of TCA cycle resulting from an inhibition of aconitase by fluorocitrate, as a cause of depletion of the high-energy phosphates. It is highly probable that the accumulation of citrate was due to the formation of fluoroacetate, an inhibitor of aconitase, from 5-FU via alpha-fluoro-beta-alanine, a major degradation product of 5-FU, for it is known that beta-alanine is usually converted to acetate.
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004562:Electrocardiography; D005463:Fluoroacetates / Q000494:pharmacology; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007928:Lethal Dose 50; D008297:Male; D009206:Myocardium / Q000378:metabolism
D005463:Fluoroacetates; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005472:Fluorouracil