Comparative acute toxicity of chlorocitrate and fluorocitrate in dogs.
The high-dose effects of chlorocitrate [(-)-threo-chlorocitric acid] were compared in vivo to another halogenated citrate analog, and a well-known inhibitor of the tricarboxylic acid (TCA) cycle, fluorocitrate. The compounds were given iv to two dogs per sex per group, and a control group received an equimolar amount of citric acid. Chlorocitrate (100 mg/kg) showed TCA cycle inhibition as did fluorocitrate (8 mg/kg) in that both caused depletion of ATP and accumulation of citrate in the liver. Chlorocitrate was a significantly weaker inhibitor of citrate metabolism than fluorocitrate as evidenced by a substantially lower accumulation of serum citrate despite a much higher dose. Both halocitrates produced a similar diabetes-like syndrome (hyperglycemia, glycosuria) mediated by a significant hyperglucagonemia and slight hypoinsulinemia. Chlorocitrate was more potent in this effect and a much greater buildup of plasma lactate ensued (18- versus 3.7-fold increase), enough to explain lethality observed in earlier studies. In contrast, fluorocitrate produced a severe life-threatening hypocalcemia (-30%), and hypercalcuria was observed. This effect on calcium distribution was only minimal with chlorocitrate. Both halocitrates had a similar depressive effect on circulation as evidenced by hypothermia, bradycardia, and elongation of the QT-interval. These changes were considered to be the result of lactic acidosis and the ongoing ion imbalance since heart ATP levels were not depleted.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002951:Citrates / Q000378:metabolism / Q000633:toxicity*; D019343:Citric Acid; D002952:Citric Acid Cycle / Q000187:drug effects; D004285:Dogs; D004573:Electrolytes / Q000097:blood; D006943:Hyperglycemia / Q000139:chemically induced; D006996:Hypocalcemia / Q000139:chemically induced
D002951:Citrates; D004573:Electrolytes; C032936:chlorocitric acid; D019343:Citric Acid; C007744:fluorocitrate; D000255:Adenosine Triphosphate