Comparison of the metabolic and toxic effects of 2-chloropropionate and dichloroacetate.
The metabolic and toxic effects of 2-chloropropionate and dichloroacetate, activators of the pyruvate dehydrogenase complex, were compared. In 4-hr fasted mice, the oral LD50 values for 2-chloropropionate and dichloroacetate were 15.4 +/- 0.1 and 32.1 +/- 1.1 mmol/kg, respectively. In suckling rats, both compounds effectively lowered blood lactate and glucose levels and increased blood ketone bodies. Although comparable effects were brought about by both compounds on other metabolites, dichloroacetate caused a greater increase in blood ketone bodies. In a prolonged oral toxicity study using male rats, both compounds decreased growth rate and food consumption and caused neurotoxic effects. Both compounds brought about hind limb weakness, slower nerve conduction velocities and decreased diameter of tibial nerves. 2-Chloropropionate treatment caused testicular abnormalities manifested by testicular maturation arrest and degeneration of germ cells. 2-Chloropropionate-treated rats had significantly lower plasma triacylglycerol levels than control or dichloroacetate-treated rats. In mature rats, total serum ketone bodies were increased by dichloroacetate but not significantly elevated by 2-chloropropionate. Although 2-chloropropionate may lack sufficient safety to warrant chronic use in humans, it is a useful research tool for studying the metabolic effects of activation of the pyruvate dehydrogenase complex. Since 2-chloropropionate is not converted to oxalate and is not as ketogenic as dichloroacetate, 2-chloropropionate may be useful clinically in situations requiring only short-term therapy.
D000085:Acetates / Q000633:toxicity*; D000818:Animals; D003999:Dichloroacetic Acid / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006843:Hydrocarbons, Chlorinated; D007657:Ketone Bodies / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008660:Metabolism / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D009431:Neural Conduction / Q000187:drug effects; D010525:Peripheral Nerves / Q000187:drug effects; D011422:Propionates / Q000633:toxicity*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D013737:Testis / Q000187:drug effects / Q000473:pathology
D000085:Acetates; D006843:Hydrocarbons, Chlorinated; D007657:Ketone Bodies; D011422:Propionates; D011768:Pyruvate Dehydrogenase Complex; D003999:Dichloroacetic Acid; C021974:2-chloropropionic acid