Metabolic consequences of methylenecyclopropylglycine poisoning in rats.
We describe the effects of methylenecyclopropylglycine in fasted rats. A 75% decrease in the blood glucose concentration and an increase of lactate and pyruvate were observed 6 h after administration of 100 mg of this amino acid/kg. By contrast with the effects reported for hypoglycin [Williamson & Wilson (1965) Biochem. J. 94, 19c-21c], the plasma concentrations of ketone bodies decreased after administration of methylenecyclopropylglycine and the concentrations of branched-chain amino acids in the plasma were increased 6-fold. The oxidation of decanoylcarnitine or of palmitate was nearly completely inhibited in rat liver mitochondria from methylenecyclopropylglycine-poisoned rats. The activities of acetoacetyl-CoA and of 3-oxoacyl-CoA thiolase were decreased to 25% and less than 10% of the controls. There was a pronounced aciduria, due to the excretion of dicarboxylic acids and of oxidation products of branched-chain amino acids. The accumulation of the toxic metabolite methylenecyclopropylformyl-CoA in the mitochondrial matrix was detected after administration of methylenecyclopropylglycine. Similarly we confirmed experimentally that methylenecyclopropylacetyl-CoA accumulates in mitochondria incubated with methylenecyclopropylpyruvate.
Melde
K
K
University of Konstanz, Federal Republic of Germany.
Jackson
S
S
Bartlett
K
K
Sherratt
H S
HS
Ghisla
S
S
D000214:Acyl Coenzyme A / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002264:Carboxylic Acids / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes / Q000378:metabolism / Q000633:toxicity*; D005215:Fasting; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000633:toxicity*; D007700:Kinetics; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D000214:Acyl Coenzyme A; D002264:Carboxylic Acids; D003521:Cyclopropanes; D007004:Hypoglycemic Agents; C059830:methylenecyclopropylglycine; D005998:Glycine