Mechanism of hypoglycaemic action of methylenecyclopropylglycine

Abstract

The effects of methylenecyclopropylglycine (MCPG), the lower homologue of hypoglycin A, on starved rats are described. Upon oral ingestion of MCPG (43 mg/kg), a 50% decrease in blood glucose compared with controls was observed after 4 h. The plasma concentrations of lactate and non-esterified fatty acids were substantially increased during this period. The activity of general acyl-CoA dehydrogenase from isolated rat liver mitochondria was not significantly changed. By contrast, the activity of 2-methyl-(branched-chain)-acyl-CoA dehydrogenase decreased by over 80%. The enzyme activity of enoyl-CoA hydratase (crotonase) from pig kidneys decreased by 80% on incubation with the hypothetically toxic metabolite of MCPG, methylenecyclopropylformyl-CoA. These results suggest that the inhibition spectrum of MCPG is quite different from that of hypoglycin A and that similar physiological effects might result from inhibition of different enzymes of beta-oxidation, e.g. hypoglycaemia and lacticacidemia. Accumulation of medium-chain acyl-CoA thioesters is probably at the origin of disturbances in pyruvate metabolism.

Evidence for the Natural Toxins from the Mushroom Trogia venenata as a Cause of Sudden Unexpected Death in Yunnan Province, China

“…Consequently, cells can no longer use lipids as an energy source, and a profound hypoglycemia results. [16,17] In the chemical structures of 1 and 2 there is a d-unsaturated bond, which is similar to hypoglycin. Further investigations are needed to determine if 1 and 2 have this specific or a similar biochemical effect.…”

Quantification of Metabolites for Assessing Human Exposure to Soapberry Toxins Hypoglycin A and Methylenecyclopropylglycine

“…34–35 Both hypoglycin A and MCPG are documented compounds that can induce encephalopathy and hypoglycemia in animal studies. 8–12,22,26 …”

Novel methylenecyclopropyl‐based acyl‐CoA dehydrogenase inhibitor

“…MCPA‐CoA, a ‘suicide’ or mechanism‐based inhibitor [7], causes irreversible inhibition through covalent modification of the flavin prosthetic group [7, 13]. The lower homologue, methylenecyclopropyl formyl‐CoA (MCPF‐CoA), exhibits a rather different target specificity, giving potent inhibition of 2MeBCD and IVD whilst SCAD is rather weakly inhibited and MCAD and LCAD are unaffected [14, 15]. Inhibition by this compound is irreversible but the mechanism of action is unknown [14, 15].…”

“…The lower homologue, methylenecyclopropyl formyl‐CoA (MCPF‐CoA), exhibits a rather different target specificity, giving potent inhibition of 2MeBCD and IVD whilst SCAD is rather weakly inhibited and MCAD and LCAD are unaffected [14, 15]. Inhibition by this compound is irreversible but the mechanism of action is unknown [14, 15]. Recently it was reported that spiropentane acetyl‐CoA (SPA‐CoA) preferentially inhibited octanoyl‐CoA dehydrogenase activity in liver homogenates [16].…”