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Pharmacological Reviews, Vol 21, 105-130, Copyright © 1969 by the American Society for Pharmacology and Experimental Therapeutics

HYPOGLYCIN AND HYPOGLYCIN-LIKE COMPOUNDS

R. BRESSLER 1, C. CORREDOR 1, and K. BRENDEL 1

1 Departments of Biochemistry, Physiology and Pharmacology, and Medicine, Duke University, Durham, North Carolina

Hypoglycin and hypoglycin-like compounds cause profound hypoglycemia which may be largely attributed to their effects on gluconeogenesis. The toxicity of these agents is due to their capacity to become activated to acyl CoA derivatives whose further oxidation is impaired. Because the activated compounds serve as substrates for the carnitine acetyltransferase, tissue levels of both free carnitine and coenzyme A are depressed. The depression of these cofactors results in a decrease in long-chain fatty acid oxidation, whose products (acetyl CoA, NADH, ATP) are necessary for gluconeogenesis. Moreover, the decreased oxidation of long-chain fatty acids may also result in augmented glycolysis due to relief of the inhibitory effects of long-chain fatty acid oxidation on glycolysis. Replacement of coenzyme A and carnitine prevent inhibition of long-chain fatty acid oxidation and glyconeogenesis by 4-pentenoate. Addition of noncarnitinedependentfatty acids or palmitylcarnitine as substrates also partially prevent the 4-pentenoate depression of gluconeogenesis.

The inability to completely reverse the toxic effects of these compounds in vitro and in vivo suggests that they may be exerting as yet poorly established effects on oxidative phosphorylation and the electron transport system.




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