Studies of the Action of Hypoglycin‐a, an Hypoglycaemic Substance

Feng, Pengfei; Patrick, S. J.

doi:10.1111/j.1476-5381.1958.tb00206.x

Cited by 40 publications

(14 citation statements)

References 17 publications

(4 reference statements)

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“…Extreme hypoglycemia (11) and depletion of liver glycogen (12) have been observed in the cases of this disease. These same in vivo effects have been observed in experimental animals after injection of hypoglycin A (13,14). Several groups of investigators subsequently concluded that the hypoglycemia and depletion of glycogen were due to the decreased gluconeogenesis resulting from impairment of long chain fatty acid metabolism (15)(16)(17).…”

supporting

confidence: 60%

Hypoglycin A: A Specific Inhibitor of Isovaleryl CoA Dehydrogenase

Tanaka

Miller

Isselbacher

1971

Proc. Natl. Acad. Sci. U.S.A.

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Evidence is presented for the specific in vivo and in vitro inhibition of isovaleryl CoA dehydrogenation by hypoglycin A and its derivative, a-ketomethylenecyclopropylpropionic acid. a-MethylbutyrylCoA dehydrogenation was also impaired, but the degree of inhibition was much lower. Isobutyryl CoA dehydrogenation was not inhibited. 4-Pentenoic acid inhibited none of these reactions. It is concluded that isovaleryl CoA is dehydrogenated by a specific enzyme, isovaleryl CoA dehydrogenase, contrary to previous assumptions that it is dehydrogenated by green acyl CoA dehydrogenase. The present concept agrees with our previous findings in isovaleric acidemia, a genetic disorder in which a specific defect of isovaleryl CoA dehydrogenase was observed. It was also demonstrated that isovaleric acidemia can be induced in experimental animals by the administration of hypoglycin A. Furthermore, some symptoms of "the vomiting sickness of Jamaica" appear to be due to isovaleric acid accumulation secondary to the ingestion of hypoglycin A.Isovaleric acidemia is a genetic defect of leucine metabolism (1-4) in which isovaleric acid accumulates in blood in large amounts. Based on the biochemical findings in this hereditary disorder, we proposed that isovaleryl CoA is dehydrogenated by a specific enzyme, isovaleryl CoA dehydrogenase (1,3) and that this enzyme is deficient in patients with isovaleric acidemia ( Fig. 1). It was previously believed that isovaleryl CoA, butyryl CoA, and hexanoyl CoA were dehydrogenated by a single enzyme, acyl CoA dehydrogenase (5,6).It has subsequently been shown that oxidation of leucine is inhibited by hypoglycin A (7,8). In contrast, oxidation of valine and isoleucine are not significantly inhibited by this compound (8). However, the specific step in the pathway of leucine metabolism that is inhibited by hypoglycin A has not been precisely identified.Hypoglycin A is an unusual amino acid having the structure of a-aminomethylenecyclopropylpropionic acid (9). It has been extracted from unripe fruits of ackee grown in Jamaica and has been identified as the cause of the "vomiting sickness of Jamaica" (10). Extreme hypoglycemia (11) In vivo experimentsAmino acids were given by stomach tube 30 min after intramuscular injection of the inhibitor. The blood samples were drawn by heart puncture 150 min after injection of the inhibitor. Short chain fatty acid analyses were performed by gasliquid chromatography (GLC) (1).In vitro experiments Incubations were for 3 hr at 37°C. The tissues and the incubation medium were homogenized after acidification with 0.5 ml of 2 N H2SO4 and extracted with 20 vol of chloroform-methanol 2:1. The filtered extract was separated into two phases by mixing with 0.2 N NaOH (0.2 vol of the extract). Unlabeled carrier was added to the homogenate before extraction.Only the upper alkaline layer, which contains most of the water soluble salts of carboxylic acids and acidic conjugates, was analyzed. The steam-distillable fractions after acid hydrolysis were designated as total fr...

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confidence: 60%

Hypoglycin A: A Specific Inhibitor of Isovaleryl CoA Dehydrogenase

Tanaka

Miller

Isselbacher

1971

Proc. Natl. Acad. Sci. U.S.A.

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“…These glycogen reserves are not replaced as fast as they are used and hypoglycaemia results Senior and Sherratt, 1968). The greater toxicity of hypoglycin in starved than in fed animals supports this notion, since the onset of hypoglycaemia depends on depletion of glycogen reserves (Feng and Patrick, 1958;Senior and Sherratt, 1969). Hill (1952) observed that malnutrition, particularly deficiencies of the B-group of vitamins, appears to predispose to the toxic effects of hypoglycin.…”

Section: Discussionmentioning

confidence: 99%

The protective effects of feeding on the hepatic ultrastructure of rats treated with hypoglycin

Brooks

Audretsch

1971

The Journal of Pathology

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“…The metabolite reacts with some essential cofactors for β-oxidation (coenzyme A, carnitine) and inhibits Acyl-CoA dehydrogenase, which also plays a role in β-oxidation [8,9]. This results in reduced fatty acid metabolism, bringing about increased glucose use and blocking hepatic gluconeogenesis, leading to severe hypoglycaemia preceded by depletion of hepatic glycogen stores [10][11][12]. HGA poisoning causes 'Jamaican vomiting sickness' syndrome, which is characterized by gastrointestinal distress, with symptoms such as nausea, abdominal pain and uncontrollable vomiting [13].…”

Section: Introductionmentioning

confidence: 99%