Hypoglycine A

... Injection of hypoglycin into fasted rats maintained on a standard diet caused severe prostration, hypothermia and a massive dicarboxylic aciduria. Rats maintained on a diet containing clofibrate appeared normal after injection of hypoglycin, but had a marked dicarboxylic aciduria which was less than that induced in rats on a normal diet. After administration of hypoglycin, butyryl-CoA and decanoyl-CoA, but not palmitoyl-CoA, dehydrogenase activities were strongly inhibited (80-95%) in the livers of animals on a standard diet. Clofibrate feeding decreased the inhibition of these dehydrogenases to about 40-60%. It was concluded that although clofibrate protects against the toxic effects of hypoglycin, some enzyme inhibitions as indicated by dicarboxylic aciduria are only partly prevented.

...Clofibrate feeding apparently protected the animals against the toxic, hypoglycemic and hypothermic effects of hypoglycin...and completely prevented the ultrastructural damage caused by hypoglycin. After hypoglycin administration, hepatic mitochondrial butyryl-CoA dehydrogenase activity was inhibited by more than 90% and, surprisingly, the activity of the peroxisomal enzymes studied was largely preserved. When hypoglycin was given to rats fed on a clofibrate-containing diet, the oxidation of decanoylcarnitine, which was incomplete after hypoglycin treatment alone, remained incomplete with uncoupled mitochondria, but became apparently complete with coupled mitochondria. In the latter condition, there was a slowing of the rate during the last quarter of the pulse of oxygen uptake. Further, butyryl-CoA dehydrogenase activity was much less affected by hypoglycin in clofibrate-fed animals. ...

ADMIN OF GLYCINE (75 MG/KG, IP) TO RATS INJECTED WITH HYPOGLYCIN (150 MG/KG, IP) PREVENTED DEATH, HYPOGLYCEMIA, AND HYPOTHERMIA AND GREATLY DECR THE RISE IN PLASMA CONCN OF ISOVALERATE PLUS 2-METHYLBUTYRATE, BUTYRATE, AND METHYLENECYCLOPROPYLACETATE, AN END PRODUCT OF HYPOGLYCIN METAB.

Generally, hypoglycin is an amino acid and chemically related to lysine. It competitively binds to enzymes used in the catabolism of lysine and is the reason why it and its metabolitemethylene cyclopropyl acetic acid (MCPA) are toxic. The metabolite MCPA also is a potent inhibitor of acyl CoA dehydrogenase, preventing the metabolism of fatty acids. It has been shown that oxidation of leucine is inhibited by hypoglycin A. In contrast, oxidation of valine and isoleucine are not significantly inhibited by this compound. However, the specific step in the pathway of leucine metabolism that is inhibited by hypoglycin A has not been precisely identified. Hypoglycemia and depletion of glycogen were due to the decreased gluconeogenesis resulting from impairment of long chain fatty acid metabolism after injection of hypoglycin A. Hypoglycin A or its metabolite, methylenecyclopropylacetic acid, and also 4-pentenoic acid (4-PE) were shown to inhibit long-chain fatty acid oxidation; whereas oxidation of straight short chain fatty acids including butyrate, hexanoate, and octanoate was not inhibited. Hypolglycin A inhibits dehydrogenation of isovaleryl-CoA and alpha-methylbutyryl-CoA by liver slices in vitro, and that it induces isovaleric and alpha-methylbutyric acidemias in experimental animals in vivo. (PMID: 4636318; PMID:5276292)

/HUMAN EXPOSURE STUDIES/ Metabolic food reaction to unripe fruit of the tropical tree Blighia sapida ... causing severe vomiting, coma, and acute hypoglycemia sometimes resulting in death, especially among the malnourished /caused by/ hypoglycin A, isolated from the fruit /Jamacian vomiting sickness/

/HUMAN EXPOSURE STUDIES/ Toxins such as hypoglycin ... and their metabolites inhibit beta-oxidation pathways and can produce Reye's syndrome-like presentations.

/HUMAN EXPOSURE STUDIES/ THS /(Toxic Hypoglycemic Syndrome)/ is characterized by acute onset of profuse vomiting, convulsions, coma, and sometimes death. Profound hypoglycemia (blood glucose levels as low as 3 mg/dL is observed in most cases. This problem is endemic in Jamaica, with 271 cases reported to the JMH since 1980. ... Unripe ackee contains hypoglycin A, a water-soluble liver toxin that induces hypoglycemia by inhibiting gluconeogenesis secondary to its limiting of cofactors (CoA and carnitine) essential for oxidation of long-chain fatty acids. Potential risk behaviors for ackee poisoning include 1) selection and cooking of unripe ackee; 2) purchase of tampered, forcibly opened ackee; and 3) reuse of the water in which unripe ackee has been cooked. Undernutrition is also thought to be associated with both susceptibility to and severity of THS, particularly among children in Jamaica. In Jamaica, the epidemiology of ackee poisoning has not been well characterized, and the true incidence and mortality are believed to be underreported.... No cases of THS are known to have been reported among persons from the United States visiting Jamaica, nor have cases been reported in the United States.[

/CASE REPORTS/ An acute illness (Jamaican vomiting sickness) which affected two adults after eating unripe ackee fruit was investigated. Analyses of serum and urine samples were performed to compare the patterns of organic acidaemia and aciduria with those reported from childhood cases. The main conclusion from the comparison is that the toxic ackee constitutent, hypoglycin, produces essentially the same metabolic effects in adults as in children.

For more Human Toxicity Excerpts (Complete) data for HYPOGLYCIN (6 total), please visit the HSDB record page.

/LABORATORY ANIMALS: Acute Exposure/ IN THE PRESENCE OF THE HYPOGLYCIN METABOLITES METHYLENECYCLOPROPYLPYRUVATE (MCPP) AND METHYLENECYCLOPROPYLACETATE (MCPA), RAT LIVER MITOCHONDRIA OXIDIZED PALMITOYL-CARNITINE ONLY AS FAR AS BUTYRATE AND AT A DECR RATE. MCPA SPECIFICALLY INHIBITED BUTYRYL-COA DEHYDROGENASE IN INTACT MITOCHONDRIA AND IN SOL EXTRACTS SUPPLEMENTED WITH ATP AND COASH. MCPP AND MCPA (1 MMOL) CAUSED A RAPID DECR IN COASH CONCN IN MITOCHONDRIA; ACETYL-COA CONCN WERE UNAFFECTED.

/LABORATORY ANIMALS: Acute Exposure/ ADMIN OF HYPOGLYCIN TO RATS CAUSED SEVERE HYPOGLYCEMIA AND HYPOTHERMIA AND CAUSED SEVERAL VOLATILE FATTY ACIDS TO ACCUM IN THE PLASMA. SEVERAL SHORT-CHAIN ACYL-COA DEHYDROGENASE ACTIVITIES WERE IRREVERSIBLY INACTIVATED IN EXTRACTS OF MITOCHONDRIA ISOLATED FROM LIVERS TAKEN FROM RATS AFTER ADMIN OF HYPOGLYCIN. SOME OF THE BRANCHED-CHAIN ACYL-COA ESTERS WERE NOT, AS OFTEN ASSUMED, SUBSTRATES FOR THE BUTYRYL-COA DEHYDROGENASE OF BETA-OXIDATION, AND THERE WERE SOME SPECIFIC BRANCHED-CHAIN ACYL-COA DEHYDROGENASES.

/LABORATORY ANIMALS: Acute Exposure/ ACCUMULATION IN RAT PLASMA OF ISOVALERATE, 2-METHYLBUTYRATE, BUTYRATE, HEXANOATE, AND PROPIONATE IN THE 24 HR FOLLOWING HYPOGLYCIN ADMINISTRATION COINCIDED WITH THE DISAPPEARANCE FROM LIVER MITOCHONDRIA OF ISOVALERYL-COA DEHYDROGENASE AND BUTYRYL-COA DEHYDROGENASE (EC 1.3.99.2) ACTIVITIES AND OF PALMITOYLCARNITINE OXIDN.

/LABORATORY ANIMALS: Acute Exposure/ Thirty experimental and fifteen control Wistar rats were studied to determine whether hypoglycin A influences insulin levels in the body to contribute to the state of hypoglycemia usually observed in Jamaican vomiting sickness, a condition arising after ingestion of unripe ackees. This fruit also grows in other Caribbean islands, as well as North and Central America. Hypoglycin A is one of the toxic compounds found in unripe ackees and is capable of inducing hypoglycemia. A fall in blood glucose occurred after administration of hypoglycin A. The lowest level of 42.60 +/- 4.84 mg/dl was attained 3 hr after administration of the drug. This alteration of blood glucose from the fasting level of 80.31 +/- 5.20 mg/dl was significant (P<0.01). The blood glucose level in the control rats showed no significant change from the fasting level. The insulin level in portal and peripheral blood showed no significant change. Results showed that, although hypoglycin A induced severe hypoglycemia after intravenous application, there was no significant change in insulin levels. This observation suggests that hypoglycin A has a mechanism of action other than an alteration in insulin levels to induce hypoglycemia.

For more Non-Human Toxicity Excerpts (Complete) data for HYPOGLYCIN (7 total), please visit the HSDB record page.

Undernutrition is also thought to be associated with both susceptibility to and severity of Toxic Hypoglycemic Syndrome (THS), particularly among children in Jamaica. In Jamaica, the epidemiology of ackee poisoning has not been well characterized, and the true incidence and mortality are believed to be underreported[

Treatment consists primarily of gastrointestinal decontamination and supportive care. ... In symptomatic patients or in adults with large intentional ingestions, activated charcoal should be administered. Respiratory support may be required in patients with depressed levels of consciousness and respiratory depression. General supportive care should be provided for treatment of hypoglycemia, hypotension and dysrhythmias. /CNS Depressant Plants/

LD50 Rat oral 98 mg/kg

LD50 Rat intraperitoneal 97 mg/kg

Hypoglycemia-inducing component of the akee plant (Blighia sapida); [Merck Index] A water-soluble liver toxin found in the seeds, pods, and unripe fruit of the ackee plant; Ackee is the national fruit of Jamaica, where it is associated with Jamaican vomiting sickness or Toxic Hypoglycemic Syndrome (THS); [HSDB]