Hypoglycin A

141.17

141.17

303803

Yellow plates from methanol + water

63.3

Solid

1.1522 (rough estimate)

280-284 °C

258.21°C (rough estimate)

1.4300 (estimate)

Specific optical rotation at 32 °C for D (sodium) line = +9.2 deg.

A REVIEW WITH 54 REFERENCES OF THE MECHANISM OF GLUCONEOGENESIS INHIBITION AND HYPOGLYCEMIC ACTION OF HYPOGLYCIN AND 4-PENTENOIC ACID.[SENIOR AE ET AL; MECHANISM OF THE HYPOGLYCEMIC EFFECTS OF HYPOGLYCIN AND 4-PENTENOIC ACID; PAN-AM ASSOC BIOCHEM SOC SYMP 3(HYPOGLYCIN, PROC SYMP, 1974) 109 (1975)]|A REVIEW WITH 52 REFERENCES. INHIBITION OF FATTY ACID OXIDN BY HYPOGLYCIN AND 4-PENTENOIC ACID MAY BE CAUSED BY INHIBITION OF SPECIFIC ENZYMES OF BETA-OXIDATION.[SHERRATT HS A ET AL; ON THE MECHANISM OF INHIBITION OF FATTY ACID OXIDATION BY HYPOGLYCIN AND BY 4-PENTENOIC ACID; PAN-AM ASSOC BIOCHEM SOC SYMP 3(HYPOGLYCIN, PROC SYMP, 1974) 127 (1975)]

... 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.

LD50 Rat oral 98 mg/kg|LD50 Rat intraperitoneal 97 mg/kg

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[

TRANSAMINATION RESULTS IN FORMATION OF METHYLENECYCLOPROPANEPYRUVIC ACID, WHICH UNDERGOES DECARBOXYLATION TO METHYLENECYCLOPROPANE ACETIC ACID; PYRIDOXAL PHOSPHATE PLUS MG(2+) IONS AND THIAMINE PYROPHOSPHATE, MG(2+) IONS PLUS COENZYME-A ARE THE COFACTORS INVOLVED IN THE TWO REACTION STEPS.|Numerous abnormal metabolites were identified in large amounts in the urine of hypoglycin-treated rats... . analysis. ... Ten of them have not been previously associated with hypoglycin administration: these are several hydroxy compounds, including those from the valine and isoleucine pathways, 2-oxo-adipic acid, n-butyrylglycine and isovaleryl glucuronide. These results indicate that the pathways of isoleucine and valine metabolism are inhibited at their respective acyl-CoA dehydrogenation steps, as is the case for fatty acid, leucine and lysine metabolism, as previously shown.|... 14C- and 3H-labelled palmitic acid was administered with hypoglycin to rats, and radioactivity was measured in urinary dicarboxylic acids... . Both isotopes were incorporated into adipic and sebacic acids, indicating a precursor-product relationship. Glutaric acid was, essentially, unlabelled. Preferential incorporation of C-16, relative to C-1 of palmitate ... could be deduced ... . It thus appears that omega-oxidation of the fatty acid intervenes predominantly at an intermediate stage of chain-shortening, when inhibition of beta-oxidation by hypoglycin becomes more pronounced.|Hypoglycin A, which is now simply called hypoglycin, is metabolized by means of transamination and oxidative decarboxylation to methylene cyclopropyl acetic acid (MCPA).[

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.[|...SUGGESTED THAT TOXICITY IS DUE TO FORMATION OF METHYLENECYCLOPROPANE ACETIC ACID, WHICH INHIBITS THE OXIDN OF FATTY ACIDS, AND THAT THEIR ACCUMULATION DECR RESPIRATION AND UNCOUPLES PHOSPHORYLATION. /JAMACAN VOMITING SICKNESS/|..hypoglycin A, isolated from the fruit, may interfere with oxidation of fatty acids, so that glycogen stores have to be metabolized for energy, with depletion of carbohydrates, resulting in hypoglycemia. /Jamacian vomiting sickness/|... Short-chain acyl-CoA (SCADH), medium-chain acyl-CoA (MCADH) and isovaleryl-CoA (IVDH) dehydrogenases were severely and irreversibly inactivated by /(methylenecyclopropyl)acetyl-CoA (MCPA-CoA), the toxic metabolite of hypoglycin/ , while 2-methyl-branched chain acyl-CoA dehydrogenase (2-meBCADH) was only slowly and mildly inactivated. Long-chain acyl-CoA dehydrogenase (LCADH) was not significantly inactivated, even after prolonged incubation with MCPA-CoA. Inactivation of SCADH, MCADH and IVDH was effectively prevented by the addition of substrate. This mode of inactivation by MCPA-CoA explains the urinary metabolite profile in hypoglycin treated-rats, which includes large amounts of metabolites from fatty acids and leucine, and relatively small amounts of those from valine and isoleucine.|For more Mechanism of Action (Complete) data for HYPOGLYCIN (6 total), please visit the HSDB record page.

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/

/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.

hypoglycin

A COLORIMETRIC METHOD, APPLICABLE TO EXTRACTS OF BIOL SAMPLES, IS REPORTED FOR MEASURING THE TOXIC AMINO ACID HYPOGLYCIN.