ABSTRACT
A recent article concluded that glutamic acid probably plays a central role in the vomiting and neurological features of ackee poisoning. The present article draws attention to misconceptions in the basis of that hypothesis, and reviews important evidence supporting a different view
Subject(s)
Humans , Plant Poisoning , Acidosis/chemically induced , Vomiting/chemically induced , Aspartic Acid/poisoning , Cyclopropanes/poisoning , Hypoglycins/poisoning , Glutamates/poisoningABSTRACT
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.
Subject(s)
Cyclopropanes/toxicity , Hypoglycins/toxicity , Plant Poisoning/etiology , Vomiting/chemically induced , Adult , Fatty Acids/blood , Fatty Acids/urine , Humans , MaleABSTRACT
The metabolic origin of dicarboxylic acids which are produced as a result of hypoglycin poisoning (Jamaican vomiting sickness) was investigated. 14C- and 3H-labelled palmitic acid was administered with hypoglycin to rats, and radioactivity was measured in urinary dicarboxylic acids that were isolated by gas-liquid chromatography. 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, while not evident from data for fraction of isotopic dose incorporated, could be deduced by comparing ratios of 14C:3H in precursor with those ratios in products. 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.
Subject(s)
Cyclopropanes/toxicity , Dicarboxylic Acids/biosynthesis , Hypoglycins/toxicity , Palmitic Acids/metabolism , Animals , Carbon Radioisotopes , Chromatography, Gas , Dicarboxylic Acids/urine , Kinetics , Male , Palmitic Acid , Rats , Rats, Inbred Strains , TritiumABSTRACT
1. In isolated rat liver cells, hypoglycin is a less effective inhibitor of gluconeogenesis than its transamination product, methylenecyclopropylpyruvate (ketohypoglycin). 2. Methylenecyclopropylpyruvate at 0.3 mM inhibits gluconeogenesis from all substrates tested, except fructose. 3. Methylenecyclopropylpyruvate does not affect 14CO2 release from [1(-14)C]palmitate, but, in the absence of lactate, inhibits ketogenesis and causes a decrease in the [beta-hydroxybutyrate]/[acetoacetate] ratio. These effects are masked when lactate (10 mM) is present. 4. In the presence of lactate and palmitate, 0.3 mM-methylenecyclopropylpyruvate produces a fall in total acid-soluble CoA and a relative increase in short-chain acyl-CoA at the expense of CoA and acetyl-CoA without changing the ATP, ADP and aspartate contents or the [lactate]/[pyruvate] ratio. 5. Many of the effects of methylenecyclopropylpyruvate observed are consistent with inhibition of butyryl-CoA dehydrogenase and of specific CoA-dependent enzymes involved in gluconeogenesis.
Subject(s)
Cyclopropanes/pharmacology , Gluconeogenesis/drug effects , Hypoglycins/pharmacology , Liver/metabolism , Animals , In Vitro Techniques , Keto Acids/pharmacology , Ketone Bodies/biosynthesis , Liver/cytology , Liver/drug effects , Male , Palmitates/metabolism , RatsABSTRACT
An enzyme which catalyses oxidative decarboxylation of branched-chain alpha-keto acids was extracted from rat liver mitochondria with the aid of NaClO4. Purification yielded a product which appeared homogenous upon electrophoresis. Some kinetic data are reported; however, the enzyme is inactive with alpha-ketoisovalerate. The tenacity of binding to mitochondria, specificity, and other features, suggest that the decarboxylase may be a component of an enzyme complex named alpha-ketoisocaproate: alpha-keto-beta-methylvalerate dehydrogenase.
Subject(s)
Ketone Oxidoreductases/isolation & purification , Mitochondria, Liver/enzymology , Multienzyme Complexes/isolation & purification , Amino Acids, Branched-Chain , Animals , Caproates , Keto Acids , Ketone Oxidoreductases/metabolism , Male , Multienzyme Complexes/metabolism , Osmotic Pressure , Rats , Substrate Specificity , ValeratesABSTRACT
We identified methylenecyclopropylacetic acid, a known metabolite of hypoglycin A, in the urine of two patients with Jamaican vomiting sickness. Excretion of unusual dicarboxylic acids such as 2-ethylmalonic, 2-methylsuccinic, glutaric, adipic and dicarboxylic acids with eight and 10 carbon chains were also detected in both patients. The amounts of these dicarboxylic acids were 70 to 1000 times higher than normal. These metabolites have also been identified in urine of hypoglycin-treated rats. This evidence links hypoglycin A to Jamaican vomiting sickness as its causative agent. Urinary excretion of short-chain fatty acids was also increased up to 300 times higher than normal. These results indicate that, despite their clinical and histologic similarities, the cause and biochemical mechanisms of Jamaican vomiting sickness differ distinctly from those of Reye's syndrome in which these abnormal urinary metabolites are not appreciably increased.
Subject(s)
Foodborne Diseases/metabolism , Fruit/poisoning , Vomiting/etiology , Animals , Child, Preschool , Cyclopropanes/metabolism , Diagnosis, Differential , Dicarboxylic Acids/urine , Fatty Acids, Volatile/blood , Fatty Acids, Volatile/urine , Female , Foodborne Diseases/etiology , Foodborne Diseases/urine , Gluconeogenesis , Humans , Hydroxy Acids/urine , Hypoglycemia/etiology , Jamaica , Rats , Reye Syndrome/diagnosis , Toxins, Biological/metabolism , Valerates/urineABSTRACT
Large amounts of ethylmalonic acid have been identified in urines from two patients with the vomitting sickness of Jamaica. The amounts were 178 and 882 mug per mg creatinine which are 70 and 350 times, respectively, over control values. Other short and medium chain dicarboxylic acids including glutaric and adipic acids and those with eight and ten carbon chain, saturated and cis-unsaturated, were also detected in large quantities as in the case of hypoglycin treated rats; urine. However, the large increase of urinary ethylmalonic acid in these two human cases is in a sharp contrast to the findings in hypoglycin treated rats in which urinary ethylmalonic acid increased only 3 times over control. It appears that ethylmalonic acid is produced in the cases with the vomiting sickness of Jamaica by carboxylation of n-butyryl-CoA which is not oxidized further due to the inhibition by hypoglycin A. In case of hypoglycin-treated rats, n-butyryl-CoA is mainly conjugated with glycine or deacylated to free butyric acid.
Subject(s)
Malonates/urine , Vomiting/urine , Animals , Child, Preschool , Chromatography, Gas , Creatinine/urine , Diet , Humans , Jamaica , Male , Mass Spectrometry , Rats , Vomiting/chemically inducedABSTRACT
Extracts of liver mitochondria from donor rats given hypoglycin, the toxic amino acid from the ackee plant (Blighia sapida) showed drastically reduced levels of acyl-CoA dehydrogenase activity with butyryl-CoA as substrate. Activity with octanoyl- and palmitoyl-CoA was unaffected. Evidence that the active agent is methylenecyclopropylacetyl-CoA, a hypoglycin metabolite, was obtained by observing effects of the compound on a partially purified enzyme mixture prepared from rabbit liver. At 13 muM concentration, it strongly inhibited butyryl-CoA dehydrogenase (EC 1.3.99.2) with butyryl-CoA as substrate; it was far less effective with palmitoyl-CoA as substrate for the other similar enzymes present in the preparation. Unlike normal substrates of the acyl-CoA dehydrogenases, the compound itself, and not a reaction product, is inhibitory. The observed effect is consistent with quite general inhibition of fatty acid beta-oxidation by hypoglycin.
