Fatty acids generate dicarboxylic acids in hypoglycin poisoning - abstract

We investigated the metabolic origin of certain dicarboxylic acids which appears in urine of hypoglycin poisoned subjects (Jamaican vomiting sickness). These include hexanedioic (adipic), octanedioic (suberic) and decanedioic (sebacic) acids which, with unsaturated variants, are also excreted in some rare congenital diseases (glutaric acidaemia Type II, generalized dicarboxlic acidaemias), and in ketosis. Long-chain fatty acids have been established as precursors only in the case of diabetic, ketotic rats. In one report, evidence for this origin was negative for the case of hypoglycin poisoning, but no alternative precursors appear likely and the problem has remained unresolved since 1972. The present work utilized palmitic acid labelled either with Tritium, or with 14c at various atoms of the molecule as a tracer in hypoglycin-treated rats. Suberate and sebacate, isolated from urines by gas liquid chromatography, were found to be radioactively labelled, and hence, significant conversion of fatty acid to dicarboxylic acid was demonstrated. A further conclusion emerged from the relative labelling yielded by [1-14C] - and [16-14C] palmitic acid. After chain shortening by 3 -4 cycles of fatty acid á-oxidation, w-oxidation appears to intervene as a consequence of inhibition of the former process by the hypoglycin metabolite methylenecyclopropylacetyl-CoA. This sequence is in contrast to the ketotic animal, in which initial w-oxidation of fatty acid apparently precedes bilateral á-oxidation. In fasted hypoglycin-poisoned rats, excretion of each of these compounds is not insignificant, being about 7 - 33 mg/24 hr(1 - 4 mg/mg creatinine) (AU)

Jamaican vomiting sickness: biochemical investigation of two cases

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 metabolities 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 histological similarities, the cause and biochemical mechanisms of Jamaican vomiting sickness differ distinctly from those of Reye's syndrome in which these abnormal urinary metabolities are not appreciably increased.(AU)

Effect of starvation on renal metabolism in the rat

The effects of starvation an the acid base status of the rat and on the gluconeogenic and ammoniagenic capacity of rat renal-cortical slices were examined. Starvation for 48 or 72 hrs did not affect acid-base status, and urinary ammonia production did not change. Kidney cortical slices from starved as compared to fed rats showed increased gluconeogenic capicity when incubated with the substrated pyruvate, succinate, fumarate, malate, 2-oxoglutarate, glutamine and glutamate. Renal cortical tissues from starved rats also had increased activity of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. Renal cortical slices from starved rats did not differ from those of fed rats in the ability to produce ammonia from glutamine or glutamate, nor was there any difference in the activity of glutaminase between these groups. These results show that renal gluconeogenic capacity is increased in starved rats in the absence of systemic acidosis, and starvation does not lead to an increase in urinary ammonia excretion or renal ammoniagenic capacity. (AU)