A possible role for Δ-aminolaevulinic acid in acute intermittent porphyria

McGillion, Francis B. (1974) A possible role for Δ-aminolaevulinic acid in acute intermittent porphyria. PhD thesis, University of Glasgow.

Abstract

From a consideration of past work on acute intermittent porphyria, it appeared that the porphyrin precursor most likely to be involved in the production of the clinical manifestations of the disease was δ-aminolaevulinic acid (ALA).A series of experimental investigations on ALA was carried out on both human and animal systems. The main findings were as follows: a) The blood ALA concentrations of a number of porphyries in remission, were significantly higher than the concentrations in normal subjects. In one porphyric subject ALA was detected in the cerebro-spinal fluid. b) Rats which were made experimentally porphyric by increasing ALA synthetase activity by treatment with ally-isopropyl-acetamide; were significantly more susceptible than untreated rats to convulsions induced chemically by isonicotinyl hydrazide. Rats pretreated with ALA however, did not show this increased susceptibility to induced convulsions. c) ALA was found to be capable of passing the blood-brain barrier at blood concentrations known to occur in acute porphyria. Acute ethanol intoxication inhibited this process. ALA was capable of remaining unchanged in the brain tissue against a brain-blood concentration gradient, for up to three days. d) ALA produced beliavioural changes when administered to experimental animals. In mice a single dose of ALA given intraperitoneally, caused an initial significant depression in spontaneous activity, which was soon followed by a significant increase in spontaneous activity, which lasted for at least ninety minutes after ALA administration. Mice chronically pretreated with ethanol demonstrated a similar pattern of response to ALA. Rats chronically pretreated with ALA, showed signs of severe behavioural disturbance. Spontaneous activity and all parameters measuring inquisitiveness were severely depressed. Withdrawal and righting reflexes were, however, normal. e) The substance 2,4-dimethyl-3-etliylpyrrole , which is commonly found in schizophrenics and which may be formed by a reaction involving ALA, was found to be present in the urine of subjects with porphyria, but not in the urine of normal subjects. None of these porphyric subjects showed signs of mental abnormality. f) At blood concentrations known to occur in acute porphyria, ALA was found to be capable of penetration into the following tissues:- heart, brain, liver, kidney, spleen, ileum and mesenteric fat .g) In the anaesthetised and pithed rat preparations, ALA was found to cause a fall in blood pressure. It was considered unlikely, on the basis of supportive evidence from experiments, that ALA did this by acting centrally, neurally on cardiac muscle on adrenergic or cholinergic receptors, or by histamine release. The action thought most likely to account for this fall was a histamine like action on the capillaries. h) On the isolated perfused rabbit ear artery, ALA produced no statistically significant changes in the response of the preparation to injected noradrenaline or to periarterial sympathetic nerve stimulation. i) Using the isolated guinea pig ileum, it was found that ALA had no statistically significant effect on the response of the muscle to injected acetylcholine or histamine, or to electrical field stimulation. j) ALA was found to be capable of inhibition of the total ATPase fraction of the guinea pig ileum. It did not, however, as might be expected on this basis, significantly increase the neural output of acetylcholine from muscle strips of ileum. The significance of these findings is discussed with particular emphasis on the possibility that ALA may play a role in the production of the clinical manifestations of acute intermittent porphyria.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: health and environmental sciences, porphyria.
• Subjects: R Medicine > R Medicine (General)
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Goldberg, Professor A.
• Date of Award: 1974
• Depositing User: Alastair Arthur
• Unique ID: glathesis:1974-83266
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 14 Nov 2022 12:28
• Last Modified: 14 Nov 2022 14:03
• Thesis DOI: 10.5525/gla.thesis.83266
• URI: https://theses.gla.ac.uk/id/eprint/83266

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