Monopyrroles in porphyria and related disorders

Graham, Douglas J.M. (1978) Monopyrroles in porphyria and related disorders. PhD thesis, University of Glasgow.

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Abstract

The hereditary porphyrias are a group of disorders in which the genetic defect results in an abnormality in the biosynthetic pathway leading to the respiratory pigment haem. The characteristic result of this is excessive synthesis and excretion of the tetrapyrrolic porphyrins sind, in the acute porphyrias, their precursors 6-aminolaevulinic acid (ALA.) and porphobilinogen. The acute attacks of acute porphyria show certain similarities to psychiatric disorders and the finding of a pyrrolic metabolite in the urine of patients with acute intermittent porphyria (AIP) and certain psychiatric disorders was the common factor that implicated this metabolite in the aetiology of certain manifestations of these disorders. Identification of the metabolite proved difficult but it was eventually unambiguously identified as 3-ethyl-5-hydroxy-4,5-dimethyl-Δ3-pyrrolin-2-one (OHHPL). The work contained in this thesis describes clinical and biochemical investigations into the occurrence and properties of this compound. Initially a qualitative method was used to detect OEHPL and it was shown to be present in the urine of patients with acute porphyria in attack and remission but to be undetectable in patients who were latent for the disease. Using a gas-liquid chromatography method developed for the quantitative assay of OHHPL, it was shown that in carriers of the AIP gene defect there was no significant difference in OHHPL excretion in latency, attack and remission, but that levels in these patients were significantly greater than in control subjects. No correlation could be shown between OHHPL excretion and clinical condition either in the group of patients or in multiple estimations in single patients. However, a significant association was found between the excretion of OHHPL and that of ALA. and PBG and it was also shown that in the porphyric patients ALA and PBG excretion were related in a linear fashion. Quantitation of OHHPL in groups of psychiatric patients showed that there was a significant elevation of OHHPL excretion in psychotic patients who were undergoing drug therapy and also in groups of patients with schizophrenia and organic brain disease. In the patients with schizophrenia there was a negative correlation between the clinical condition of the patients as assessed on the Hamilton-Lorr rating scale and urinary OHHPL. In an attempt to exatmine further the relationship between OHHPL and PBG and ALA in the patients with porphyria a group of patients, industrial lead workers, with sub-clinical lead poisoning were studied. These patients had raised blood lead and increased urinary excretion of ALA resulting from an inhibition by lead of the enzyme 6-aminolaevulinic acid dehydratase (ALA.D). OKHPL and PBG concentrations in the urine of these workers were within the normal range. It was found that there was a negative association between OHHPL and ALA levels which suggested that the ALA-OHHPL association in the porphyric patients was purely a result of the ALA-PBG relationship.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QR Microbiology
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Goldberg, Prof. Abraham
Date of Award: 1978
Depositing User: Mrs Marie Cairney
Unique ID: glathesis:1978-30691
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 16 Jul 2018 10:21
Last Modified: 16 Jul 2018 10:35
URI: http://theses.gla.ac.uk/id/eprint/30691

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