Metabolism of catecholamines in some clinical disorders

Tippett, Patricia Anne Trevella (1987) Metabolism of catecholamines in some clinical disorders. University of Southampton, Doctoral Thesis.

Abstract

This study is concerned with catecholamine metabolism in clinical disease: namely, in the inherited metabolic disorder phenylketonuria and in a group of catecholamine secreting tumours. A reliable and specific method was developed using high pressure liquid chromatography with electrochemical detection for the determination of catecholamine output. This allowed changes in catecholamine metabolism to be defined and these are not always reflected by the production of their urinary metabolites. In classical phenylketonuria the urinary excretion of noradrenaline and adrenaline was shown to be in the lower part of the reference range and only dopamine concentrations were markedly reduced. This finding is contrary to the general thought that all catecholamine levels are reduced in this condition. In classical phenylketonuria there is increased excretion of m-hydroxymandelic acid, which is formed from m-octopamine, an amine which displaces brain catecholamines in animal studies. Oral loading tests with the putative precursor L-m-tyrosine were performed to explore a possible relationship between th production of the meta-phenolamines and catecholamines in this inherited disorder. The results showed an inverse relationship between noradrenaline and adrenaline excretions and that of m-hydroxymandelic acid for up to eight hours after the load. Dopamine output was not appreciably changed by the load, a result which differs from the demonstrated increase in the production of its metabolite, 3,4-dihydroxyphenylalanine, after similar administration of L-m-tyrosine to subjects with this metabolic disorder. The raised urinary dopamine levels in a healthy adult after an oral L-m-tyrosine load are further confirmation that this amino acid is metabolised via ring hydroxylation. In the same study there was decreased excretion of adrenaline and noradrenaline for eight hours after the load, a finding which correlates with the effect of L-m-tyrosine on displacement of brain amines in animals, apparently after decarboxylation to the meta-phenolamines. Dopamines excretion was shown to be a useful prognostic indicator in patients with malignant phaeochromocytoma. Ten of fifteen patients with this tumour had raised dopamine excretion. The survival time for the patients with normal dopamine excretion was better than that for the patients with increased dopamine excretion (p< 0.003). Comparison of the urinary concentrations of dopamine and its metabolite homovanillic acid in patients with malignancy showed that four patients with widespread metastases and raised dopamine excretion had normal homovanillic acid excretion. From this study dopamine excretion appeared to be a more discriminating biochemical index of malignancy and progression of the disease than homovanillic acid.

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