Tetrahydrobiopterin Metabolism in Mental Retardation

  • Chandrakant Morar

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Optimal ‘conditions for the separation and detection of pteridines by high performance liquid chromatography (HPLC) were obtained. The retention time, reproducibility relative fluorescence and minimal detection limits of various pterins under fixed conditions was noted.

The stability of pterins under different oxidation conditions was investigated. Acid- and alkaline-oxidation of reduced biopterins produced almost stoichiometric conversion to biopterin or pterin and was used to quantitate dihydrobiopterin and tetrahydrobiopterin levels. atmospheric oxidation of tetrahydrobiopterin at various pH showed it to be most unstable, especially at alkaline pH. Tetrahydrobiopterin oxidation was rapid in the presence of superoxide ions and was suppressed by superoxide dismutase. Ascorbate in the presence of iron acted as a potent oxidising agent; probably by a free-radical mechanism.

The analysis of tetrahydrobiopterin (THB) by HPLC and by Crithidia-assay was compared. Crithidia-assay values were usually lower. Tetrahydrobiopterin losses probably occur in Crithidia~assay during incubation / autoclaving procedures.

Biological samples from phenylketonurics, malignant hyperphenylalaninaemics, and healthy subjects were analysed. Phenylketonuric urine showed elevated biopterin level and normal neopterin-biopterin ratio. Dihydropteridine reductase (DHPR) deficient subjects showed low urine THB level with low blood DHPR activity. Acute oral phenylalanine loading in man produces a transient rise in total biopterin and in the rat a decrease in brain per cent THB,

Reduced THB synthesis with low biopterin level and high neopterin-biopterin ratio was noted in senile dementia brains. Down's syndrome patients showed low plasma neopterin indicating a possible synthesis defect. Acute lymphoblastic leukaemia children on methotrexate showed elevated urinary biopterin excretion whilst fragile-X patients showed no change from controls. Affective bipolar patients had low urine pterin levels. The implications of these changes are discussed.

Animal experiments show lead, aluminium and methotrexate to reduce brain per cent THB level and diethylstilboestrol to lower total biopterin pool. The mechanisms and consequences of such changes are discussed.
Date of Award1984
Original languageEnglish
Awarding Institution
  • Aston University

Keywords

  • Tetrahydrobiopterin metabolism
  • mental retardation

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