Metabolism of Biopterin and its Derivatives in Man and the Rat

Abstract

In-vitro studies of tetrahydrobiopterin synthesis and dihydropteridine reductase activity have shown that these are affected by pharmacological preparations, phenylalanine and tryptophan metabolites, neurotransmitters and metal ions. Tetrahydrobiopterin given orally to man does not appear in the serum at a measurable rate. A small amount of biopterin asses unaltered across the bowel wall. Crithidia factor is synthesised in the foetus as early as the twelfth week of gestation and there is evidence for early variation in concentrations within the brain. In adults a range of tissues contain Crithidia factor with the pineal gland being especially rich. All the evidence points to the essential supply of tetrahydrobiopterin being endogenous. Males have significantly (p = < 0,05) higher serum Crithidia factor levels (1.75 + 0.0Bug/L.) than unmedicated females (1.53 + 0.4ug/L,) and females taking oral contraceptives (1.44 + 0.05ug/L.). There were significant changes in serum Crithidia factor levels during the menstrual cycle. Hyperphenylalaninaemia produces high levels of serum Crithidia factor by the canpetitive inhibition of dihydropteridine reductase by phenylpyruvic acid. In malignant hyperphenylalaninaemia due to defective synthesis of dihydrobiopterin the serum Crithidia factor is low and does not respond to phenylalanine loading. In dihydropteridine reductase deficiency the serum Crithidia factor is raised before phenylalanine loading. In coeliac disease and malignant disease serum Crithidia factor is low. In carcinoid disease tissue levels of Crithidia factor are high although serum levels are low. Women in the third trimester of pregnancy have low serum Crithidia factor levels, probably this is the result of increased cortisol levels. In manic-depressive psychosis serum Crithidia factor levels are increased and it is suggested that this is due to an increased rate of tetrahydrobiopterin synthesis. Senile demented patients have low serum Crithidia factor levels and impaired phenylalanine clearance. A model has been proposed for the regulation of tetrahydrobiopterin in health and disease which depends on:- a) Dihydropteridine reductase activity and b) de novo synthesis of purine precursors. Endogenous influences on cellular tetrahydrobiogterin may come from diseased states or normal physiological changes. Exogenous influences may occur in medication and poisoning.