Dihydropteridine Reductase

Abstract

A reliable assay for rat dihydropteridine reductase(DHPR) was used to determine DHPR activity in various rat tissues including the brain and blood. A correlation was observed between brain and blood DHPR activity. Methotrexate was seen to be both an in vivo and in vitro inhibitor of rat DHPR activity. Rat DHPR activity was determined in various nutritional states. DHPR activity was found to be decreased by starvation and increased following overfeeding. Evidence was found for a change in the ratio of the NADH- and NADPH-specific DHPR enzyme activities and activation of the enzyme by phosphorylation. A change in the molecular form of brain DHPR following alterations in nutritional status was observed. DHPR activity was seen to be decreased following exposure to ethanol. The effect of hyperglycaemia and hypoglycaemia on rat DHPR activity was investigated. Alterations in DHPR activity during hyperglycaemia, induced by the diabetogenic agents streptozotocin or alloxan, were observed to be due to the non-diabetogenic action of both agents. Hypoglycaemia, induced by administration of "long-acting" insulin was observed to decrease brain DHPR activity. Glucocorticoid administration was observed to decrease rat brain DHPR activity. The in vivo effect of the neurotoxins lead and aluminium on rat DHPR activity was investigated. Exposure to lead and aluminium decreased DHPR activity in the blood and lead exposure decreased brain DHPR activity. Gallium and scandium were investigated as possible models for aluminium neurotoxicity. Exposure to gallium and scandium decreased blood and brain DHPR activity. DHPR activity in human renal dialysis patients exposed to high levels of aluminium was investigated. DHPR activity was observed to be significantly decreased in patients exposed to aluminium. An inverse relationship between blood DHPR activity and aluminium was observed. Chelation therapy with desferrioxamine was seen to increase DHPR activity in patients exposed to aluminium. The effect of hyperphenylalaninemia on rat DHPR activity was studied. A possible rat model for human hyperphenylalaninemia was investigated. A decrease in both blood and brain DHPR activity was observed following phenylalanine loading. The effect of arginine loading on rat DHPR activity was also investigated. Arginine was observed to decrease blood DHPR activity. The mechanism and consequences of the changes in DHPR activity are discussed by consideration of the results presented in this thesis and known pathological conditions.