Dihydropteridine reductase from man and the rat

Abstract

Dihydropteridine reductase has been purified from rat liver and human brain tissue samples by affinity chromatography using sodium 1,2-naphthoquinone-4-sulphonate as the ligand. The rat liver dihydropteridine reductase was purified over 960 fold over the original supernatant and Km's for the two substrates NADH and quinonoid dimethyldihydropterin (qDMPH2) were 1.7 x 10¯5M and 2.1 x 10¯5 respectively.  Human brain dihidropteridine reductase was purified 20 fold over the orignal supernatant and Km's for NADH and qDMPH2 were 1.9 x 10¯5M and 2.9 x 10‾5M respectively. The effect of lead on d1hydropteridrne reductase activity in vivo was investigated using rat brains from animals subjected to a leaded water regime from conception. Lead at subclinical lead poisoning levels significantly inhibited enzyme activity in these brain samples. In vitro experiments using human brain dihydropteridine reductase showed lead to significantly inhibit enzyme activity in an irreversible manner. Dihydropteridine reductase activity in crude tissue preparations was increased in rat liver as a consequence of oestrogen dosing, whilst purified rat liver enzyme was strongly inhibited by oestrone, oestradiol and their catechol derivatives. The inhibition of dihydropteridine reductase by these oestrogens possibly being related, by its subsequent effects on neurotransmitter synthesis, to the mood changes observed in pre-menstrual tension. A variety of human tumour samples along with normal tissue were assayed as crude preparations for dihydropteridrne reductase activity; breast tumours showed a highly significantly increased activity as compared to normal breast tissue but tumours of the gut did not appear to have any change in enzyme activity. Human brain dihydropteridine reductase activity was elevated in temporal lobe samples from patients suffering from senile dementia of the Alzheimer type as compared to age matched controls, but this elevation was not significant. Dihydropteridine reductase activity was measured in several human brain regions.