NADH stimulates endogenous dopamine biosynthesis by enhancing the recycling of tetrahydrobiopterin in rat phaeochromocytoma cells

AbstractTreatment of Parkinson patients with l-DOPA (3,4-dihydroxy-l-phenylalanine) leads to endproduct inhibition of tyrosine hydroxylase, the key enzyme in dopamine biosynthesis and the enzyme needing tetrahydrobiopterin and iron as cofactors. To overcome this problem an alternative treatment was investigated which attempted to stimulate endogenous dopamine biosynthesis. Incubation of rat PC 12 cells with NADH (β-nicotinamide adeninedinucleotide) leads to increased dopamine production. We investigated the possibility that this increase of dopamine biosynthesis was due to stimulation of quinonoid dihydropteridine reductase, the enzyme which recycles the inactive dihydrobiopterin to the active tetrahydrobiopterin. The experiments showed that whereas NADH is able to increase dopamine production in PC 12 cells (rat phaeochromocytoma cells, clone PC 12) up to three-fold, no influence is exerted by NADH on pteridine metabolism; neither are tetrahydrobiopterin concentrations nor the de novo-biosynthesis of pteridines from guanosine triphosphate altered by NADH. Further no influence of NADH on protein de novo synthesis of quinonoid dihydropteridine reductase was observed. However, NADH was able to directly increase the catalytic activity of this enzyme. Our results suggest that the stimulation of dopamine biosynthesis by NADH is due to more rapid regeneration of quinonoid dihydrobiopterin to tetrahydrobiopterin