COMPETITION FOR TETRAHYDROBIOPTERIN BETWEEN PHENYLALANINE-HYDROXYLASEAND NITRIC-OXIDE SYNTHASE IN RAT-LIVER

Tetrahydrobiopterin (BH4) is an important cofactor for two hepatic enz ymes, inducible nitric oxide synthase (iNOS) and phenylalanine hydroxy lase (PAH), and competition for BH4 between the two enzymes might limi t hepatic iNOS or PAH activity, To test this hypothesis, we determined whether conversion of phenylalanine to tyrosine was modified by chang es in NO synthase activity, and conversely whether NO synthesis was li mited by the rate of phenylalanine conversion to tyrosine in rat hepat ocytes and perfused livers, NO production was decreased only slightly, when flux through PAH was maximized in isolated perfused livers, and in isolated hepatocytes only when BH4 synthesis was inhibited, Increas es in NO synthesis did not reduce tyrosine formation from phenylalanin e. Phenylalanine markedly increased biopterin synthesis, whereas argin ine had no effect, Thus, basal BH4 synthesis appears to be adequate to support iNOS activity, whereas BH4 synthesis is increased to support PAH activity.