Decrease in tetrahydrobiopterin content and neurotransmitter amine biosynthesis in rat brain by an inhibitor of guanosine triphosphate cyclohydrolase.
To investigate the regulatory role of tetrahydrobiopterin in neurotransmitter amine biosynthesis, 2,4-diamino-6-hydroxypyrimidine, a potent inhibitor of guanosine triphosphate cyclohydrolase which is a rate-limiting enzyme of tetrahydrobiopterin biosynthesis, was administered intraperitoneally to weanling rats. Four h after 4 injections at 4-h intervals, the biopterin contents in plasma and liver were reduced to the level of 9 and 3.5%, respectively, of those in the control group injected with saline; while the contents in the whole brain, neocortex + striatum, diencephalon, and brainstem were 34, 50, 33 and 28%, respectively, of the control level. When in vivo tyrosine and tryptophan hydroxylase activities were measured over a 30-min period after the inhibition of aromatic amino acid decarboxylase, the accumulation of dihydroxyphenylalanine was reduced to 74, 77, 67 and 69% of the control in the whole brain, neocortex + striatum, diencephalon, and brainstem, respectively; and the accumulation of 5-hydroxytryptophan, to 71, 74, 66 and 65% of the control, respectively. On the other hand, 5-hydroxytryptamine and 5-hydroxyindole acetic acid contents were not altered in any brain regions, although norepinephrine and dopamine contents were reduced to approximately 70% of the control in the brainstem and the contents of dopamine metabolites were significantly decreased in the diencephalon and brainstem. Plasma phenylalanine level was significantly elevated, while the plasma tyrosine level was reduced, compared with the control level of these amino acids. These results indicate that the drug-treated rats could be an animal model for tetrahydrobiopterin-deficient disease involving neurological disorder.
D006916:5-Hydroxytryptophan / Q000096:biosynthesis; D000311:Adrenal Glands / Q000378:metabolism; D000619:Aminohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001679:Biogenic Amines / Q000096:biosynthesis*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D004298:Dopamine / Q000096:biosynthesis; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors*; D006834:Hydrazines / Q000494:pharmacology; D006897:Hydroxyindoleacetic Acid / Q000096:biosynthesis; D007042:Hypoxanthines / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D009638:Norepinephrine / Q000096:biosynthesis; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000096:biosynthesis
D001679:Biogenic Amines; D006834:Hydrazines; D007042:Hypoxanthines; D018377:Neurotransmitter Agents; D001708:Biopterins; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D004295:Dihydroxyphenylalanine; C004297:3-hydroxybenzylhydrazine; D006916:5-Hydroxytryptophan; D000619:Aminohydrolases; D006136:GTP Cyclohydrolase; C017202:2,4-diaminohypoxanthine; C003402:sapropterin; D004298:Dopamine; D009638:Norepinephrine