Autoradiographic distribution of [14C]tetrahydrobiopterin and its developmental change in mice

Tetrahydrobiopterin (BH4) is a regulatory factor of phenylalanine degradation as well as of catecholamine, serotonin and nitric oxide synthesis. To understand the in vivo metabolism of BH4, whole-body autoradiography was performed on mice at various developmental stages after injection of a low dose (45 micrograms/kg) of radiolabeled BH4. In adult mice, high levels of radioactivity were accumulated in the liver and kidney, suggesting that BH4 in these organs is supplied not only by intracellular de novo biosynthesis but also by uptake from the blood. In contrast, little radioactivity was found in the brain, adrenal medulla and bone marrow, in which high levels of endogenous BH4 are found, suggesting that BH4 in these organs is supplied mainly by intracellular biosynthesis. Biopterin, a fully oxidized form of BH4, was not accumulated in any tissues and was excreted rapidly. In pregnant mice, maternal BH4 passed through the placenta and was distributed uniformly to the fetal tissues. Neonatal (5- and 7-day-old) mice had a similar distribution pattern of labeled BH4 to that of adult mice, except for the liver and kidney: in the liver, selective accumulation of BH4 in the adult was not observed in 5-day-old mice; in the kidney, the distribution of high radioactivity to the inner cortex observed in the adult was found in neither 5- nor 7-day-old mice. The developmental increase in hepatic BH4 accumulation was correlated with those of the activities of phenylalanine hydroxylase and GTP cyclohydrolase I, the rate-limiting enzyme of the BH4 biosynthetic pathway.