| First Author | Kure S | Year | 2004 |
| Journal | Mol Genet Metab | Volume | 83 |
| Issue | 1-2 | Pages | 150-6 |
| PubMed ID | 15464429 | Mgi Jnum | J:93169 |
| Mgi Id | MGI:3056048 | Doi | 10.1016/j.ymgme.2004.06.016 |
| Citation | Kure S, et al. (2004) Wild-type phenylalanine hydroxylase activity is enhanced by tetrahydrobiopterin supplementation in vivo: an implication for therapeutic basis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab 83(1-2):150-156 |
| abstractText | We previously proposed a novel disease entity, tetrahydrobiopterin (BH(4))-responsive phenylalanine hydroxylase (PAH) deficiency, in which administration of BH(4) reduced elevated levels of serum phenylalanine [J. Pediatr. 135 (1999) 375-378]. Subsequent reports indicate that the prevalence of BH(4)-responsive PAH deficiency is much higher than initially anticipated. Although growing attention surrounds treatment with BH(4), little is known about the mechanism of BH(4) responsiveness. An early report indicates that BH(4) concentration in rat liver was 5ÎŒM where K(m) for BH(4) of rat PAH was estimated to be 25ÎŒM in an oxidation experiment using a liver slice, suggesting relative insufficiency of BH(4) in liver in vivo. In the present study, we developed a breath test for mice using [1-(13)C]phenylalanine in order to examine the BH(4) responsiveness of normal PAH in vivo. The reliability of the test was verified using BTBR mice and its mutant strain lacking PAH activity, Pah(enu2). BH(4) supplementation significantly enhanced (13)CO(2) production in C57BL/6 mice when phenylalanine was pre-loaded. Furthermore, BH(4) apparently activated PAH in just 5min. These observations suggest that submaximal PAH activity occurs at the physiological concentrations of BH(4) in vivo, and that PAH activity can be rapidly enhanced by supplementation with BH(4). Thus, we propose a possible hypothesis that the responsiveness to BH(4) in patients with PAH deficiency is due to the fact that suboptimal physiological concentrations of BH(4) are normally present in hepatocytes and the enhancement of the residual activity may be associated with a wide range of mutations. |
