Department of Pediatrics, University of Torino, Torino, Italy.
Metabolism. 2010 May;59(5):645-52. doi: 10.1016/j.metabol.2009.09.008. Epub 2009 Nov 14.
Conflicting results have been reported concerning the efficacy of tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydroxylase, for reducing phenylalanine (Phe) concentration in phenylketonuria (PKU). We aimed to test quantitatively the effects of BH4 in PKU patients. Seven fully characterized patients were selected among a population of 130 PKU subjects as harboring PKU mutations predicted as BH4 responsive and previously considered responsive to a cofactor challenge. They received a simple Phe (100 mg/kg) and 2 combined Phe (100 mg/kg) and BH4 (20 mg/kg) oral loading tests. Cofactor was administered either before or after the amino acid. The concentrations of Phe, tyrosine (Tyr), and biopterin were measured over 24 hours after loading. The comparative analysis of the loading tests showed that in all patients plasma Phe concentrations peaked within 3 hours, and fell within 24 hours by about 50% in benign, 20% in mild, and 15% in severe phenylalanine hydroxylase deficiency regardless of BH4 administration. A consistent or moderate increase of plasma Tyr, again independent of the cofactor challenge, was observed only in the less severe forms of PAH deficiency. Mean blood biopterin concentration increased 6 times after simple Phe and 34 to 39 times after combined loading tests. The administration of BH4 does not alter Phe and Tyr metabolism in PKU patients. The clearance of plasma Phe after oral loading and, as well as Tyr production, is not related to cofactor challenge but to patient's phenotype. The assessment of BH4 responsiveness by the methods so far used is not reliable, and the occurrence of BH4-responsive forms of PKU still has to be definitely proven.
关于四氢生物蝶呤（BH4）作为苯丙氨酸羟化酶的辅助因子降低苯丙酮尿症（PKU）患者苯丙氨酸（Phe）浓度的疗效，已有相互矛盾的结果报道。我们旨在定量检测 BH4 在 PKU 患者中的作用。在 130 名 PKU 患者中，选择了 7 名具有 PKU 突变的患者作为研究对象，这些突变被预测为 BH4 反应型，并被认为对辅助因子挑战有反应。他们接受了简单的 Phe（100mg/kg）和 2 种联合 Phe（100mg/kg）和 BH4（20mg/kg）口服负荷试验。辅助因子在氨基酸之前或之后给予。负荷试验后 24 小时内测量 Phe、酪氨酸（Tyr）和生物蝶呤的浓度。负荷试验的比较分析表明，在所有患者中，血浆 Phe 浓度在 3 小时内达到峰值，并在 24 小时内下降 50%左右，良性患者下降 50%，轻度患者下降 20%，严重患者下降 15%，无论是否给予 BH4。仅在较轻的 PAH 缺乏症患者中观察到血浆 Tyr 的一致或中度增加，这再次与辅助因子挑战无关。在简单 Phe 负荷后，平均血液生物蝶呤浓度增加了 6 倍，在联合负荷试验后增加了 34 到 39 倍。BH4 的给予并不能改变 PKU 患者的 Phe 和 Tyr 代谢。口服负荷后血浆 Phe 的清除率以及 Tyr 的产生与辅助因子挑战无关，而与患者的表型有关。迄今为止使用的方法评估 BH4 反应性不可靠，BH4 反应型 PKU 的发生仍需得到明确证实。
