Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria
Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria
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DOI：
10.1172/jci5017
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发表时间：
1999-04-01
影响因子：
15.9
通讯作者：
Bremer, HJ
中科院分区：
文献类型：
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作者：
Pietz, J;Kreis, R;Bremer, HJ
大的中性氨基酸(LNAA)，包括苯丙氨酸(Phe)，通过L类型的氨基酸载体竞争跨越血脑屏障(BBB)。因此，苯丙酮尿症(PKU)患者血浆Phe升高会损害大脑对其他LNAA的摄取。Phe升高和LNAAs耗竭的直接影响可能是PKU患者脑发育和功能障碍的主要原因。相反，当所有其他LNAA的血浆浓度增加时，对载体的竞争可能被用来降低Phe的流入。在口服苯丙氨酸挑战期间，通过定量H-1磁共振波谱测量PKU患者的大脑苯丙氨酸，验证了这一假说，在补充和不补充所有其他LNAA的情况下。两个系列的基础血浆Phe与1000mU/L相似，脑Phe与250mU/L相似。在没有补充LNAA的情况下，口服苯丙氨酸后，脑内苯丙氨酸的含量增加到接近400mU/L。脑电(EEG)频谱分析显示大脑活动严重受扰。在同时补充LNAA的情况下，Phe的内流完全被阻止，并且脑电活动没有减慢。这些结果对于进一步表征LNAA携带者和PKU脑功能障碍的病理生理学基础以及PKU患者的治疗具有重要意义，因为持续补充LNAA可能会改善脑功能。
Large neutral amino acids (LNAAs), including phenylalanine (Phe), compete for transport across the blood-brain barrier (BBB) via the L-type amino acid carrier. Accordingly, elevated plasma Phe impairs brain uptake of other LNAAs in patients with phenylketonuria (PKU). Direct effects of elevated brain Phe and depleted LNAAs are probably major causes for disturbed brain development and function in PKU. Competition for the carrier might conversely be put to use to lower Phe influx when the plasma concentrations of all other LNAAs are increased. This hypothesis was tested by measuring brain Phe in patients with PKU by quantitative H-1 magnetic resonance spectroscopy during an oral Phe challenge with and without additional supplementation with all other LNAAs. Baseline plasma Phe was similar to 1,000 mu mol/l and brain Phe was similar to 250 mu mol/l in both series. Without LNAA supplementation, brain Phe increased to similar to 400 mu mol/l after the oral Phe load. Electroencephalogram (EEG) spectral analysis revealed acutely disturbed brain activity. With concurrent LNAA supplementation, Phe influx was completely blocked and there was no slowing of EEG activity. These results are relevant for further characterization of the LNAA carrier and of the pathophysiology underlying brain dysfunction in PKU and for treatment of patients with PKU, as brain function might be improved by continued LNAA supplementation.