Fukui S, Schwarcz R, Rapoport S I, Takada Y, Smith Q R
Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892.
J Neurochem. 1991 Jun;56(6):2007-17. doi: 10.1111/j.1471-4159.1991.tb03460.x.
To evaluate the potential contribution of circulating kynurenines to brain kynurenine pools, the rates of cerebral uptake and mechanisms of blood-brain barrier transport were determined for several kynurenine metabolites of tryptophan, including L-kynurenine (L-KYN), 3-hydroxykynurenine (3-HKYN), 3-hydroxyanthranilic acid (3-HANA), anthranilic acid (ANA), kynurenic acid (KYNA), and quinolinic acid (QUIN), in pentobarbital-anesthetized rats using an in situ brain perfusion technique. L-KYN was found to be taken up into brain at a significant rate [permeability-surface area product (PA) = 2-3 x 10(-3) ml/s/g] by the large neutral amino acid carrier (L-system) of the blood-brain barrier. Best-fit estimates of the Vmax and Km of saturable L-KYN transfer equalled 4.5 x 10(-4) mumol/s/g and 0.16 mumol/ml, respectively. The same carrier may also mediate the brain uptake of 3-HKYN as D,L-3-HKYN competitively inhibited the brain transfer of the large neutral amino acid L-leucine. For the other metabolites, uptake appeared mediated by passive diffusion. This occurred at a significant rate for ANA (PA, 0.7-1.6 x 10(-3) ml/s/g), and at far lower rates (PA, 2-7 x 10(-5) ml/s/g) for 3-HANA, KYNA, and QUIN. Transfer for KYNA, 3-HANA, and ANA also appeared to be limited by plasma protein binding. The results demonstrate the saturable transfer of L-KYN across the blood-brain barrier and suggest that circulating L-KYN, 3-HKYN, and ANA may each contribute significantly to respective cerebral pools. In contrast, QUIN, KYNA, and 3-HANA cross the blood-brain barrier poorly, and therefore are not expected to contribute significantly to brain pools under normal conditions.
为评估循环犬尿氨酸对脑内犬尿氨酸池的潜在贡献，采用原位脑灌注技术，测定了戊巴比妥麻醉大鼠体内色氨酸的几种犬尿氨酸代谢产物（包括L-犬尿氨酸（L-KYN）、3-羟基犬尿氨酸（3-HKYN）、3-羟基邻氨基苯甲酸（3-HANA）、邻氨基苯甲酸（ANA）、犬尿酸（KYNA）和喹啉酸（QUIN））的脑摄取率及血脑屏障转运机制。结果发现，L-KYN通过血脑屏障的大中性氨基酸载体（L-系统）以显著速率（通透表面积乘积（PA）=2 - 3×10⁻³ ml/s/g）被摄取入脑。饱和性L-KYN转运的Vmax和Km的最佳拟合估计值分别为4.5×10⁻⁴ μmol/s/g和0.16 μmol/ml。由于D,L-3-HKYN竞争性抑制大中性氨基酸L-亮氨酸的脑转运，同一载体可能也介导3-HKYN的脑摄取。对于其他代谢产物，摄取似乎由被动扩散介导。ANA以显著速率发生被动扩散（PA，0.7 - 1.6×10⁻³ ml/s/g），而3-HANA、KYNA和QUIN的被动扩散速率则低得多（PA，2 - 7×10⁻⁵ ml/s/g）。KYNA、3-HANA和ANA的转运似乎也受血浆蛋白结合的限制。这些结果表明L-KYN可饱和性地穿越血脑屏障，并提示循环中的L-KYN、3-HKYN和ANA可能各自对相应的脑内池有显著贡献。相比之下，QUIN、KYNA和3-HANA穿越血脑屏障的能力较差，因此在正常情况下预计对脑内池的贡献不大。
