Goldlust A, Su T Z, Welty D F, Taylor C P, Oxender D L
Department of Biotechnology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, MI 48105, USA.
Epilepsy Res. 1995 Sep;22(1):1-11. doi: 10.1016/0920-1211(95)00028-9.
Gabapentin is a novel anticonvulsant drug. The anticonvulsant mechanism of gabapentin is not known. Based on the amino acid structure of gabapentin we explored its possible effects on glutamate and gamma-aminobutyric acid (GABA) metabolism in brain as they may relate to its anticonvulsant mechanisms of action. Gabapentin was tested for its effects on seven enzymes in the metabolic pathways of these two neurotransmitters: alanine aminotransferase (AL-T), aspartate aminotransferase (AS-T), GABA aminotransferase (GABA-T), branched-chain amino acid aminotransferase (BCAA-T), glutamine synthetase (Gln-S), glutaminase (GLNase), and glutamate dehydrogenase (GDH). In the presence of 10 mM gabapentin, only GABA-T, BCAA-T, and GDH activities were affected by this drug. Inhibition of GABA-T by gabapentin was weak (33%). The Ki values for inhibition of cytosolic and mitochondrial forms of GABA-T (17-20 mM) were much higher than the Km values for GABA (1.5-1.9 mM). It is, therefore, unlikely that inhibition of GABA-T by gabapentin is clinically relevant. As with leucine, gabapentin stimulated GDH activity. The GDH activity in rat brain synaptosomes was activated 6-fold and 3.4-fold, respectively, at saturating concentrations (10 mM) of leucine and gabapentin. The half-maximal stimulation by gabapentin was observed at approximately 1.5 mM. Gabapentin is not a substrate of BCAA-T, but it exhibited a potent competitive inhibition of both cytosolic and mitochondrial forms of brain BCAA-T. Inhibition of BCAA-T by this drug was reversible. The Ki values (0.8-1.4 mM) for inhibition of transamination by gabapentin were close to the apparent Km values for the branched-chain amino acids (BCAA) L-leucine, L-isoleucine, and L-valine (0.6-1.2 mM), suggesting that gabapentin may significantly reduce synthesis of glutamate from BCAA in brain by acting on BCAA-T.
加巴喷丁是一种新型抗惊厥药物。加巴喷丁的抗惊厥机制尚不清楚。基于加巴喷丁的氨基酸结构，我们探讨了其对大脑中谷氨酸和γ-氨基丁酸（GABA）代谢可能产生的影响，因为这些影响可能与其抗惊厥作用机制有关。对加巴喷丁在这两种神经递质代谢途径中的七种酶的作用进行了测试：丙氨酸转氨酶（AL-T）、天冬氨酸转氨酶（AS-T）、GABA转氨酶（GABA-T）、支链氨基酸转氨酶（BCAA-T）、谷氨酰胺合成酶（Gln-S）、谷氨酰胺酶（GLNase）和谷氨酸脱氢酶（GDH）。在存在10 mM加巴喷丁的情况下，只有GABA-T、BCAA-T和GDH的活性受到该药物的影响。加巴喷丁对GABA-T的抑制作用较弱（33%）。加巴喷丁抑制胞质和线粒体形式的GABA-T的Ki值（17 - 20 mM）远高于GABA的Km值（1.5 - 1.9 mM）。因此，加巴喷丁对GABA-T的抑制作用在临床上不太可能具有相关性。与亮氨酸一样，加巴喷丁刺激GDH活性。在亮氨酸和加巴喷丁的饱和浓度（10 mM）下，大鼠脑突触体中的GDH活性分别被激活了6倍和3.4倍。加巴喷丁在约1.5 mM时观察到半数最大刺激作用。加巴喷丁不是BCAA-T的底物，但它对脑BCAA-T的胞质和线粒体形式均表现出强效竞争性抑制作用。该药物对BCAA-T的抑制作用是可逆的。加巴喷丁抑制转氨作用的Ki值（0.8 - 1.4 mM）接近支链氨基酸（BCAA）L-亮氨酸、L-异亮氨酸和L-缬氨酸的表观Km值（0.6 - 1.2 mM），这表明加巴喷丁可能通过作用于BCAA-T显著减少大脑中由BCAA合成谷氨酸的过程。
