Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. 856 62

Gabapentin (GPN) is a new antiepileptic agent currently in used as add-on therapy in adult patients suffering from partial seizures. The extent of liver damage at different dosage and long term treatment with GPN is not yet clear. Therefore this study was undertaken to find out the possibility of liver damage by this drug. Adult male (Wistar) rats of 180-220 g were administered intraperitoneally with GPN (20 or 100 mg/kg) for 45 days. After the experimental period, the liver function tests were carried out in control and experimental groups. The activity of liver enzymes, with 20 mg/kg of GPN were not significantly different from the control group but, the serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, direct bilirubin and total bilirubin were enhanced significantly with 100 mg/kg of GPN. Total protein and albumin decreased in this group as compared with control animals. The histopathology of the liver parenchymal cells also showed minute foci of necrosis in a few rats treated with high dose of GPN, whereas, at therapeutic dose the histopathology and biochemical indices showed almost normal values. At therapeutic dose GPN is a safer drug with regards to liver function and hepatocellular damage as compared with other antiepileptic drugs.
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PMID:Chronic effect of gabapentin on liver function in adult male rats. 2444 36