Effects Of Topiramate On The Activities Of GST And The Expression Of MDR In Rats

Background and Purpose: The tolerance of organism to its non-intrinsic contents (foreign substance) grew up during the organism was evolved. When foreign substance came in, Organism can identify and resist them by a series of biochemical transformations. Every drug is foreign substance of organism and organism could form resistance to it. Researchs have approved that the tolerance of drugs were owing to multidrug resistance gene (MDR1), glutathione S-transferase(GST) and topoisomerase II (TOPO II ) et al. Topiramate (TPM) is a new antiepileptic drug (AED) which has been developed in recent years. It is a sulfamate-substituted nosaccharide(2,3:4,5-bis -o-(1-methylethylidene)-beta-D-fructopyranose sulfamate), its molecular formula is C12H21NO8S and molecular weight is 339.36. There are several mechanisms of action related to anticonvulsants for TMP: (1)inhibition spontaneous repetitive firing(SFR) by blockes voltage gated sodium channels; (2)enhancement inhibitory gamma-aminobutyric acid(GABAergic) neurotrans -mission by enhance the activities of GABA(A) receptor in CNS(central neurvous system); (3)blockade the glutamate induced actions of neurotransmis -sion by inhibits AMPA/kainate subtype of glutamate recepter. There were many reports all over the world that TPM had been demonstrated efficacy in various refractory patients receving monotherapy or add-on therapy, it is safe and few adverse side effects, and can be tolerated well. But our clinical practice had found some epileptic patients with poorly or no effecacy in the patients receving TMP. If TPM enhanced the activity of GST(glutathione S-transferase), a hepatic enzyme related to drug resistances , or induced theover-expression of the multidrug resistance gene in astrocytes. We would find the mechanisms of topiramate resistance in epilepsy. MDR1 is a kind of regulated gene and GST is a detoxifcation enzyme induced by many drugs , so we investigated Pgp expression with flow cytometry (FCM)and the activity of GST with chemical colorimetry in culture astrocytes, and detected the activity of GST in the serum of the epileptic patients with TPM therapy .Methods : 1 .Postnatal wistar rats (within 24 hours) astrocyte cell culture was established. Different concentration of TPM was added to the culture media. Flow cytometry(FCM) for Pgp after 10days and 15days and chemical colorimetry for GST after 5days,10days , 15days and 20days. 2.Moreover we detected the activity of the GST in the serum in 31 epileptic patients with chemical colorimetry, and compared the difference of GST between pretherapy and at 4weeks and Sweeks after therapy with TPM.Results: 1. Effets of topiramate on GST activity. (1) The activity of GST was no significant difference in the normal astrocytes without TPM at every tune pouit. (2) At 5th day, the GST activity was no difference in the astrocytes with TPM 5ug/ml, lOug/ml, 20ug/ml, 40ug/ml and 80ug/ml. but it increased with 160ug/ml. At 10th day, the GST activity showed increased or great increased in every concentration of TPM compared with their collators. After 10days, the activity of GST had no significant change any longer. (3)The GST activity showed a dose-proportional increase with the concentration of add-on TPM.2. TPM induced Pgp expression. The percentage of Pgp in astrocytes was no significant difference in every concentration of TPM compared with no ADEs at 10th day and 15th day.3. The serum GST activity in patients with epilepsy increased after receving TPM compared that in before, especially at 8th week it was quiet higher than that in 4th week and before accepted TPM therapy. But at 4th weekthe GST activities showed no significant difference compared with before.Conclusion: 1. Topiramate can enhance the GST activity in astrocytes in certain duration, and enhanced with dose-proportion. The effects showed hi short time with higher concentration of TPM. The activity of GST was not great change after it arrived stable levels. It is similar to the metabolic drug-resistance of AEDs. This study suggested...