抗てんかん薬のepoxide hydrolaseおよびglutathione S-transferase活性に対する作用  [in Japanese] Effect of Antiepileptic Drugs on Epoxide Hydrolase and Glutathione S-transferase Activities  [in Japanese]

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Abstract

抗てんかん薬 (antiepileptic drugs: AED) の催奇性の機序解明の一環として、胎児毒性との関連が指摘されているepoxide体の加水分解酵素epoxide hydrolase (EH) および抱合酵素glutathione S-transferase (GST) の両酵素活性に与えるcarbarnazepine (CBZ) 、phenobarbital (PB) 、phenytoin (PHT) 、valproic acid (VPA) 、zonisamide (ZNS) の影響を検討した。ラット肝マイクロゾームを用いて両酵素の活性を各AEDの影響下で対照群と比較検討したところ、VPAはEHおよびGST (2-2、4-4、7-7) 活性を治療濃度 (50~100μg/ml) より濃度依存性に抑制し、CBZ (10μg/m<I>l</I>) およびPB (40μg/m<I>l</I>) は治療濃度よりGST7-7活性を有意に抑制した。一方、PHTおよびZNSはEH、GSTの両酵素活性に対し治療濃度では影響を与えなかった。以上の結果から、VPA、CBZおよびPBを含む多剤併用時の奇形発現の増加の一因として、これらの薬剤によるepoxide解毒機構の低下が関与する可能性が示唆された。

Epoxide hydrolase (EH) and glutathione S-transferase (GST) are involved in the detoxification of epoxide, which may be attributable to the mechanism of ter-atogenicity of antiepileptic drugs (AEDs).In this study, such AEDs as phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ), zonisamide (ZNS) and valproic acid (VPA) on the activities of these enzymes were investigated using rat liver microsomes.Within respective therapeutic concentrations, PHT, PB, CBZ and ZNS did not affect EH activity while VPA showed a concentration-dependent inhibitory effect on EH activity at 100μg/m<I>l</I>or more.Regarding the activities of GST isozymes, PHT and ZNS did not affect the activities at any concentrations studied while CBZ (10μg/m<I>l</I> or more) and PB (40μg/m<I>l</I> or more) inhibited GST 7-7 activity.VPA showed concentration-dependent inhibitory effects on activities of GST 1-1, 2-2, 4-4 ad 7-7 at 100μg/m<I>l</I> or more.These results may partly explain the increased incidences of malformation in offspring exposed to AED polytherapy including VPA, CBZ and PB through the accumulation of epoxide intermediates of AEDs.

Journal

  • Journal of the Japan Epilepsy Society

    Journal of the Japan Epilepsy Society 15(3), 165-171, 1997-10-31

    JAPAN EPILEPSY SOCIETY

References:  25

Codes

  • NII Article ID (NAID)
    10008555783
  • NII NACSIS-CAT ID (NCID)
    AN10043823
  • Text Lang
    JPN
  • Article Type
    ART
  • ISSN
    09120890
  • Data Source
    CJP  IR  J-STAGE 
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