医薬品による毒性発現に係わるオーファン加水分解酵素の機能解明

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  • 深見 達基
    金沢大学医薬保健研究域薬学系薬物代謝安全性学研究室

書誌事項

タイトル別名
  • Role of Human Orphan Esterases in Drug-induced Toxicity
  • イヤクヒン ニ ヨル ドクセイ ハツゲン ニ カカワル オーファン カスイブンカイ コウソ ノ キノウ カイメイ

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説明

  Esterases hydrolyze compounds containing ester, amide, and thioester bonds, causing prodrug activation or detoxification. Among esterases, carboxylesterases have been studied in depth due to their ability to hydrolyze a variety of drugs. However, there are several drugs for which the involved esterase(s) is unknown. We found that flutamide, phenacetin, rifamycins (rifampicin, rifabutin, and rifapentine), and indiplon are hydrolyzed by arylacetamide deacetylase (AADAC), which is highly expressed in human liver and gastrointestinal tissues. Flutamide hydrolysis is considered associated with hepatotoxicity. Phenacetin, a prodrug of acetaminophen, was withdrawn due to side effects such as methemoglobinemia and renal failure. It was demonstrated in vitro and in vivo using mice that AADAC is responsible for phenacetin hydrolysis, which leads to methemoglobinemia. In addition, it was shown that AADAC-mediated hydrolysis attenuates the cytotoxicity of rifamycins. Thus AADAC plays critical roles in drug-induced toxicity. Another orphan esterase, α/β hydrolase domain containing 10 (ABHD10), was found responsible for deglucuronidation of acyl-glucuronides including mycophenolic acid acyl-glucuronide and probenecid acyl-glucuronide. Because acyl-glucuronides appear associated with toxicity, ABHD10 would function as a detoxification enzyme. The roles of orphan esterases are becoming increasingly understood. Further studies will facilitate our knowledge of the pharmacologic and toxicological significance of orphan esterases in drug therapy.<br>

収録刊行物

  • 薬学雑誌

    薬学雑誌 135 (11), 1235-1244, 2015-11-01

    公益社団法人 日本薬学会

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