Fukami Tatsuki, Kariya Motoki, Kurokawa Takaya, Iida Azumi, Nakajima Miki
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
Eur J Pharm Sci. 2015 Oct 12;78:47-53. doi: 10.1016/j.ejps.2015.07.006. Epub 2015 Jul 8.
Human arylacetamide deacetylase (AADAC) is an esterase responsible for the hydrolysis of some drugs, including flutamide, indiplon, phenacetin, and rifamycins. AADAC is highly expressed in the human liver, where carboxylesterase (CES) enzymes, namely, CES1 and CES2, are also expressed. It is generally recognized that CES1 prefers compounds with a large acyl moiety and a small alcohol or amine moiety as substrates, whereas CES2 prefers compounds with a small acyl moiety and a large alcohol or amine moiety. In a comparison of the chemical structures of known AADAC substrates, AADAC most likely prefers compounds with the same characteristics as does CES2. However, the substrate specificity of human AADAC has not been fully clarified. To expand the knowledge of substrates of human AADAC, we measured its hydrolase activities toward 13 compounds, including known human CES1 and CES2 substrates, using recombinant enzymes expressed in Sf21 cells. Recombinant AADAC catalyzed the hydrolysis of fluorescein diacetate, N-monoacetyldapsone, and propanil, which possess notably small acyl moieties, and these substrates were also hydrolyzed by CES2. However, AADAC could not hydrolyze another CES2 substrate, procaine, which possesses a moderately small acyl moiety. In addition, AADAC did not hydrolyze several known CES1 substrates, including clopidogrel and oseltamivir, which have large acyl moieties and small alcohol moieties. Collectively, these results suggest that AADAC prefers compounds with smaller acyl moieties than does CES2. The role of AADAC in the hydrolysis of drugs has been clarified. For this reason, AADAC should receive attention in ADMET studies during drug development.
人芳基乙酰胺脱乙酰酶（AADAC）是一种酯酶，负责水解某些药物，包括氟他胺、茚地普隆、非那西丁和利福霉素。AADAC在人肝脏中高度表达，羧酸酯酶（CES）即CES1和CES2也在肝脏中表达。一般认为，CES1更喜欢以具有大酰基部分和小醇或胺部分的化合物作为底物，而CES2更喜欢以具有小酰基部分和大醇或胺部分的化合物作为底物。在比较已知AADAC底物的化学结构时，AADAC最有可能更喜欢与CES2具有相同特征的化合物。然而，人AADAC的底物特异性尚未完全阐明。为了扩展对人AADAC底物的认识，我们使用在Sf21细胞中表达的重组酶，测量了它对13种化合物的水解活性，这些化合物包括已知的人CES1和CES2底物。重组AADAC催化了具有特别小的酰基部分的荧光素二乙酸酯、N-单乙酰氨苯砜和敌稗的水解，并且这些底物也被CES2水解。然而，AADAC不能水解另一种具有中等小酰基部分的CES2底物普鲁卡因。此外，AADAC没有水解几种已知的CES1底物，包括具有大酰基部分和小醇部分的氯吡格雷和奥司他韦。总体而言，这些结果表明，AADAC比CES2更喜欢具有更小酰基部分的化合物。AADAC在药物水解中的作用已经阐明。因此，在药物开发过程中的ADMET研究中，AADAC应受到关注。
