Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan.
Drug Metab Dispos. 2014 Apr;42(4):751-8. doi: 10.1124/dmd.113.056184. Epub 2014 Jan 24.
Human arylacetamide deacetylase (AADAC) catalyzes the hydrolysis of some clinically used drugs, but the information available on its substrates is limited. To increase our knowledge of the AADAC substrates, we examined whether AADAC catalyzes the hydrolysis of indiplon, which was initially developed as a hypnotic sedative drug. It has been reported that approximately 30-40% of the administered indiplon was hydrolyzed to deacetylindiplon in humans, but the enzyme responsible for this hydrolysis had not been identified. We detected high levels of indiplon hydrolase activity in human liver microsomes (HLMs), but the levels found in human liver cytosol and plasma were scarcely detectable. Recombinant AADAC showed a high level of indiplon hydrolase activity, whereas recombinant carboxylesterase 1 (CES1) and 2 (CES2) showed marginal activity. The indiplon hydrolase activity of HLM was potently inhibited by vinblastine, a potent inhibitor of AADAC and CES2, but it was not inhibited by digitonin and telmisartan, inhibitors of CES1 and CES2, respectively. In a panel of 24 individual HLM samples, the indiplon hydrolase activities were significantly correlated with the hydrolase activities of flutamide, phenacetin, and rifampicin, which are known AADAC substrates. An HLM sample with a homozygous AADAC*3 allele, which was previously found to exhibit decreased enzyme activity, showed the lowest indiplon hydrolase activity among the 24 tested samples. Collectively, we found that human AADAC is responsible for the hydrolysis of indiplon. Thus, we can add indiplon to the list of human AADAC substrates.
人芳基乙酰胺脱乙酰酶（AADAC）催化一些临床使用药物的水解，但关于其底物的信息有限。为了增加我们对 AADAC 底物的了解，我们研究了 AADAC 是否催化最初开发为催眠镇静药物的吲达哌酮的水解。据报道，约 30-40%的给予的吲达哌酮在人体内被水解为去乙酰吲达哌酮，但负责这种水解的酶尚未确定。我们在人肝微粒体（HLM）中检测到高水平的吲达哌酮水解酶活性，但在人肝胞质和血浆中发现的水平几乎检测不到。重组 AADAC 显示出高水平的吲达哌酮水解酶活性，而重组羧酸酯酶 1（CES1）和 2（CES2）则显示出边际活性。HLM 的吲达哌酮水解酶活性被长春碱强烈抑制，长春碱是 AADAC 和 CES2 的有效抑制剂，但不受皂角苷和替米沙坦的抑制，分别是 CES1 和 CES2 的抑制剂。在 24 个人肝微粒体样本的小组中，吲达哌酮水解酶活性与已知的 AADAC 底物氟他胺、非那西汀和利福平的水解酶活性显著相关。先前发现具有降低酶活性的纯合 AADAC*3 等位基因的 HLM 样本在 24 个测试样本中表现出最低的吲达哌酮水解酶活性。总的来说，我们发现人 AADAC 负责吲达哌酮的水解。因此，我们可以将吲达哌酮添加到人类 AADAC 底物列表中。
