Carboxylesterase-2 is a highly sensitive target of the antiobesity agent orlistat with profound implications in the activation of anticancer prodrugs.
Carboxylesterase-2 is a highly sensitive target of the antiobesity agent orlistat with profound implications in the activation of anticancer prodrugs.
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DOI：
10.1016/j.bcp.2012.11.026
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发表时间：
2013-02-01
影响因子：
5.8
通讯作者：
Yan, Bingfang
中科院分区：
文献类型：
--
作者：
Xiao, Da;Shi, Deshi;Yang, Dongfang;Barthel, Benjamin;Koch, Tad H.;Yan, Bingfang
奥利司他是最常用的减肥药，其作用机制是通过抑制胃肠道脂肪酶来减少脂质吸收。这些酶，如羧酸酯酶（CES），在结构上属于α/β水解酶折叠超家族。脂肪酶和CES在功能上也是相关的。一些CES（例如，人CES 1）已显示水解脂质。本研究旨在检验奥利司他抑制CES 1的效力高于CES 2（一种几乎没有脂肪酶活性的羧酸酯酶）的假设。检测了肝微粒体和重组CES对标准底物和抗癌前药氨基甲酸戊酯、多沙唑烷（PPD）的对氨基苄基氨基甲酸酯和伊立替康水解的抑制作用。与假设相反，1 nM的奥利司他抑制了75%的CES 2活性，但对CES 1没有抑制作用，使CES 2成为奥利司他最敏感的靶点之一。抑制在一些CES 2多态性变体之间变化。奥利司他预处理降低PPD的细胞杀伤活性。某些小鼠而非大鼠的CES也是高度敏感的。CES 2负责许多常见药物的水解，并在胃肠道和肝脏中大量表达。如果与奥利司他联合给药，这种羧酸酯酶的抑制可能是这些药物治疗活性改变的主要来源。此外，奥利司他与各种类型的器官毒性有关，本研究提供了可能参与这些毒理学反应的替代靶点。
Orlistat has been the most used anti-obesity drug and the mechanism of its action is to reduce lipid absorption by inhibiting gastrointestinal lipases. These enzymes, like carboxylesterases (CESs), structurally belong to the α/β hydrolase fold superfamily. Lipases and CESs are functionally related as well. Some CESs (e.g., human CES1) have been shown to hydrolyze lipids. This study was designed to test the hypothesis that orlistat inhibits CESs with higher potency toward CES1 than CES2, a carboxylesterase with little lipase activity. Liver microsomes and recombinant CESs were tested for the inhibition of the hydrolysis of standard substrates and the anticancer prodrugs pentyl carbamate of p-aminobenzyl carbamate of doxazolidine (PPD) and irinotecan. Contrary to the hypothesis, orlistat at 1 nM inhibited CES2 activity by 75% but no inhibition on CES1, placing CES2 one of the most sensitive targets of orlistat. The inhibition varied among some CES2 polymorphic variants. Pretreatment with orlistat reduced the cell killing activity of PPD. Certain mouse but not rat CESs were also highly sensitive. CES2 is responsible for the hydrolysis of many common drugs and abundantly expressed in the gastrointestinal track and liver. Inhibition of this carboxylesterase probably presents a major source for altered therapeutic activity of these medicines if co-administered with orlistat. In addition, orlistat has been linked to various types of organ toxicities, and this study provides an alternative target potentially involved in these toxicological responses.
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影响因子：
4.1
作者：
Lehner, R;Vance, DE
通讯作者：
Vance, DE
影响因子：
4.1
作者：
Liu, Fu-Jun;Song, Xiulong;Yan, Bingfang
通讯作者：
Yan, Bingfang
影响因子：
3.5
作者：
HERMIER, D;HALES, P;BRINDLEY, DN
通讯作者：
BRINDLEY, DN
影响因子：
2.4
作者：
Moyad, Mark A.
通讯作者：
Moyad, Mark A.
DOI：
10.1111/j.1432-1033.1994.tb18878.x
发表时间：
1994-06-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
LOOKENE, A;SKOTTOVA, N;OLIVECRONA, G
通讯作者：
OLIVECRONA, G