In vitro metabolism of pyripyropene A and ACAT inhibitory activity of its metabolites.
In vitro metabolism of pyripyropene A and ACAT inhibitory activity of its metabolites.
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吡咯平 A 的体外代谢及其代谢物的 ACAT 抑制活性。
DOI：
10.1038/ja.2014.91
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
H.
中科院分区：
文献类型：
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作者：
Ohshiro;T.; Matsuda;D.; Ohtawa;M.; Yamazaki;H.; Nagamitsu. T.; Tomoda;H.
真菌来源的Pyripyropene A （PPPA, 1）是酰基辅酶A：胆固醇酰基转移酶2 （ACAT2）的选择性抑制剂，在致动脉粥样硬化小鼠模型中被证明具有口服活性。采用超快速液相色谱法和液相色谱/串联质谱法分析了人、兔、大鼠和小鼠肝微粒体和血浆中1的体外代谢产物。在所有物种的肝微粒体中，依次水解发生在1- o -乙酰基残基上，然后是1- 11- o -乙酰基残基上，而7- o -乙酰基残基对水解具有抗性。此外，新生成的11-醇羟基残基在人和小鼠肝微粒体中发生脱氢，而吡啶环在人和兔肝微粒体中发生氧化。另一方面，7- o -乙酰基残基的水解仅在小鼠血浆中进行。这些数据表明，1的体外代谢谱在动物物种之间存在细微差异。肝微粒体和血浆中PPPA代谢物均显著降低ACAT2抑制活性。这些发现将有助于我们合成新的PPPA衍生物，在体内研究中比1更有效。
Pyripyropene A (PPPA, 1) of fungal origin, a selective inhibitor of acyl-CoA: cholesterol acyltransferase 2 (ACAT2), proved orally active in atherogenic mouse models. The in vitro metabolites of 1 in liver microsomes and plasma of human, rabbit, rat and mouse were analyzed by ultra fast liquid chromatography and liquid chromatography/tandem mass spectrometry. In the liver microsomes from all species, successive hydrolysis occurred at the 1-O-acetyl residue, then at the 11-O-acetyl residue of 1, while the 7-O-acetyl residue was resistant to hydrolysis. Furthermore, dehydrogenation of the newly generated 11-alcoholic hydroxyl residue occurred in human and mouse-liver microsomes, while oxidation of the pyridine ring occurred in human and rabbit liver microsomes. On the other hand, hydrolysis of the 7-O-acetyl residue proceeded only in the mouse plasma. These data indicated that the in vitro metabolic profiles of 1 have subtle differences among animal species. All of the PPPA metabolites observed in liver microsomes and plasma markedly decreased ACAT2 inhibitory activity. These findings will help us to synthesize new PPPA derivatives more effective in in vivo study than 1.