Cholesterol's inhibition effect on entering of chlorzoxazone into phosphatidylethanolamine bilayer: Relevance to cytochrome P450 drug metabolism at endoplasmic reticulum membranes
Cholesterol's inhibition effect on entering of chlorzoxazone into phosphatidylethanolamine bilayer: Relevance to cytochrome P450 drug metabolism at endoplasmic reticulum membranes
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胆固醇对氯唑沙宗进入磷脂酰乙醇胺双层的抑制作用：与内质网膜细胞色素P450药物代谢的相关性
DOI：
10.1016/j.bbamem.2022.183954
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Takahashi Hiroshi
中科院分区：
文献类型：
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作者：
Kano Shusei;Takahashi Hiroshi
许多药物通过内质网（ER）膜中的细胞色素P450（CYP）代谢。最近的研究表明，CYP底物药物进入ER膜的脂质疏水部分后到达ER活性位点。为了阐明胆固醇（Chol）在CYP相关药物代谢过程中的作用，我们使用模型膜系统研究了CYP底物药物的脂质双层进入，如下所示。模型膜系统由棕榈酰-油酰-磷脂酰乙醇胺（POPE）和Chol组成。磷脂酰乙醇胺是ER膜的第二种主要磷脂成分。氯唑沙宗（CZX）被用作CYP底物药物。量热分析表明，CZX的加入降低了POPE的凝胶-液晶相转变温度; X射线衍射表明，CZX分布在液晶相双层膜中，但没有分布在凝胶相POPE双层膜中。在Chol的存在下，透析和X-射线结构分析表明，Chol抑制CZX进入双层与Chol浓度的增加。ER膜中的Chol浓度（5-10 mol%）远低于质膜中的Chol浓度（约30 mol%）。这一事实可能允许CYP底物药物比其他细胞器膜更容易进入ER膜的疏水部分，从而产生有效的药物代谢。
Many drugs are metabolized by cytochrome P450 (CYP) in the endoplasmic reticulum (ER) membrane. Recent studies have shown that CYP-substrate drugs reach the CYP active site after entering the lipid hydrophobic part of the ER membrane. To clarify the role of cholesterol (Chol) in the CYP-related drug metabolic process, we investigated the lipid bilayer entry of CYP-substrate drugs using a model membrane system as follows. The model membrane system comprised palmitoyl-oleoyl-phosphatidylethanolamine (POPE) and Chol. Phosphatidylethanolamine is the second major phospholipid component of ER membranes. Chlorzoxazone (CZX) was used as the CYP-substrate drug. Calorimetric measurements showed that the addition of CZX to POPE bilayers decreased the gel–liquid crystal phase transition temperature; X-ray diffraction indicated that CZX distributes into the liquid crystal phase bilayers but not practically the gel phase POPE bilayers. In the presence of Chol, dialysis and X-ray structural analyses showed that Chol inhibited CZX entry into the bilayer with an increase in Chol concentration. The Chol concentration in the ER membrane (5–10 mol%) is much lower than that in the plasma membrane (approximately 30 mol%). This fact may allow CYP-substrate drugs to enter the hydrophobic portion of the ER membrane more easily than other organelle membranes, yielding efficient drug metabolism.