Kim Hyung-Ryong, Lee Geum-Hwa, Cho Eun Yi, Chae Soo-Wan, Ahn Taeho, Chae Han-Jung
Department of Dental Pharmacology, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Republic of Korea.
J Cell Sci. 2009 Apr 15;122(Pt 8):1126-33. doi: 10.1242/jcs.038430.
This study investigated the molecular mechanism by which Bax inhibitor 1 (BI1) abrogates the accumulation of reactive oxygen species (ROS) in the endoplasmic reticulum (ER). Electron uncoupling between NADPH-dependent cytochrome P450 reductase (NPR) and cytochrome P450 2E1 (P450 2E1) is a major source of ROS on the ER membrane. ER stress produced ROS accumulation and lipid peroxidation of the ER membrane, but BI1 reduced this accumulation. Under ER stress, expression of P450 2E1 in control cells was upregulated more than in BI1-overexpressing cells. In control cells, inhibiting P450 2E1 through chemical or siRNA approaches suppressed ROS accumulation, ER membrane lipid peroxidation and the resultant cell death after ER stress. However, it had little effect in BI1-overexpressing cells. In addition, BI1 knock down also increased ROS accumulation and expression of P450 2E1. In a reconstituted phospholipid membrane containing purified BI1, NPR and P450 2E1, BI1 dose-dependently decreased the production of ROS. BI1 bound to NPR with higher affinity than P450 2E1. Furthermore, BI1 overexpression reduced the interaction of NPR and P450 2E1, and decreased the catalytic activity of P450 2E1, suggesting that the flow of electrons from NPR to P450 2E1 can be modulated by BI1. In summary, BI1 reduces the accumulation of ROS and the resultant cell death through regulating P450 2E1.
本研究调查了Bax抑制剂1（BI1）消除内质网（ER）中活性氧（ROS）积累的分子机制。NADPH依赖性细胞色素P450还原酶（NPR）与细胞色素P450 2E1（P450 2E1）之间的电子解偶联是ER膜上ROS的主要来源。ER应激导致ROS积累和ER膜的脂质过氧化，但BI1减少了这种积累。在ER应激下，对照细胞中P450 2E1的表达上调幅度大于BI1过表达细胞。在对照细胞中，通过化学或siRNA方法抑制P450 2E1可抑制ROS积累、ER膜脂质过氧化以及ER应激后导致的细胞死亡。然而，在BI1过表达细胞中其作用甚微。此外，敲低BI1也会增加ROS积累和P450 2E1的表达。在含有纯化的BI1、NPR和P450 2E1的重构磷脂膜中
