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First published online April 1, 2009
doi: 10.1242/10.1242/jcs.038430

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Bax inhibitor 1 regulates ER-stress-induced ROS accumulation through the regulation of cytochrome P450 2E1

Hyung-Ryong Kim^1,*, Geum-Hwa Lee^2,*, Eun Yi Cho³, Soo-Wan Chae^2,4, Taeho Ahn^5, and Han-Jung Chae^2,4,

¹ Department of Dental Pharmacology, School of Dentistry, Wonkwang University, Iksan, Chonbuk, 570-749, Republic of Korea
² Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University, Jeonju, 560-182, Republic of Korea
³ School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea
⁴ Clinical Trial Center, Chonbuk Hospital, Jeonju, 561-712, Republic of Korea
⁵ Department of Biochemistry, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea

Authors for correspondence (e-mails: hjchae{at}chonbuk.ac.kr; thahn{at}chonnam.ac.kr)

Accepted 1 December 2008

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.

Key words: BAX inhibitor 1, Reactive oxygen species, Endoplasmic reticulum, NADPH-P450 reductase, Cytochrome P450, Nicotinamide adenine dinucleotide phosphate, Microsomal monooxygenase, Unfolded protein response

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