Reduction of arsenic-induced cytotoxicity through Nrf2/HO-1 signaling in HepG2 cells

被引：32
作者：
Abiko, Yumi [1 ]
Shinkai, Yasuhiro [1 ]
Sumi, Daigo [2 ]
Kumagai, Yoshito [1 ]
机构：
[1] Univ Tsukuba, Grad Sch Comprehens Human Sci, Doctoral Program Life Syst Med Sci, Tsukuba, Ibaraki 3058575, Japan
[2] Tokushima Bunri Univ, Fac Pharmaceut Sci, Tokushima 7708514, Japan
来源：
JOURNAL OF TOXICOLOGICAL SCIENCES | 2010年 / 35卷 / 03期
关键词：
Arsenite; Nrf2; Heme oxygenase-1; Cytotoxicity; HEME OXYGENASE-1; TRANSCRIPTION FACTOR; NRF2; ACTIVATION; INDUCTION; APOPTOSIS; LIVER; ACCUMULATION; TARGET; GENES;
D O I：
10.2131/jts.35.419
中图分类号：
R99 [毒物学（毒理学）];
学科分类号：
100405 ;
摘要：
Our previous study indicated that Nrf2 is a key transcription factor in cellular defenses against inorganic arsenite (iAsIII). However, the role of heme oxygenase-1 (HO-1), which is regulated by Nrf2, in iAsIII-induced cytotoxicity is poorly understood. To address this issue, we examined the contribution of HO-1 to iAsIII-mediated Nrf2 activation and in protection against iAsIII cytotoxicity in HepG2 cells. Exposure of HepG2 cells to iAsIII (10 mu M) caused persistent induction of HO-1 accompanied by prolonged Nrf2 activation, whereas siRNA-mediated knockdown of HO-I decreased prolonged Nrf2 activation. Pretreatment with either HO-1 siRNA or HO inhibitor (tin protoporphyrin IX) significantly enhanced iAsIII-induced cytotoxicity. These results suggest that iAsIII-induced HO-1 appears, at least in part, to act as a positive feedback regulator of Nrf2 activation, thereby diminishing its cytotoxicity in HepG2 cells.
引用
收藏
页码：419 / 423
页数：5
相关论文
共 20 条
[1]   Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene [J].
Alam, J ;
Stewart, D ;
Touchard, C ;
Boinapally, S ;
Choi, AMK ;
Cook, JL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (37) :26071-26078
[2]   Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts [J].
Aono, J ;
Yanagawa, T ;
Itoh, K ;
Li, BJ ;
Yoshida, H ;
Kumagai, Y ;
Yamamoto, M ;
Ishii, T .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2003, 305 (02) :271-277
[3]   Arsenic induced apoptosis in rat liver following repeated 60 days exposure [J].
Bashir, S ;
Sharma, Y ;
Irshad, M ;
Nag, TC ;
Tiwari, M ;
Kabra, M ;
Dogra, TD .
TOXICOLOGY, 2006, 217 (01) :63-70
[4]   Heme oxygenase-1: Redox regulation and role in the hepatic response to oxidative stress [J].
Bauer, M ;
Bauer, I .
ANTIOXIDANTS & REDOX SIGNALING, 2002, 4 (05) :749-758
[5]   An Nrf2 small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements [J].
Itoh, K ;
Chiba, T ;
Takahashi, S ;
Ishii, T ;
Igarashi, K ;
Katoh, Y ;
Oyake, T ;
Hayashi, N ;
Satoh, K ;
Hatayama, I ;
Yamamoto, M ;
Nabeshima, Y .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 236 (02) :313-322
[6]   Carbon monoxide induces heme oxygenase-1 via activation of protein kinase R-like endoplasmic reticulum kinase and inhibits endothelial cell apoptosis triggered by endoplasmic reticulum stress [J].
Kim, Ki Mo ;
Pae, Hyun-Ock ;
Zheng, Min ;
Park, Raekil ;
Kim, Young-Myeong ;
Chung, Hun-Taeg .
CIRCULATION RESEARCH, 2007, 101 (09) :919-927
[7]   Arsenic: Signal transduction, transcription factor, and biotransformation involved in cellular response and toxicity [J].
Kumagai, Yoshito ;
Sumi, Daigo .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2007, 47 :243-262
[8]   Carbon monoxide mediates heme oxygenase 1 induction via Nrf2 activation in hepatoma cells [J].
Lee, BS ;
Heo, J ;
Kim, YM ;
Shim, SM ;
Pae, HO ;
Kim, YM ;
Chung, HT .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2006, 343 (03) :965-972
[9]   Liver is a target of arsenic carcinogenesis [J].
Liu, Jie ;
Waalkes, Michael P. .
TOXICOLOGICAL SCIENCES, 2008, 105 (01) :24-32
[10]  
Mazumder D. N. G., 2001, Journal of the Indian Medical Association, V99, P311
12