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学科主题: 基础医学
题名:
Loss of 5-lipoxygenase activity protects mice against paracetamol-induced liver toxicity
作者: Pu, Shiyun1; Ren, Lin1; Liu, Qinhui2; Kuang, Jiangying1; Shen, Jing1; Cheng, Shihai1; Zhang, Yuwei3; Jiang, Wei4,5; Zhang, Zhiyong1; Jiang, Changtao6; He, Jinhan1,2
刊名: BRITISH JOURNAL OF PHARMACOLOGY
发表日期: 2016
DOI: 10.1111/bph.13336
卷: 173, 期:1, 页:66-76
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy
关键词[WOS]: ACTIVATED-RECEPTOR-ALPHA ; PREGNANE-X RECEPTOR ; PPAR-ALPHA ; ACETAMINOPHEN HEPATOTOXICITY ; CONCISE GUIDE ; CYTOCHROME-P450 ENZYMES ; ARRIVE GUIDELINES ; OXIDATIVE STRESS ; GENE-EXPRESSION ; PHARMACOLOGY
英文摘要:

Background and PurposeParacetamol (acetaminophen) is the most widely used over-the-counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5-Lipoxygenase (5-LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5-LO could protect mice against paracetamol-induced hepatic toxicity.

Experimental ApproachBoth genetic deletion and pharmacological inhibition of 5-LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real-time PCR were used to assess liver toxicity.

Key ResultsDeletion or pharmacological inhibition of 5-LO in mice markedly ameliorated paracetamol-induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5-LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro-toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5-LO-/- mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR , a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5-LO-/- mice.

Conclusions and ImplicationsThe activity of 5-LO may play a critical role in paracetamol-induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress.

语种: 英语
所属项目编号: 81270926 ; 81471068 ; 2014JQ0034 ; 2013SCU04A17
项目资助者: National Science Foundation of China ; Distinguished Young Scientists of Sichuan Province ; Young Scientist Fellowship of Sichuan University
WOS记录号: WOS:000366977000006
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内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/66101
Appears in Collections:基础医学院_期刊论文

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作者单位: 1.Sichuan Univ, West China Hosp, Dept Pharm, Collaborat Innovat Ctr Biotherapy, Chengdu 610064, Sichuan, Peoples R China
2.Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, Lab Clin Pharm & Adverse Drug React, Chengdu 610064, Sichuan, Peoples R China
3.Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, Div Endocrinol & Metab, Chengdu 610064, Sichuan, Peoples R China
4.Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, Mol Med Res Ctr,State Key Lab Biotherapy, Chengdu 610064, Sichuan, Peoples R China
5.Sichuan Univ, West China Hosp, Ctr Canc, Collaborat Innovat Ctr Biotherapy, Chengdu 610064, Sichuan, Peoples R China
6.Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Beijing 100871, Peoples R China

Recommended Citation:
Pu, Shiyun,Ren, Lin,Liu, Qinhui,et al. Loss of 5-lipoxygenase activity protects mice against paracetamol-induced liver toxicity[J]. BRITISH JOURNAL OF PHARMACOLOGY,2016,173(1):66-76.
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