异甘草素对醋氨酚诱导的急性肝细胞损伤的保护作用

中国临床药理学与治疗学 ›› 2008, Vol. 13 ›› Issue (3): 293-298.

异甘草素对醋氨酚诱导的急性肝细胞损伤的保护作用

章道华^1,2, 叶岚岚¹, 程昊¹, 余伟¹, 杨静¹, 郭鹏²

¹武汉大学基础医学院药理学系;
²武汉大学药学院药物化学系, 武汉430071, 湖北

收稿日期:2007-08-17 修回日期:2007-08-17 发布日期:2020-10-15
通讯作者: 郭鹏, 男, 医学博士, 教授, 研究方向:手性药物分子设计与合成。Tel:027-68753581 E-mai l:guopeng @whu.edu.cn;杨静, 男, 教授, 博士生导师, 研究方向:分子药理和新药研究。Tel:027-68758665 E-mai l:yangjingliu @yahoo.com.cn

Cytoprotective effect and its mechanisms of isoliquiritigenin on acetaminophen induced acute injury of hepatocytes

ZHANG Dao-hua^1,2, YE Lan-lan¹, CHENG Hao¹, YU Wei¹, YANG Jing¹, GUO Peng²

¹Department of Pharmacology of Basic Medical College;
²Department of Chemical Pharmacy of Pharmacy College,Wuhan University, Wuhan 430071, Hubei, China

Received:2007-08-17 Revised:2007-08-17 Published:2020-10-15

摘要/Abstract

摘要： 目的研究异甘草素(isoliquiritigenin, ISL)对醋氨酚(AAP)诱导的肝细胞损伤的保护作用及机制。方法以AAP 20 mmol L 培养原代肝细胞12 h 造成急性化学性肝损伤模型。肝细胞随机分为正常组,AAP 损伤组, ISL 预处理组和ISL 加N-硝基-L-精氨酸甲酯(L-NAME)预处理组。酶学测定培养液ALT 、AST 活性, 肝细胞CYP2E1 活性和谷胱甘肽(GSH)含量, RT-PCR 测定肝细胞CYP2E1 mRNA 表达水平, 放射免疫分析测定肝细胞cAMP 和cGMP 含量, 三明治ELISA 方法测定核转录调节因子(NF-κB 等)活性。结果 ISL 浓度(5~ 20 μmol L)依赖性抑制AAP 引起的ALT 和AST升高;下调肝细胞CYP2E1 活性和mRNA 表达, 最大抑制率分别可达75.7%和78.7%, 同时明显抑制AAP 引起的肝细胞GSH 含量下降;加入LNAME 2.0 mmol L 可阻断ISL 20 μmol L 对肝细胞的保护作用;ISL 不能逆转AAP 引起的肝细胞cAMP 含量下降, 但可浓度依赖性提高cGMP 含量(最高可达4.75 倍);ISL 浓度依赖性抑制AAP 所致NF-κB 活性的提高, 抑制率分别为24.8%、37.3%和64.1%。结论 ISL 对CYP2E1 介导的AAP 肝细胞损伤具有保护作用, 可能与通过NOcGMP通路, 抑制NF-κB 激活和下调CYP2E1 表达有关。

关键词: 异甘草素, 醋氨酚, 肝细胞, CYP2E1, 环鸟苷酸

Abstract: AIM: To study the cytoprotective action and mechanisms of isoliquiritigenin(ISL)on acute injury of hepatocytes induced by acetaminophen. METHODS: Rat hepatocytes in sandwich cultures were randomly divided into control group, model group, ISL group and ISL plus L-NAME groups.The acute injury of hepatocytes was induced by being exposed into acetaminophen (20 mmol L)for 12 h.In the pretreatment groups, L-NAME and or ISL were given before administration of acetaminophen.The activities of ALT and AST in medium were measured by using enzyme assays.The CYP2E1 expression in hepatocytes was determined by using enzyme assays and semiquantitative RT-PCR.The contents of cGMP and cAMP in hepatocytes were measured by radioimmunoassay.The activites of nuclear transcription regulation factors such as NF-κB were determined by sandwich ELISA. RESULTS: ISL (5-20 μmol L)reduced the increase of the ALT and AST levels dose-dependently. And the cytochrome P450(CYP)2E1(aniline hydroxylase, ANH)activity was decreased by 75.7% maximumly and the mRNA expression was inhibited in a dose (50-200 μg mL)dependent manner, the maximum inhibitory rate was 78.7%.In addition, ISL remarkably increased the glutathione content decreased by acetaminophen of hepatocytes. L-NAME (2 mmol L)could reverse the protective effect of ISL (20 μmol L).ISL could not reverse the decrease of the level of cAMP induced by acetaminophen of hepatocytes but ISL could dose-dependently enhance the intracellular cGMP content (to 4.75 times maximumly)and suppress the NF-κB activation, the inhibitory rates were 24.8%,37.3% and 64.1%. CONCLUSION: ISL can protect the injury of hepatocytes induced by acetaminophen.It may be relate to the inhibition of NF-κB activation and down regulation of CYP2E1 expression via NO-cGMP pathways.

Key words: isoliquiritigenin, acetaminophen, hepatocyte, CYP2E1, cGMP

中图分类号:

R965.2

章道华, 叶岚岚, 程昊, 余伟, 杨静, 郭鹏. 异甘草素对醋氨酚诱导的急性肝细胞损伤的保护作用[J]. 中国临床药理学与治疗学, 2008, 13(3): 293-298.

ZHANG Dao-hua, YE Lan-lan, CHENG Hao, YU Wei, YANG Jing, GUO Peng. Cytoprotective effect and its mechanisms of isoliquiritigenin on acetaminophen induced acute injury of hepatocytes[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(3): 293-298.

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