Novel protective mechanisms for cholestatic hepatotoxicity-application to drug improving hepatic function

胆汁淤积性肝毒性的新保护机制——改善肝功能药物的应用

• 批准号: 17590114
• 负责人: MIYATA Masaaki
• 金额: $ 2.24万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590114/
• 关键词: lithocholic acid; lipid metabolism; microarray; PCN; hepatotoxicity; cholestasis; phospholipid; リン脂質

Lithocholic acid (LCA) administration to experimental animals is known to cause delayed cholestatic liver injury. Protective mechanisms of LCA-induced liver damage were analyzed by co-treatment of mice with pregnenolone-16 a -carbonitrile (PCN) or quinacrine. First, we tried to explore a novel protective mechanism for LCA-induced cholestatic liver injury using microarray analysis. Time-dependent changes in gene expression and liver damage diagnostic markers were analyzed in mice fed a 0.6% LCA diet for 3 days (LCA3), 5 days (LCA5) and 9 days (LCA9). Significant increases in serum alanine aminotransferase and alkaline phosphatase activities were found in LCA5 and LCA9, respectively. More than 2-fold changes relative to control group were found in 57 (LCA3), 271 (LCA5) and 1426 (LCA9) out of 8451 probes in microarray assays. In this study, we have focused on lipid metabolism and transport. Expression levels of annexin A2 and phospholipid scramblase 1 were markedly increased in LCA5 and L … More CA9. Those of phosphatidic acid phosphatase 2A, 2C and lipoprotein lipase were also increased in LCA9. Marked changes in gene expression involved in lipid transfer between liver and plasma were also found in LCA9. On the other hand, decreases in gene expression involved in the energy production system such as β-oxidation and TCA cycle were observed in a time-dependent manner in LCA-fed mice. These data suggest disruption of lipid metabolism and transport in LCA-fed mice. These changes disappeared in mice co-treated with pregnenolone-16 a-carbonitrile (PCN) which protects against LCA-induced toxicity. Hepatic phospholipid, triacylglycerol and biliary phospholipid concentrations were decreased in LCA9, whereas the concentrations were increased in LCA/PCN co-treated mice. Furthermore, co-treatment of mice with phospholipase A2 inhibitor, quinacrine decreased LCA-induced liver injury and increased hepatic phospholipids concentration. These results suggest that the enhancement of hepatic phospholipids level is one of the protective mechanisms for LCA-induced cholestatic liver injury. Less

石胆酸（LCA）给药可引起迟发性胆汁淤积性肝损伤。通过孕烯醇酮-16 a -碳腈（PCN）和醌（quinacrine）对lca诱导小鼠肝损伤的保护机制进行了分析。首先，我们试图利用微阵列分析探索lca诱导的胆汁淤积性肝损伤的一种新的保护机制。分析0.6% LCA饲喂3 d （LCA3）、5 d （LCA5）和9 d （LCA9）小鼠基因表达和肝损伤诊断标志物的时间依赖性变化。LCA5和LCA9的血清丙氨酸转氨酶和碱性磷酸酶活性均显著升高。在8451个探针中，有57个（LCA3）、271个（LCA5）和1426个（LCA9）的变化是对照组的2倍以上。在本研究中，我们主要关注脂质代谢和转运。LCA5和lca9中膜联蛋白A2和磷脂超燃酶1的表达水平显著升高。LCA9中磷脂酸磷酸酶2A、2C和脂蛋白脂肪酶的表达均升高。在LCA9中还发现了肝脏和血浆之间脂质转移相关基因表达的显著变化。另一方面，在lca喂养的小鼠中，以时间依赖性的方式观察到与β-氧化和TCA循环等能量产生系统相关的基因表达减少。这些数据表明，lca喂养的小鼠脂质代谢和运输受到破坏。这些变化在与孕烯醇酮-16 a-碳腈（PCN）共处理的小鼠中消失，PCN可以保护小鼠免受lca诱导的毒性。LCA9组小鼠肝脏磷脂、甘油三酯和胆道磷脂浓度降低，而LCA/PCN组小鼠肝脏磷脂、甘油三酯和胆道磷脂浓度升高。此外，与磷脂酶A2抑制剂奎纳克里共处理小鼠可减轻lca诱导的肝损伤，并增加肝脏磷脂浓度。提示肝脏磷脂水平升高是lca诱导的胆汁淤积性肝损伤的保护机制之一。少

项目成果

Role for enhanced fecal excretion of bile acid in hydroxysteroid sulfotransferase-mediated protection against lithocholic acid-induced liver toxicity

增强胆汁酸粪便排泄在羟基类固醇磺基转移酶介导的针对石胆酸诱导的肝毒性的保护中的作用

• 发表时间: 2006
• 期刊: Xenobiotica 36
• 作者: M.Miyata;H.Watase;W.Hori;M.Shimada;K.Nagata;F.J.Gonzalez;Y.Yamazoe
• 通讯作者: Y.Yamazoe

Chenodeoxycholic acid-mediated activation of the famesoid X receptor negatively regulates hydroxysteroid sulfotransferase

鹅去氧胆酸介导的法尼醇 X 受体激活负向调节羟基类固醇磺基转移酶

• 发表时间: 2006
• 期刊: Drug Metab. Pharmacokin. 21
• 作者: M.Miyata;Y.Matsuda;H.Tsuchiya;H.Kitada;T.Akase;M.Shimada;K.Nagata;F.J.Gonzalez;Y.Yamazoe
• 通讯作者: Y.Yamazoe

Chenodeoxycholic acid-mediated activation of the farnesoid X receptor negatively regulates hydroxysteroid sulfotransferase

• DOI: 10.2133/dmpk.21.315
• 发表时间: 2006-01-01
• 期刊: DRUG METABOLISM AND PHARMACOKINETICS
• 影响因子: 2.1
• 作者: Miyata, Masaaki;Matsuda, Yoshiki;Yamazoe, Yasushi
• 通讯作者: Yamazoe, Yasushi