Bile acids, key compounds for the mechanistic analyses of hepatotoxicity, and nuclear receptor interaction

胆汁酸，肝毒性机制分析和核受体相互作用的关键化合物

• 批准号: 15390043
• 负责人: YAMAZOE Yasushi
• 金额: $ 9.79万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390043/
• 关键词: hepatotoxicity; nuclear receptor; induction; Bile acid; Liver toxicity; FXR; PXR; Lithocholic acid

Supplement of 1% lithocholic acid (LCA) in the diet for 5-9 days resulted in elevated levels of the marker for liver damage aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities in both FXR-null and wild-type female mice. The levels were clearly higher in wild-type mice than in FXR-null mice. Consistent with liver toxicity marker activities, serum and liver levels of bile acids, particularly LCA and tauroLCA, were clearly higher in wild-type mice than in FXR-null mice after 1% LCA supplement. Marked increases in hepatic sulfating activity for LCA (5.5-fold) and hydroxysteroid sulfotransferase St2a (5.8-fold) were detected in liver of FXR-null mice. A 7.4-fold higher 3a-sulfated bile acid concentration was observed in gallbladder bile of FXR-null mice fed a LCA diet compared to that of wild-type mice. These results indicate that LCA sulfation catalyzed by hydroxysteroid sulfotransferase is at least one pathway for protection against LCA-induced liver damage. Further … More more, northern blot analysis using FXR-null, PXR-null and FXR-PXR double-null mice suggests a repressive role of these nuclear receptors on basal St2a expression.FXR-null mice are highly sensitive to cholic acid (CA)-induced liver toxicity. AST activity was elevated 15.7-fold after feeding a 0.25% CA diet, whereas only slight increases in serum AST (1.7-fold and 2.5-fold) were observed in wild-type mice fed 0.25% and 1% CA diet, respectively. The bile acid output rate was 2.0-fold and 3.7-fold higher after feeding of 0.25 and 1.0% CA diet in wild-type mice, respectively. On the other hand, no significant increase in bile acid output rate was observed in FXR-null mice fed 0.25% CA diet in contrast to a significant decrease observed in mice fed a 1.0% CA diet in spite of the markedly higher levels of hepatic tauro-conjugated bile acids. These results suggest that the CA-induced enhancement of canalicular bile acid output rate is involved in adaptive responses for prevention of CA-induced toxicity. Less

在饲料中添加1%石胆酸(LCA)5-9天后，FXR基因缺失和野生型雌性小鼠肝损伤标志物天冬氨酸氨基转移酶(AST)和碱性磷酸酶(ALP)活性均升高。野生型小鼠的这一水平明显高于FXR基因缺失小鼠。与肝脏毒性标记物活性一致，补充1%LCA后，野生型小鼠的血清和肝脏胆汁酸水平，特别是LCA和tauroLCA，明显高于FXR缺陷型小鼠。在FXR基因缺失小鼠的肝脏中，LCA的硫酸盐化活性(5.5倍)和羟基类固醇磺基转移酶St2a(5.8倍)显著增加。与野生型小鼠相比，饲喂LCA饮食的FXR基因缺失小鼠的胆汁中3a-硫酸盐胆汁酸浓度增加了7.4倍。这些结果表明，羟基类固醇磺基转移酶催化的LCA硫化至少是保护LCA所致肝损伤的一条途径。进一步的…此外，对FXR缺失、PXR缺失和FXR-PXR双缺失小鼠的Northern印迹分析表明，这些核受体对基础St2a的表达具有抑制作用。FXR缺失小鼠对胆酸(CA)诱导的肝脏毒性高度敏感。饲喂0.25%CA饲料后，AST活性提高15.7倍，而饲喂0.25%和1%CA饲料的野生型小鼠血清AST仅轻微升高(1.7倍和2.5倍)。野生型小鼠饲喂0.25%和1.0%CA饲料后，胆汁酸产生率分别提高2.0倍和3.7倍。另一方面，尽管肝脏牛磺酸结合胆汁酸水平显著升高，但饲喂0.25%CA饲料的FXR基因缺失小鼠的胆汁酸产量没有显著增加，而饲喂1.0%CA饲料的小鼠的胆汁酸产量显著降低。这些结果表明，CA诱导的小管胆汁酸产量的增加参与了预防CA毒性的适应性反应。较少

项目成果

Role of farnesoid X receptor in the enhancement of canalicular bile acid output and excretion of unconjugated bile acids: A mechanism for protection against cholic acid-induced liver toxicity

• DOI: 10.1124/jpet.104.076158
• 发表时间: 2005-02-01
• 期刊: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
• 影响因子: 3.5
• 作者: Miyata, M;Tozawa, A;Yamazoe, Y
• 通讯作者: Yamazoe, Y

M.Miyata: "Thalidomide-induced suppression of embryo fibroblast proliferation requires CYP1A1-mediated activation"Drug Metab.Dispos.. 31. 469-475 (2003)

M.Miyata：“沙利度胺诱导的胚胎成纤维细胞增殖抑制需要 CYP1A1 介导的激活”Drug Metab.Dispos.. 31. 469-475 (2003)

Regulation of drug transporter by femesoid X receptor in mice

femesoid X 受体对小鼠药物转运蛋白的调节

• 发表时间: 2004
• 期刊: Mol.Pharmaceutics 1
• 作者: Masaki Fujieda et al.;Suzuki et al.;T.Maeda
• 通讯作者: T.Maeda

Regulation of drug transporter by fernesoid X receptor in mice.

小鼠体内 Fernesoid X 受体对药物转运蛋白的调节。

• 发表时间: 2004
• 期刊: Mol.Pharmaceutics 1
• 作者: T.Maeda;M.Miyata;T.Yotsumoto;D.Kobayashi;T.Nozawa;K.Toyama;F.J.Gonzalez;Y.Yamazoe;I.Tamai
• 通讯作者: I.Tamai

M.Miyata: "Grapefruit juice intake does not enhance but rather protects against aflatoxin B1-induced liver DNA damage through a reduction in hepatic CYP3A activity"Carcinogenesis. 25. 203-209 (2003)

M.Miyata：“摄入葡萄柚汁不会增强而是通过降低肝脏 CYP3A 活性来防止黄曲霉毒素 B1 诱导的肝脏 DNA 损伤”致癌作用。