Mechanism of expression and function of drug transporters in endotoxemia

内毒素血症药物转运蛋白的表达和功能机制

• 批准号: 20590587
• 负责人: HASEGAWA Takaaki
• 金额: $ 3.16万
• 依托单位: Aichi Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20590587/
• 关键词: エンドトキシン; トランスポーター; サイトカイン; 生体膜輸送; 薬物トランスポーター; 胆汁排泄; ミカファンギン; 有機アニオン輸送系; 尿細管分泌; パラアミノ馬尿酸; Bcrp; CYP3A2; IL-6

Firstly, the effect of endotoxin (ET) on the function and expression of hepatic breast cancer resistance protein (Bcrp) was investigated in mice. In vivo clearance experiments showed that the biliary clearance (CL_<BILE>) of mitoxantrone was significantly decreased 24 h after ET injection. Both Western blot and immunofluorescence analyses also revealed that the protein levels of hepatic Bcrp were decreased 24 h after injection of ET. ET significantly induced the overproduction of the cytokines IL-6 and IL-1β. Pretreatment with IL-6 significantly decreased the CL_<BILE> of mitoxantrone. Hepatic Bcrp was significantly down-regulated by injection of IL-6 (50,000U/mouse). These findings suggest that ET reduces Bcrp-mediated hepatobiliary excretion of mitoxantrone by decreasing the expression of hepatic Bcrp, which is likely due to increased IL-6 levels. Secondly, to clarify ET-induced changes in organic anion transport ability, GFR and renal tubular secretion clearance of PAH which is a substrate for renal organic anion transporter 1 (Oat1) and Oat3 were investigated in endotoxemic rats. The expression of Oat1 and Oat3 mRNA was decreased, and the expression returned to control levels after 72 h after injection of ET. These findings suggest that the decreased mRNA levels of renal Oat1 and Oat3 are involved in the decreased renal tubular secretion clearance of PAH in endotoxemic rats and that these changes are transient and recovered time-dependently.

首先，研究了内毒素(ET)对小鼠肝乳腺癌耐药蛋白(BCRP)功能和表达的影响。体内清除实验表明，注射ET后24 h，米托蒽醌的胆汁清除量(CL&lt；胆汁&Gt；)显著降低。免疫印迹和免疫荧光分析也显示，注射ET后24 h，肝脏BCRP蛋白水平降低。ET可显著诱导细胞因子IL-6和IL-1β的过度产生。IL-6可显著降低米托蒽醌对胆汁的CL_1和GT_1。注射IL-6(50000U/只)可显著下调肝脏BCRP的表达。这些发现提示ET通过降低肝脏BCRP的表达来减少BCRP介导的米托蒽醌的排泄，这可能是由于IL-6水平升高所致。其次，观察内毒素血症大鼠肾脏有机阴离子转运体1(OAT1)和OAT3的底物PAH的GFR和肾小管分泌清除量，以阐明ET对有机阴离子转运能力的影响。注射ET后72h，OAT1、OAT3mRNA表达下降，72h后恢复至正常水平。提示内毒素血症大鼠肾组织OAT1和OAT3基因表达水平降低与肾小管分泌PAH清除量减少有关，且这些变化是短暂的，且具有时间依赖性。

项目成果

Naofen, a novel WD40-repeat protein, mediates spontaneous and tumor necrosis factor-induced apoptosis

• DOI: 10.1016/j.bbrc.2010.02.133
• 发表时间: 2010-03-26
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Feng, Guo-Gang;Li, Chang;Ishikawa, Naohisa
• 通讯作者: Ishikawa, Naohisa

Cyclooxygenenase-2 expression in invasive transitional cell carcinoma of the urinary bladder

膀胱浸润性移行细胞癌中环氧合酶-2的表达

• 发表时间: 2008
• 期刊: Mo1. Med. Reports 1
• 作者: Arakawa M;Saito H;Hasegawa T;Kato Y;Ishikawa K;Jun Ueyama;Jun Ueyama;Fumie Abe;Jun Ueyama;Fumie Abe;Yoshiyuki Yamada
• 通讯作者: Yoshiyuki Yamada

Enhanced expression of naofen in kidney of streptozotocin-induced diabetic rats: possible correlation to apoptosis of tubular epithelial cells

• DOI: 10.1007/s10157-010-0276-1
• 发表时间: 2010-06-01
• 期刊: CLINICAL AND EXPERIMENTAL NEPHROLOGY
• 影响因子: 2.3
• 作者: Sato, Yuko;Feng, Guo-Gang;Ishikawa, Naohisa
• 通讯作者: Ishikawa, Naohisa

Active ingredients of traditional Japanese (kampo) medicine, inchinkoto, in murine concanavalin A-induced hepatitis

• DOI: 10.1016/j.jep.2009.11.029
• 发表时间: 2010-02-17
• 期刊: JOURNAL OF ETHNOPHARMACOLOGY
• 影响因子: 5.4
• 作者: Mase, Akihito;Makino, Bunsho;Hasegawa, Takaaki
• 通讯作者: Hasegawa, Takaaki

Involvement of multidrug resistance-associated protein 2 (ABCC2/Mrp2) in biliary excretion of micafungin in rats.

多药耐药相关蛋白 2 (ABCC2/Mrp2) 参与大鼠米卡芬净胆汁排泄。

• DOI: 10.1016/j.lfs.2008.06.013
• 发表时间: 2008
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: F. Abe;J. Ueyama;Akiko Kimata;Miki Kato;Tamon Hayashi;M. Nadai;H. Saito;N. Takeyama;H. Noguchi;T. Hasegawa
• 通讯作者: T. Hasegawa