Molecular pharmacokinetic studies on changes in the expression and function of drug transporters in endotoxemia

内毒素血症药物转运蛋白表达和功能变化的分子药代动力学研究

• 批准号: 17590500
• 负责人: HASEGAWA Takaaki
• 金额: $ 2.24万
• 依托单位: Aichi Medical Univrsity
• 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-17590500/
• 关键词: Endotoxin; Drug transporter; Organic anion transport system; Renal excretion; Biliary excretion; Breast cancer resistant protein; Bcrp; 有機アニオン輸送担体; TNF-α; 6-メルカプトプリン

The effect of Klebsiella pneumoniae endotoxin on the function and expression of hepatic breast cancer resistance protein (BCRP) remains unknown. In the present study, we investigated the effect of K.pneumoniae endotoxin on the hepatobiliary excretion of mitoxantrone, a typical substrate of BCRP in mice at different times after intraperitoneal injection of endotoxin (10mg/kg of body weight). The biliary clearance of mitoxantrone significantly decreased by 40% and 70% 6 and 24 h after endotoxin injection, respectively. Both Western blot and immunofluorescence analyses revealed that BCRP expression decreased 6 and 24 h after injection of endotoxin, which were consistent with the results from in vivo experiments. These results suggest that endotoxin-induced decrease in BCRP-mediated hepatobiliary excretion is caused, in part, by down-regulation of hepatic BCRP expression. Endotoxin significantly induced the production of cytokines including interleukin-6 (IL-6) and IL-1β. Pretreatment with IL-1β did not decrease the hepatobiliary excretion of mitoxantrone and down-regulate hepatic BCRP expression. However, pretreatment with IL-6 significantly decreased the hepatobiliary excretion of mitoxantrone. Western blot and immunofluorescence analyses also revealed that pretreatment with IL-6 decreased the expression of BCRP, which is in line with in vivo experiments. These findings suggest that K.pneumoniae endotoxin decreases BCRP-mediated hepatobiliary excretion of mitoxantrone by decreasing the expression of hepatic BCRP, which is likely due to increased plasma IL-6 levels.

肺炎克雷伯菌内毒素对肝乳腺癌耐药蛋白（BCRP）功能和表达的影响尚不清楚。在本研究中，我们研究了肺炎克雷伯菌内毒素对小鼠腹腔注射内毒素（10 mg/kg体重）后不同时间的BCRP典型底物米托蒽醌肝胆排泄的影响。内毒素注射后6 h和24 h，米托蒽醌的胆汁清除率分别下降40%和70%。Western blot和免疫荧光分析均显示BCRP在注射内毒素后6 h和24 h表达下降，与体内实验结果一致。这些结果表明，内毒素诱导的BCRP介导的肝胆排泄减少部分是由肝脏BCRP表达下调引起的。内毒素可显著诱导IL-6和IL-1β等细胞因子的产生。IL-1β预处理不减少米托蒽醌的肝胆排泄，也不下调肝脏BCRP的表达。然而，用IL-6预处理显著降低了米托蒽醌的肝胆排泄。Western blot和免疫荧光分析也显示IL-6预处理降低BCRP的表达，这与体内实验一致。这些结果表明，肺炎克雷伯菌内毒素通过降低肝脏BCRP的表达，降低BCRP介导的米托蒽醌肝胆排泄，这可能是由于血浆IL-6水平升高。

项目成果

多糖体配合成分の抗腫瘍効果について

关于多糖复合成分的抗肿瘤作用

• 发表时间: 2006
• 期刊: Food Function 2
• 作者: Tomonaga T;et al.;野村 篤志
• 通讯作者: 野村 篤志

Toxicity of diazinon and its metabolites increases in diabetic rats.

• DOI: 10.1016/j.toxlet.2007.03.010
• 发表时间: 2007-05
• 期刊: Toxicology letters
• 影响因子: 3.5
• 作者: J. Ueyama;Dong Wang;T. Kondo;I. Saito;K. Takagi;K. Takagi;M. Kamijima;T. Nakajima;K. Miyamoto;S. Wakusawa;T. Hasegawa

病気と薬の説明ガイド

疾病与药物讲解指南

• 发表时间: 2007
• 作者: Takeuchi T;Nakanishi T;et al.;鈴木 裕二
• 通讯作者: 鈴木 裕二

Simultaneous determination of urinary dialkylphosphate metabolites of organophosphorus pesticides using gas chromatography-mass spectrometry

• DOI: 10.1016/j.jchromb.2005.12.030
• 发表时间: 2006-02-17
• 期刊: JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
• 影响因子: 3
• 作者: Ueyama, J;Saito, I;Takagi, K
• 通讯作者: Takagi, K

The pharmacokinetic properties of methamphetamine in rats with previous repeated exposure to methamphetamine: The differences between Long-Evans and Wistar rats

• DOI: 10.1538/expanim.56.119
• 发表时间: 2007-04-01
• 期刊: EXPERIMENTAL ANIMALS
• 影响因子: 2.4
• 作者: Fujimoto, Yohei;Kitaichi, Kiyoyuki;Hasegawa, Takaaki
• 通讯作者: Hasegawa, Takaaki