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.

肝癌抗癌蛋白（BCRP）Res研究的肺炎肺炎内毒素的作用，我们研究了K.pneumoniae内毒素对Mitoxantrone的肝胆管毒素的影响，MITOXANTRONE的肝脏排泄，BCRP典型的bcrp the Intaperapter in Intapaperitoxin（Intaperitoxin）的典型底物（Intapaperitoxin Afterapaptical of Aftaaperitial of Aftaaperitial time Intaaperitoxin（10M）KG体重）。注射内毒素后的40％和70％6和24小时。 - 内毒素的调节可显着诱导细胞因子的生产-6降低了BCRP的表达，这些发现表明，KA RP介导的肝胆管排泄Mitoxantrone通过降低肝BCRP的表达，这可能是由于血浆IL-6水平升高所致。

项目成果

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

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

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

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

Effect of Shiga-like toxin II from Escherichia coli O157:H7 on intestinal clearance of norfloxacin in rats

大肠杆菌 O157:H7 志贺样毒素 II 对大鼠诺氟沙星肠道清除率的影响

• 发表时间: 2006
• 期刊: Life Sci. 78
• 作者: M. Masuda;et. al.;Ando S;Mari Sampei et al.;H.Nakayama
• 通讯作者: H.Nakayama