Elucidation of physiological role of nitric oxide (NO) and cytokines in endotoxemia

阐明一氧化氮 (NO) 和细胞因子在内毒素血症中的生理作用

• 批准号: 11672296
• 负责人: HASEGAWA Takaaki
• 金额: $ 2.24万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672296/
• 关键词: endotoxin; cytokine; nitric oxide; hepatic drug-metabolizing enzyme; P-glycoproten; transport; 肝薬物代謝酵素活性; 一酸化窒素合成酵素阻害薬; 一酸化窒素発生薬; 薬物動態学

First, we investigated the role of nitric oxide (NO) in the decrease in hepatic drug-metabolizing enzyme activity caused by endotoxin (LPS) in vivo. Intraperitoneal injection of LPS (1 mg/kg) dramatically decreased the systemic clearance of AP, reflecting reduced hepatic drug-metabolizing enzyme activity, and significantly increased the level of nitrite and nitrate (NOx) in the plasma. iNOS inhibitor (10 mg/kg) reversed this decreasing AP clearance and reduced the level of NOx in plasma. The NO donor (FK-409) also decreased the systemic clearance of AP.These findings strongly suggest that excess NO plays a key role in the LPS-induced decreases in hepatic P450-mediated drug-metabolizing enzyme activity. These results caution that gram-negative bacterial infection may increase the risk of the side effects of some drugs, especially those which are metabolized mainly by the liver, and suggest that more selective iNOS inhibitors may be useful drugs for ameliorating these endotoxin-induced changes. Second, we investigated the effect of LPS on P-glycoprotein (P-gp)-mediated biliary and renal transport in vivo. LPS dramatically decreased both biliary and renal excretion of the P-gp substrate rhodamine 123 (Rho) 6 h after injection of LPS.TNF-α inhibitor, but not iNO inhibitor, protected LPS-induced decreases in the biliary and renal clearance of Rho. It was found that these decreases are caused by overproduction of TNF-α in plasma, but not by overproduction of NO.In addition, these decreases were correlated well with LPS-induced decreases in the expression of mdr1a mRNA in both livers and kidneys. This study suggests that LPS dramatically decreases P-gp-mediated biliary and renal transport by decreasing the expression of mdr1a mRNA, probably due to LPS-released cytokine, TNF-α.

首先，一氧化氮（NO）在内毒素（LPS）作用的肝药物 - 代谢酶减少中的作用。行为，显着提高了硝酸盐和硝酸盐的水平（NOX），或者（10 mg/kg）恢复了AP的降低，并降低了NOX的水平。过多的作用在HEPA TIC P450介导的药物 - 代谢酶活性中诱导了脱位。有用的药物来促进内毒素诱导的变化，我们研究了LPS对P-糖蛋白（P-gp）介导的胆汁肛门转运的影响。 α抑制剂，但不是INO抑制剂，在血浆中，胆汁和清除率降低了LPS诱导的LPS诱导的降低。 MDR1A在肝脏和肾脏中的表达和肾脏转运。

项目成果

Kitaichi K., Wang L., Takagi K., Iwase M., Shibata E., Nadai M., Takagi K., Hasegawa T.: "Decreased antipyrine clearance following endotoxin administration : in vivo evidence of the role of nitric oxide."Antimicrob.Agents Chemother.. 43. 2697-2701 (1999)

Kitaichi K.、Wang L.、Takagi K.、Iwase M.、Shibata E.、Nadai M.、Takagi K.、Hasekawa T.：“内毒素给药后安替比林清除率降低：一氧化氮作用的体内证据。

Iwase M.,Yokota M.,Kitaichi K.,Wang L., et al.: "Cardiac functional and structural alterations induced by endotoxin in rats : importance of platelet-activating factor"Crit.Care Med.(in press). 29. (2001)

Iwase M.、Yokota M.、Kitaichi K.、Wang L. 等人：“内毒素诱导的大鼠心脏功能和结构改变：血小板激活因子的重要性”Crit.Care Med.（出版中）。

Hasegawa T.,Takagi K.,Kitaichi K.: "Effects of bacterial endotoxin on drug pharmacokinetics"Nagoya J.Med.Sci.. 62. 11-28 (1999)

长谷川 T.、高木 K.、北一 K.：“细菌内毒素对药物药代动力学的影响”Nagoya J.Med.Sci.. 62. 11-28 (1999)

Naruhashi K.,Nadai M.,Nakao M.,Suzuki N.,Nabeshina T.,Hasegawa T.: "Changes in absorptive function of rat intestine injured by methotrexate"Clin.Exp.Pharmacol.Physiol.. 27. 980-986 (2000)

Naruhashi K.、Nadai M.、Nakao M.、Suzuki N.、Nabeshina T.、Hasekawa T.：“甲氨蝶呤损伤大鼠肠道吸收功能的变化”Clin.Exp.Pharmacol.Physiol.. 27. 980-986

Naruhashi K., Nadai M., Nakao M., Suzuki N., Nabeshima T., Hasegawa T.: "Changes in absorptive function of rat intestine injured by methotrexate."Clin.Exp.Pharmacol.Physiol.. 27. 980-986 (2000)

Naruhashi K.、Nadai M.、Nakao M.、Suzuki N.、Nabeshima T.、Hasekawa T.：“甲氨蝶呤损伤大鼠肠道吸收功能的变化。”Clin.Exp.Pharmacol.Physiol.. 27. 980-