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

点击翻译按钮获取中文摘要

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.