Role of tumor necrosis factor-α in down-regulation of hepatic cytochrome P450 and P-glycoprotein by endotoxin
Role of tumor necrosis factor-α in down-regulation of hepatic cytochrome P450 and P-glycoprotein by endotoxin
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DOI：
10.1016/j.ejphar.2004.11.035
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发表时间：
2005-01-10
影响因子：
5
通讯作者：
Hasegawa, T
中科院分区：
文献类型：
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作者：
Miyoshi, M;Nadai, M;Hasegawa, T
我们使用肿瘤坏死因子-α基因缺陷（TNF-α（-/-））小鼠研究了肿瘤坏死因子-α（TNF-α）在内毒素下调肝脏P-糖蛋白和细胞色素P450（CYP）中的作用。在P-糖蛋白的情况下，内毒素（10 mg/kg）显著降低野生型小鼠肝脏P-糖蛋白的表达6 h。但不是24小时。腹腔注射后。在野生型小鼠和TNF-α（-/-）小鼠之间，P-糖蛋白的结构表达没有差异。然而.内毒素对TNF-α（-/-）小鼠P-糖蛋白表达无影响。当多柔比星静脉给药时，6小时前用和不用内毒素处理的TNF-α（-/-）小鼠，在注射后3小时，内毒素处理和未处理的TNF-α（-/-）小鼠之间未观察到多柔比星血浆浓度的显著差异。这些结果表明，TNT-α在内毒素下调P-糖蛋白中起关键作用。TNF-α（-/-）小鼠肝脏CYP 3A 2和CYP 2C 11的组成型表达较xvild型小鼠有下降趋势。注射内毒素后24 h，野生型小鼠肝脏CYP 3A 2和CYP 2C 11的表达显著降低，TNF-α（-/-）小鼠的表达降低程度显著大于野生型小鼠。当静脉注射安替比林给野生型小鼠和TNF-α-/-小鼠24小时前用内毒素处理时，注射后3小时TNF-α（-/-）小鼠的血浆安替比林浓度显著高于野生型小鼠。这些结果表明，TNF-α在内毒素诱导的肝脏P-糖蛋白下调中起关键作用，并在调节肝脏CYP 3A 2和CYP 2C 11对抗内毒素诱导的急性炎症反应中起保护作用。在TNF-α（-/-）小鼠中，其它细胞因子似乎起着补偿内源性TNF-α缺乏的作用。(C)2004 Elsevier B. V.保留所有权利。
We investigated the role of tumor necrosis factor-alpha (TNF-alpha) in the down-regulation of hepatic P-glycoprotein and cytochrome P450 (CYP) by endotoxin, using TNF-alpha gene-deficient (TNF-alpha(-/-)) mice. In the case of P-glycoprotein, endotoxin (10 mg/kg significantly decreased the expression of hepatic P-glycoprotein in wild-type mice 6 h. but not 24 h. after intraperitoneal injection. with no differences in the constitutional expression of P-glycoprotein between wild-type mice and TNF-alpha(-/-) mice. However. endotoxin had no effect on the expression of P-glycoprotein in TNF-alpha(-/-) mice either 6 or 24 h after injection. When doxorubicin was administered intravenously, to TNF-alpha(-/-) mice treated 6 h earlier with and without endotoxin, no significant differences in the plasma concentrations of doxorubicin 3 h after injection were observed between endotoxin-treated and untreated TNF-alpha(-/-) mice. These results suggest that TNT-alpha plays a pivotal role in the down-regulation of P-glycoprotein by endotoxin. In the case of CYP, the constitutive expression of hepatic CYP3A2 and CYP2C11 had a tendency to decline in TNF-alpha(-/-) mice compared with that in xvild-type mice. Endotoxin significantly decreased the expression of hepatic CYP3A2 and CYP2C11 in wild-type mice 24 h after injection, and that decreased expression was significantly greater in TNF-alpha(-/-) mice than wild-type mice. When antipyrine Was administered intravenously to wild-type mice and TNF-alpha-/- mice treated 24 h earlier with endotoxin, the plasma concentrations of antipyrine in TNF-alpha(-/-) mice 3 h after injection were significantly higher than those in wild-type mice. These findings suggest that TNF-alpha plays a key role in endotoxin-induced down-regulation of hepatic P-glycoprotein, as well as plays a protective role in the regulation of hepatic CYP3A2 and CYP2C11 against endotoxin-induced acute inflammatory response. in TNF-alpha(-/-) mice, other cytokines appear to function as compensation for the lack of endogenous TNF-alpha. (C) 2004 Elsevier B.V. All rights reserved.