Role of tumor necrosis factor-α in down-regulation of hepatic cytochrome P450 and P-glycoprotein by endotoxin

Mika Miyoshi, Masayuki Nadai, Atsumi Nitta, Jun Ueyama, Akemi Shimizu, Kenji Takagi, Toshitaka Nabeshima, Kenzo Takagi, Kuniaki Saito, Takaaki Hasegawa

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Abstract

We investigated the role of tumor necrosis factor-α (TNF-α) in the down-regulation of hepatic P-glycoprotein and cytochrome P450 (CYP) by endotoxin, using TNF-α gene-deficient (TNF-α-/-) 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 significant differences in the constitutional expression of P-glycoprotein between wild-type mice and TNF-α -/- mice. However, endotoxin had no effect on the expression of P-glycoprotein in TNF-α-/- mice either 6 or 24 h after injection. When doxorubicin was administered intravenously to TNF-α-/- 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-α-/- mice. These results suggest that TNF-α 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-α-/- mice compared with that in wild-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-α-/- mice than wild-type mice. When antipyrine was administered intravenously to wild-type mice and TNF-α-/- mice treated 24 h earlier with endotoxin, the plasma concentrations of antipyrine in TNF-α-/- mice 3 h after injection were significantly higher than those in wild-type mice. These findings suggest that TNF-α 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-α-/- mice, other cytokines appear to function as compensation for the lack of endogenous TNF-α.

Original languageEnglish
Pages (from-to)229-237
Number of pages9
JournalEuropean Journal of Pharmacology
Volume507
Issue number1-3
DOIs
Publication statusPublished - 10-01-2005
Externally publishedYes

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P-Glycoprotein
Endotoxins
Cytochrome P-450 Enzyme System
Down-Regulation
Tumor Necrosis Factor-alpha
Liver
Antipyrine
Injections
Doxorubicin
Intraperitoneal Injections

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Miyoshi, Mika ; Nadai, Masayuki ; Nitta, Atsumi ; Ueyama, Jun ; Shimizu, Akemi ; Takagi, Kenji ; Nabeshima, Toshitaka ; Takagi, Kenzo ; Saito, Kuniaki ; Hasegawa, Takaaki. / Role of tumor necrosis factor-α in down-regulation of hepatic cytochrome P450 and P-glycoprotein by endotoxin. In: European Journal of Pharmacology. 2005 ; Vol. 507, No. 1-3. pp. 229-237.
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Role of tumor necrosis factor-α in down-regulation of hepatic cytochrome P450 and P-glycoprotein by endotoxin. / Miyoshi, Mika; Nadai, Masayuki; Nitta, Atsumi; Ueyama, Jun; Shimizu, Akemi; Takagi, Kenji; Nabeshima, Toshitaka; Takagi, Kenzo; Saito, Kuniaki; Hasegawa, Takaaki.

In: European Journal of Pharmacology, Vol. 507, No. 1-3, 10.01.2005, p. 229-237.

Research output: Contribution to journalArticle

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AU - Miyoshi, Mika

AU - Nadai, Masayuki

AU - Nitta, Atsumi

AU - Ueyama, Jun

AU - Shimizu, Akemi

AU - Takagi, Kenji

AU - Nabeshima, Toshitaka

AU - Takagi, Kenzo

AU - Saito, Kuniaki

AU - Hasegawa, Takaaki

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N2 - We investigated the role of tumor necrosis factor-α (TNF-α) in the down-regulation of hepatic P-glycoprotein and cytochrome P450 (CYP) by endotoxin, using TNF-α gene-deficient (TNF-α-/-) 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 significant differences in the constitutional expression of P-glycoprotein between wild-type mice and TNF-α -/- mice. However, endotoxin had no effect on the expression of P-glycoprotein in TNF-α-/- mice either 6 or 24 h after injection. When doxorubicin was administered intravenously to TNF-α-/- 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-α-/- mice. These results suggest that TNF-α 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-α-/- mice compared with that in wild-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-α-/- mice than wild-type mice. When antipyrine was administered intravenously to wild-type mice and TNF-α-/- mice treated 24 h earlier with endotoxin, the plasma concentrations of antipyrine in TNF-α-/- mice 3 h after injection were significantly higher than those in wild-type mice. These findings suggest that TNF-α 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-α-/- mice, other cytokines appear to function as compensation for the lack of endogenous TNF-α.

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