Role of tumor necrosis factor-alpha 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

doi:10.1016/j.ejphar.2004.11.035

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

Eur J Pharmacol. 2005 Jan 10;507(1-3):229-37. doi: 10.1016/j.ejphar.2004.11.035. Epub 2004 Dec 15.

Authors

Mika Miyoshi¹, Masayuki Nadai, Atsumi Nitta, Jun Ueyama, Akemi Shimizu, Kenji Takagi, Toshitaka Nabeshima, Kenzo Takagi, Kuniaki Saito, Takaaki Hasegawa

Affiliation

¹ Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi-ku, Nagoya 461-867, Japan.

PMID: 15659313
DOI: 10.1016/j.ejphar.2004.11.035

Abstract

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 significant 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 TNF-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 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-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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
Animals
Cytochrome P-450 Enzyme Inhibitors*
Cytochrome P-450 Enzyme System / biosynthesis*
Down-Regulation / drug effects
Down-Regulation / physiology*
Endotoxins / pharmacology*
Liver / physiology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Tumor Necrosis Factor-alpha / deficiency
Tumor Necrosis Factor-alpha / physiology*

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Cytochrome P-450 Enzyme Inhibitors
Endotoxins
Tumor Necrosis Factor-alpha
Cytochrome P-450 Enzyme System