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Resistance to indomethacin-induced down-regulation of hepatic cytochrome P450 enzymes in the mice with non-functional Toll-like receptor 4.

Abstract：

BACKGROUND/AIMS:Repetitive indomethacin administration induces down-regulation of hepatic cytochrome P450 (CYP) enzymes. We tested the hypothesis that an increase in intestinal permeability by indomethacin-induced intestinal injury leads to entry of bacterial endotoxin and reaching into liver via the portal vein, resulting in down-regulations of CYPs. METHODS:C3H/HeJ mice, which are resistant to endotoxin, have a mutation in Toll-like receptor 4 gene. The sensitivity to indomethacin-induced impairment of hepatic CYPs in the lipopolysaccharide (LPS)-resistant mice was examined along with LPS-sensitive (C3H/He) mice. RESULTS:Treatment of the LPS-sensitive mice with intraperitoneal indomethacin (5 mg/kg per day, 3 days) significantly decreased enzyme activities for CYP3A11, CYP2D9 and CYP1A2 but not CYP2E1. The LPS-resistant mice were resistant to the indomethacin-induced impairment of CYP2D9. The mice were also less sensitive to the effects on CYP3A11 and CYP1A2, but the activities for these isozymes in the indomethacin-treated mice were still lower than in untreated mice. Immunoblot analysis with anti-CYP3A2 and anti-CYP2D2 sera indicated that indomethacin-induced decreases in expression of the proteins recognized by the antibodies were attenuated in the LPS-resistant mice. CONCLUSIONS:We conclude that Toll-like receptor 4 is involved in the indomethacin-induced down-regulation of hepatic CYP enzymes, indicating the pivotal role of gut-derived endotoxin in the hepatic effects.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Masubuchi Y,Horie T

doi

10.1016/s0168-8278(03)00244-7

subject

Has Abstract

pub_date

2003-09-01 00:00:00

pages

349-56

issue

3

eissn

0168-8278

issn

1600-0641

pii

S0168827803002447

journal_volume

39

pub_type

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