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

J Hepatol. 2003 Sep;39(3):349-56. doi: 10.1016/s0168-8278(03)00244-7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism*
  • Down-Regulation
  • Drug Resistance
  • Endotoxemia / chemically induced
  • Enzyme Activation / drug effects
  • Indomethacin / pharmacology*
  • Lipopolysaccharides / pharmacology
  • Liver / enzymology*
  • Male
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Peptidoglycan / pharmacology
  • Receptors, Cell Surface / metabolism*
  • Toll-Like Receptors


  • Anti-Inflammatory Agents, Non-Steroidal
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Membrane Proteins
  • Peptidoglycan
  • Receptors, Cell Surface
  • Toll-Like Receptors
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • Cyp2d2 protein, rat
  • Cyp3a2 protein, rat
  • Cytochrome P-450 CYP3A
  • Indomethacin