Resistance to indomethacin-induced down-regulation of hepatic cytochrome P450 enzymes in the mice with non-functional Toll-like receptor 4.
OBJECTIVE
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.
Masubuchi
Yasuhiro
Y
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
Horie
Toshiharu
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015536:Down-Regulation; D004351:Drug Resistance; D019446:Endotoxemia / Q000139:chemically induced; D004789:Enzyme Activation / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D010457:Peptidoglycan / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051193:Toll-Like Receptors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010457:Peptidoglycan; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C119985:Cyp2d2 protein, rat; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; D007213:Indomethacin