title: Hepatic early inflammation induces downregulation of hepatic cytochrome P450 expression and metabolic activity in the dextran sulfate sodium-induced murine colitis.
abstract: Ulcerative colitis (UC) patients may have increased concentrations of drugs in their blood. We hypothesized that this response is mainly due to a decrease in the expression and activity of the drug-metabolizing enzyme, cytochrome P450 (CYP), in the liver. In this study, we have tried to demonstrate the hypothesis. UC was induced in mice by treatment with dextran sulfate sodium (DSS) solution. The mRNA and protein expression levels of CYP, inflammatory cytokine levels, and the metabolic activity of CYP3A in the liver were measured. The nuclear translocations of nuclear factor kappa B (NF-κB), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) were analyzed. The levels of hepatic inflammatory cytokines increased in the DSS-treated group. The hepatic mRNA and protein expression of CYP (CYP1A, CYP2C, CYP2D, CYP2E, and CYP3A) and the CYP3A metabolic activity significantly decreased compared to the control group. Hepatic NF-κB nuclear translocation significantly increased in the DSS-treated group. In contrast, the nuclear translocations of PXR and CAR were decreased. Lipopolysaccharides from inflammatory sites in the colon induce hepatic inflammation in DSS-induced murine colitis. This inflammation then causes an increase in the nuclear translocation of hepatic NF-κB and a decrease in the nuclear translocation of PXR and CAR, resulting in the decreased expression and activities of CYP. The results of this study indicated that at the onset of UC, the decreased activity of hepatic CYP causes an increase in the concentrations of drugs in the blood, leading to an increase in the incidence of adverse reactions.
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kusunoki
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Nobutomo
authors.initials: N
authors.lastname: Ikarashi
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Risako
authors.initials: R
authors.lastname: Kon
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ochiai
authors.affiliation: Division of Applied Pharmaceutical Education and Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Machida
authors.affiliation: Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. Electronic address: sugiyama@hoshi.ac.jp.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000150:complications / Q000201:enzymology* / Q000276:immunology; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology*; D004195:Disease Models, Animal; D006505:Hepatitis / Q000201:enzymology* / Q000209:etiology / Q000276:immunology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000077297:Pregnane X Receptor; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D014229:Triazolam / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D000090702:Constitutive Androstane Receptor; D016207:Cytokines; D016328:NF-kappa B; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014229:Triazolam; D003577:Cytochrome P-450 Enzyme System; D016264:Dextran Sulfate
keywords: Colitis; Cytochrome P450; Dextran sulfate sodium; Liver; Nuclear factor kappa B; Pregnane X receptor