title: Effects of cytokines on CYP3A4 expression and reversal of the effects by anti-cytokine agents in the three-dimensionally cultured human hepatoma cell line FLC-4.
abstract: The expression of hepatic cytochrome P450 (CYP) enzymes is altered under pathological conditions with increased levels of cytokines. In this study, we analyzed the effects of cytokines (interleukin [IL]-1β, IL-6 and tumor necrosis factor α) on the expression of CYP3A4 using newly introduced three-dimensionally cultured human hepatocarcinoma FLC-4 cells. The mRNA level of CYP3A4 was significantly decreased by IL-1β, IL-6 and tumor necrosis factor-α. Formation of α-hydroxytriazolam catalyzed by CYP3A was decreased by IL-1β and IL-6. Pre-treatment with IL-6 enhanced the cytotoxic effects of gefitinib and paclitaxel. In addition, tocilizumab and IL-1 receptor antagonist restored the decreased expression of CYP3A4 mRNA by IL-6 and IL-1β, respectively. These results obtained by using three-dimensionally cultured FLC-4 cells are consistent with results obtained by using primary human hepatocytes and results of clinical studies. Therefore, three-dimensionally cultured FLC-4 cell system may be a promising cellular tool to assess the effects of cytokines on CYP3A4 expression.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Hanaka
authors.initials: H
authors.lastname: Mimura
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. Electronic address: kaoruk@faculty.chiba-u.jp.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Linxiaoqing
authors.initials: L
authors.lastname: Xu
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Tsukuba Research Center, Kuraray, Co., Ltd., Tsukuba, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ejiri
authors.affiliation: Tsukuba Research Center, Kuraray, Co., Ltd., Tsukuba, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Hosoda
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D015153:Blotting, Western; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D000077156:Gefitinib; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D013379:Substrate Specificity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000093242:Interleukin-6 Inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D051544:Cytochrome P-450 CYP3A; D000077156:Gefitinib; D053583:Interleukin-1beta; D015850:Interleukin-6; D017239:Paclitaxel; D011799:Quinazolines; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C510163:CYP3A4 protein, human; C502936:tocilizumab
keywords: CYP3A4; Cytokine; Expression; IL-1ra; Tocilizumab