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

Drug Metabolism and Pharmacokinetics
Hanaka MimuraKan Chiba

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.

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Citations

Jul 12, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Birgit M WollmannEspen Molden
Aug 28, 2016·European Journal of Clinical Pharmacology·Hikaru SatoJunichi Kawakami
Feb 5, 2021·European Journal of Drug Metabolism and Pharmacokinetics·Subrata Deb, Scott Arrighi
May 4, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Devendra Kumar, Neerja Trivedi
Jun 22, 2021·Transplant International : Official Journal of the European Society for Organ Transplantation·Jakob MühlbacherGeorg A Böhmig

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