著者
Shinya Endo Yasuyuki Toyoda Tatsuki Fukami Miki Nakajima Tsuyoshi Yokoi
出版者
日本薬物動態学会 会長/日本薬物動態学会 DMPK編集委員長
雑誌
Drug Metabolism and Pharmacokinetics (ISSN:13474367)
巻号頁・発行日
pp.DMPK-12-RG-019, (Released:2012-06-12)
参考文献数
44
被引用文献数
14

Drug-induced liver injury (DILI) is thought to be involved in the participation of drugs that either directly affect the cell viability or elicit an immune response. However, there is limited information about the immune responses induced by drugs, including those drugs that are metabolically activated. In this study, we constructed an in vitro assay system to assess the involvement of immune-related factors induced by metabolic activation of drugs. To investigate whether CYP3A4-mediated metabolism of 10 hepatotoxic drugs are associated with immune-related responses, human monocytic leukemia THP-1 cells were co-incubated with CYP3A4 Supersomes. Cluster of differentiation (CD) 86 and CD54 expression levels on THP-1 cells were upregulated by treatment with albendazole and amiodarone (AMD), respectively, in the presence of CYP3A4. Additionally, N-desethylamiodarone (DEA), a major metabolite of AMD, upregulated the CD54 expression of THP-1 cells with CYP3A4. The release of interleukin (IL) -8 and tumor necrosis factor (TNF) α from THP-1 cells was significantly increased by the treatment of AMD or DEA with CYP3A4. Similarly, IL-8 and TNFα were also upregulated by the treatment of AMD and DEA with human liver microsomes, but were inhibited by adding ketoconazole to the cell culture. In this study, we first report that albendazole, AMD and DEA activate immune reaction when metabolically activated.