論文 - 詳細
| RRC ID | 43949 |
|---|---|
| 著者 | Endo S, Toyoda Y, Fukami T, Nakajima M, Yokoi T. |
| タイトル | Stimulation of human monocytic THP-1 cells by metabolic activation of hepatotoxic drugs. |
| ジャーナル | Drug Metab Pharmacokinet |
| Abstract |
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 is 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. |
| 巻・号 | 27(6) |
| ページ | 621-30 |
| 公開日 | 2012-1-1 |
| DOI | 10.2133/dmpk.dmpk-12-rg-019 |
| PII | DN/JST.JSTAGE/dmpk/DMPK-12-RG-019 |
| PMID | 22785256 |
| MeSH | Albendazole / adverse effects Albendazole / immunology Albendazole / metabolism Albendazole / therapeutic use Amiodarone / adverse effects Amiodarone / analogs & derivatives Amiodarone / immunology Amiodarone / metabolism Amiodarone / pharmacology Amiodarone / therapeutic use B7-2 Antigen / genetics B7-2 Antigen / immunology B7-2 Antigen / metabolism Biotransformation / drug effects Cell Line, Tumor Chemical and Drug Induced Liver Injury / blood* Chemical and Drug Induced Liver Injury / genetics Chemical and Drug Induced Liver Injury / immunology Chemical and Drug Induced Liver Injury / metabolism Cytochrome P-450 CYP3A / genetics Cytochrome P-450 CYP3A / immunology Cytochrome P-450 CYP3A / metabolism Humans Intercellular Adhesion Molecule-1 / genetics Intercellular Adhesion Molecule-1 / immunology Intercellular Adhesion Molecule-1 / metabolism Interleukin-8 / genetics Interleukin-8 / immunology Interleukin-8 / metabolism Ketoconazole / immunology Ketoconazole / metabolism Ketoconazole / pharmacology Leukemia, Myeloid / blood* Leukemia, Myeloid / drug therapy Leukemia, Myeloid / genetics Leukemia, Myeloid / metabolism Microsomes, Liver / drug effects Microsomes, Liver / immunology Microsomes, Liver / metabolism Monocytes / drug effects* Monocytes / immunology Monocytes / metabolism RNA, Messenger / genetics RNA, Messenger / immunology Tumor Necrosis Factor-alpha / genetics Tumor Necrosis Factor-alpha / immunology Tumor Necrosis Factor-alpha / metabolism Up-Regulation / drug effects |
| IF | 2.772 |
| 引用数 | 10 |
| WOS 分野 | PHARMACOLOGY & PHARMACY |
| リソース情報 | |
| ヒト・動物細胞 | THP-1(RCB1189) |