Stimulation of human monocytic THP-1 cells by metabolic activation of hepatotoxic drugs.
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.
Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
Shinya
S
Endo
Yasuyuki
Y
Toyoda
Tatsuki
T
Fukami
Miki
M
Nakajima
Tsuyoshi
T
Yokoi
D015766:Albendazole / Q000009:adverse effects / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D000638:Amiodarone / Q000009:adverse effects / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007654:Ketoconazole / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D051940:B7-2 Antigen; C497964:CD86 protein, human; D016209:Interleukin-8; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D015766:Albendazole; C036116:desethylamiodarone; D000638:Amiodarone; D007654:Ketoconazole