Ketoconazole potentiates terfenadine-induced apoptosis in human Hep G2 cells through inhibition of cytochrome p450 3A4 activity

Ying Jan Wang, Cheng Fei Yu, Li Ching Chen, Chien Ho Chen, Jen Kun Lin, Yu Chih Liang, Chien Huang Lin, Shyr Yi Lin, Chin Fa Chen, Yuan Soon Ho

研究成果: 雜誌貢獻文章

22 引文 (Scopus)

摘要

Terfenadine (TF) is a highly potent histamine H1 receptor antagonist that in clinically effective doses is free of significant central nervous system side effects. Ketoconazole (KT) is a worldwide used oral antifungal agent with a broad spectrum of activity against both superficial and systemic mycosis. Simultaneously administration of KT and TF has been reported to induce several potent symptoms including cardiotoxicity, excitotoxicity, inhibition of blood mononuclear cells proliferation, and cardiovascular toxicity. However, the intracellular molecular mechanisms of TF-KT interactions in cells were still uncertain. In this study, we first demonstrated that TF (5-30 μM) induced apoptosis in several types of human cancer cell lines including human hepatoma (Hep G2), colorectal cancer (COLO 205), and fibroblast (CCD 922SK) cells for 24 h. The cellular responses to TF-induced apoptosis were demonstrated to be associated with the p53-signaling pathway, including induction of p53, p21/Cip1, p27/Kip1, bax protein expression and inhibition of bcl-2 protein expression. To realized the role of H1 receptor involved in TF-induced apoptosis, different H1 receptor antagonists including promethazine, mequitazine, and chlorpheniramin (50-100 μM) were administered and demonstrated that these chemicals cannot induced apoptosis through the H1 receptor signaling pathway. Interestingly, we found that the apoptotic effect of TF (2.5 μM) was significantly potentiated by KT (1 μM) treatment in Hep G2 cells through inhibition of the cytochrome p450 3A4 (CYP 3A4) activity. Such results were demonstrated by decreased of the TF activity with recombinant CYP 3A4, which prepared from baculovirus-infected insect cells. Our results provide the molecular basis of TF-KT interaction and this information should allow more rational forecasting of the risk for TF therapy during co-administration of KT.
原文英語
頁(從 - 到)147-159
頁數13
期刊Journal of Cellular Biochemistry
87
發行號2
DOIs
出版狀態已發佈 - 2002

指紋

Terfenadine
Cytochrome P-450 CYP3A
Ketoconazole
Hep G2 Cells
Apoptosis
Histamine H1 Receptors
Cyclin-Dependent Kinase Inhibitor p27
Histamine H1 Antagonists
Promethazine
bcl-2-Associated X Protein
Mycoses
Antifungal Agents
Baculoviridae
Cell proliferation
Neurology
Fibroblasts
Charge coupled devices
Cell Communication
Toxicity
Insects

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

引用此文

@article{84dba24279c340a3be98abb8043ecb28,
title = "Ketoconazole potentiates terfenadine-induced apoptosis in human Hep G2 cells through inhibition of cytochrome p450 3A4 activity",
abstract = "Terfenadine (TF) is a highly potent histamine H1 receptor antagonist that in clinically effective doses is free of significant central nervous system side effects. Ketoconazole (KT) is a worldwide used oral antifungal agent with a broad spectrum of activity against both superficial and systemic mycosis. Simultaneously administration of KT and TF has been reported to induce several potent symptoms including cardiotoxicity, excitotoxicity, inhibition of blood mononuclear cells proliferation, and cardiovascular toxicity. However, the intracellular molecular mechanisms of TF-KT interactions in cells were still uncertain. In this study, we first demonstrated that TF (5-30 μM) induced apoptosis in several types of human cancer cell lines including human hepatoma (Hep G2), colorectal cancer (COLO 205), and fibroblast (CCD 922SK) cells for 24 h. The cellular responses to TF-induced apoptosis were demonstrated to be associated with the p53-signaling pathway, including induction of p53, p21/Cip1, p27/Kip1, bax protein expression and inhibition of bcl-2 protein expression. To realized the role of H1 receptor involved in TF-induced apoptosis, different H1 receptor antagonists including promethazine, mequitazine, and chlorpheniramin (50-100 μM) were administered and demonstrated that these chemicals cannot induced apoptosis through the H1 receptor signaling pathway. Interestingly, we found that the apoptotic effect of TF (2.5 μM) was significantly potentiated by KT (1 μM) treatment in Hep G2 cells through inhibition of the cytochrome p450 3A4 (CYP 3A4) activity. Such results were demonstrated by decreased of the TF activity with recombinant CYP 3A4, which prepared from baculovirus-infected insect cells. Our results provide the molecular basis of TF-KT interaction and this information should allow more rational forecasting of the risk for TF therapy during co-administration of KT.",
keywords = "Apoptosis, Cytochrome p450 (3A4), Ketoconazole, P53, Terfenadine",
author = "Wang, {Ying Jan} and Yu, {Cheng Fei} and Chen, {Li Ching} and Chen, {Chien Ho} and Lin, {Jen Kun} and Liang, {Yu Chih} and Lin, {Chien Huang} and Lin, {Shyr Yi} and Chen, {Chin Fa} and Ho, {Yuan Soon}",
year = "2002",
doi = "10.1002/jcb.10282",
language = "English",
volume = "87",
pages = "147--159",
journal = "Journal of Cellular Biochemistry",
issn = "0730-2312",
publisher = "Wiley-Liss Inc.",
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TY - JOUR

T1 - Ketoconazole potentiates terfenadine-induced apoptosis in human Hep G2 cells through inhibition of cytochrome p450 3A4 activity

AU - Wang, Ying Jan

AU - Yu, Cheng Fei

AU - Chen, Li Ching

AU - Chen, Chien Ho

AU - Lin, Jen Kun

AU - Liang, Yu Chih

AU - Lin, Chien Huang

AU - Lin, Shyr Yi

AU - Chen, Chin Fa

AU - Ho, Yuan Soon

PY - 2002

Y1 - 2002

N2 - Terfenadine (TF) is a highly potent histamine H1 receptor antagonist that in clinically effective doses is free of significant central nervous system side effects. Ketoconazole (KT) is a worldwide used oral antifungal agent with a broad spectrum of activity against both superficial and systemic mycosis. Simultaneously administration of KT and TF has been reported to induce several potent symptoms including cardiotoxicity, excitotoxicity, inhibition of blood mononuclear cells proliferation, and cardiovascular toxicity. However, the intracellular molecular mechanisms of TF-KT interactions in cells were still uncertain. In this study, we first demonstrated that TF (5-30 μM) induced apoptosis in several types of human cancer cell lines including human hepatoma (Hep G2), colorectal cancer (COLO 205), and fibroblast (CCD 922SK) cells for 24 h. The cellular responses to TF-induced apoptosis were demonstrated to be associated with the p53-signaling pathway, including induction of p53, p21/Cip1, p27/Kip1, bax protein expression and inhibition of bcl-2 protein expression. To realized the role of H1 receptor involved in TF-induced apoptosis, different H1 receptor antagonists including promethazine, mequitazine, and chlorpheniramin (50-100 μM) were administered and demonstrated that these chemicals cannot induced apoptosis through the H1 receptor signaling pathway. Interestingly, we found that the apoptotic effect of TF (2.5 μM) was significantly potentiated by KT (1 μM) treatment in Hep G2 cells through inhibition of the cytochrome p450 3A4 (CYP 3A4) activity. Such results were demonstrated by decreased of the TF activity with recombinant CYP 3A4, which prepared from baculovirus-infected insect cells. Our results provide the molecular basis of TF-KT interaction and this information should allow more rational forecasting of the risk for TF therapy during co-administration of KT.

AB - Terfenadine (TF) is a highly potent histamine H1 receptor antagonist that in clinically effective doses is free of significant central nervous system side effects. Ketoconazole (KT) is a worldwide used oral antifungal agent with a broad spectrum of activity against both superficial and systemic mycosis. Simultaneously administration of KT and TF has been reported to induce several potent symptoms including cardiotoxicity, excitotoxicity, inhibition of blood mononuclear cells proliferation, and cardiovascular toxicity. However, the intracellular molecular mechanisms of TF-KT interactions in cells were still uncertain. In this study, we first demonstrated that TF (5-30 μM) induced apoptosis in several types of human cancer cell lines including human hepatoma (Hep G2), colorectal cancer (COLO 205), and fibroblast (CCD 922SK) cells for 24 h. The cellular responses to TF-induced apoptosis were demonstrated to be associated with the p53-signaling pathway, including induction of p53, p21/Cip1, p27/Kip1, bax protein expression and inhibition of bcl-2 protein expression. To realized the role of H1 receptor involved in TF-induced apoptosis, different H1 receptor antagonists including promethazine, mequitazine, and chlorpheniramin (50-100 μM) were administered and demonstrated that these chemicals cannot induced apoptosis through the H1 receptor signaling pathway. Interestingly, we found that the apoptotic effect of TF (2.5 μM) was significantly potentiated by KT (1 μM) treatment in Hep G2 cells through inhibition of the cytochrome p450 3A4 (CYP 3A4) activity. Such results were demonstrated by decreased of the TF activity with recombinant CYP 3A4, which prepared from baculovirus-infected insect cells. Our results provide the molecular basis of TF-KT interaction and this information should allow more rational forecasting of the risk for TF therapy during co-administration of KT.

KW - Apoptosis

KW - Cytochrome p450 (3A4)

KW - Ketoconazole

KW - P53

KW - Terfenadine

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