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

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)147-159
Number of pages13
JournalJournal of Cellular Biochemistry
Volume87
Issue number2
DOIs
Publication statusPublished - 2002 Oct 16

Fingerprint

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

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Wang, Ying-Jan ; Yu, Cheng Fei ; Chen, Li Ching ; Chen, Chien Ho ; Lin, Jen Kun ; Liang, Yu Chih ; Lin, Chien Huang ; Lin, Shyr Yi ; Chen, Chin Fa ; Ho, Yuan Soon. / Ketoconazole potentiates terfenadine-induced apoptosis in human Hep G2 cells through inhibition of cytochrome p450 3A4 activity. In: Journal of Cellular Biochemistry. 2002 ; Vol. 87, No. 2. pp. 147-159.
@article{bd05562589f54e4f9cf4321a6e0beaee,
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.",
author = "Ying-Jan Wang 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",
month = "10",
day = "16",
doi = "10.1002/jcb.10282",
language = "English",
volume = "87",
pages = "147--159",
journal = "Journal of Cellular Biochemistry",
issn = "0730-2312",
publisher = "Wiley-Liss Inc.",
number = "2",

}

Ketoconazole potentiates terfenadine-induced apoptosis in human Hep G2 cells through inhibition of cytochrome p450 3A4 activity. / Wang, Ying-Jan; Yu, Cheng Fei; Chen, Li Ching; Chen, Chien Ho; Lin, Jen Kun; Liang, Yu Chih; Lin, Chien Huang; Lin, Shyr Yi; Chen, Chin Fa; Ho, Yuan Soon.

In: Journal of Cellular Biochemistry, Vol. 87, No. 2, 16.10.2002, p. 147-159.

Research output: Contribution to journalArticle

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 - 2002/10/16

Y1 - 2002/10/16

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.

UR - http://www.scopus.com/inward/record.url?scp=0036386412&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036386412&partnerID=8YFLogxK

U2 - 10.1002/jcb.10282

DO - 10.1002/jcb.10282

M3 - Article

VL - 87

SP - 147

EP - 159

JO - Journal of Cellular Biochemistry

JF - Journal of Cellular Biochemistry

SN - 0730-2312

IS - 2

ER -