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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\u2013KT interactions in cells were still uncertain. In this study, we first demonstrated that TF (5\u201330 \u03bcM) 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\u2010induced apoptosis were demonstrated to be associated with the <jats:italic>p53<\/jats:italic>\u2010signaling pathway, including induction of <jats:italic>p53<\/jats:italic>, <jats:italic>p21<\/jats:italic>\/<jats:italic>Cip1<\/jats:italic>, <jats:italic>p27<\/jats:italic>\/<jats:italic>Kip1<\/jats:italic>, <jats:italic>bax<\/jats:italic> protein expression and inhibition of <jats:italic>bcl\u20102<\/jats:italic> protein expression. To realized the role of H1 receptor involved in TF\u2010induced apoptosis, different H1 receptor antagonists including promethazine, mequitazine, and chlorpheniramin (50\u2013100 \u03bcM) 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 \u03bcM) was significantly potentiated by KT (1 \u03bcM) 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\u2010infected insect cells. Our results provide the molecular basis of TF\u2013KT interaction and this information should allow more rational forecasting of the risk for TF therapy during co\u2010administration of KT. J. Cell. Biochem. 87: 147\u2013159, 2002. \u00a9 2002 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcb.10282","type":"journal-article","created":{"date-parts":[[2002,10,9]],"date-time":"2002-10-09T03:19:51Z","timestamp":1034133591000},"page":"147-159","source":"Crossref","is-referenced-by-count":20,"title":["Ketoconazole potentiates terfenadine\u2010induced apoptosis in human Hep G2 cells through inhibition of cytochrome p450 3A4 activity"],"prefix":"10.1002","volume":"87","author":[{"given":"Ying\u2010Jan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng\u2010Fei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010Ching","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien\u2010Ho","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen\u2010Kun","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Chih","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien\u2010Huang","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyr\u2010Yi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin\u2010Fa","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan\u2010Soon","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2002,9,19]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1989.tb05410.x"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498259509061850"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(96)90004-0"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1211\/0022357991772628"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01535739"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0028-2243(79)90065-0"},{"key":"e_1_2_6_8_1","first-page":"47","article-title":"Cytochrome P450 3A4 in vivo ketoconazole competitive inhibition: Determination of Ki and dangers associated with high clearance drugs in general","volume":"2","author":"Boxenbaum H","year":"1999","journal-title":"J Pharm Pharma Sci"},{"key":"e_1_2_6_9_1","first-page":"89","article-title":"Human in vivo competitive inhibition of P450 substrates: Increased plasma concentrations as a function of hepatic extraction ratio and percent inhibition","volume":"2","author":"Boxenbaum H","year":"1999","journal-title":"J Pharm Pharma Sci"},{"key":"e_1_2_6_10_1","first-page":"71","article-title":"Clinical investigation of terfenadine, a non\u2010sedating antihistamine","volume":"44","author":"Brandon ML","year":"1980","journal-title":"Ann Allergy"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.5.1973"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.2000.9062"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02620991"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01318885"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02627-5"},{"key":"e_1_2_6_16_1","first-page":"1169","article-title":"WAF1\/CIP1 is induced in p53\u2010mediated G1 arrest and apoptosis","volume":"54","author":"el\u2010Deiry WS","year":"1994","journal-title":"Cancer Res"},{"key":"e_1_2_6_17_1","first-page":"991","article-title":"Biotransformation of tirilazad in human: 2. 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