Paclitaxel-resistance conferred by altered expression of efflux and influx transporters for paclitaxel in human hepatoma cell line HepG2

• TAKANO Mikihisa

  Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University

• OTANI Yoshifumi

  Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University

• TANDA Minori

  Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University

• KAWAMI Masashi

  Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University

• NAGAI Junya

  Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University

• YUMOTO Ryoko

  Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University

書誌事項

タイトル別名

• Paclitaxel-resistance Conferred by Altered Expression of Efflux and Influx Transporters for Paclitaxel in the Human Hepatoma Cell Line, HepG2
• Paclitaxel-resistance conferred by altered expression of efflux and influx transporters for paclitaxel in the human cell line, HepG2

抄録

  Paclitaxel-resistant HepG2 (PR-HepG2) cells were established by long-term exposure of HepG2 cells to paclitaxel and expression and function of efflux (P-glycoprotein, MRP2) and influx (OATP1B3) transporters for paclitaxel were examined to understand the mechanisms underlying the resistance. mRNA expression of P-glycoprotein (P-gp) increased in PR-HepG2 more than in HepG2 cells, while that of MRP2 did not change. Interestingly, mRNA expression of OATP1B3 drastically decreased in PR-HepG2 cells. [³H]Paclitaxel uptake was less in PR-HepG2 than in HepG2 cells and the uptake in both cells increased by metabolic inhibition. The uptake of [³H]paclitaxel and rhodamine 123 increased by verapamil, a P-gp inhibitor. Probenecid, an MRP inhibitor, did not affect [³H]paclitaxel uptake in both cells. Sulfobromophthalein, an OATP1B3 inhibitor, inhibited [³H]paclitaxel uptake in HepG2 but not in PR-HepG2 cells. Cytotoxicity studies showed that the resistance of PR-HepG2 cells to paclitaxel was reversed by verapamil. PR-HepG2 cells showed cross-resistance to doxorubicin, a P-gp substrate, but not to cisplatin. These results indicate that enhanced expression and function of P-gp may be a predominant mechanism of paclitaxel resistance in PR-HepG2 cells and the reduced influx via OATP1B3 may also serve to lower intracellular paclitaxel concentration in cooperation with P-gp-mediated efflux.<br>

収録刊行物

• Ｄｒｕｇ　Ｍｅｔａｂｏｌｉｓｍ　ａｎｄ　Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ

  Ｄｒｕｇ　Ｍｅｔａｂｏｌｉｓｍ　ａｎｄ　Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ 24 (5), 418-427, 2009

  日本薬物動態学会

キーワード

• paclitaxel
• multidrug resistance
• HepG2 cells
• P-glycoprotein (MDR1/ABCB1)
• multidrug resistance-associated protein 2 (MRP2/ABCC2)
• organic anion transporting polypeptide 1B3 (OATP1B3/SLCO1B3)

詳細情報

• CRID: 1390282680156766848
• NII論文ID: 10025724568
• NII書誌ID: AA1162652X
• DOI: 10.2133/dmpk.24.418
• ISSN: 18800920
• ISSN: 13474367
• Web Site: http://api.elsevier.com/content/article/PII:S1347436715301270?httpAccept=text/xml
• Web Site: http://api.elsevier.com/content/article/PII:S1347436715301270?httpAccept=text/plain
• Web Site: https://search.jamas.or.jp/link/ui/2010097864
• 本文言語コード: en
• データソース種別:
  • JaLC
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可