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Research ArticleArticle

Induction of Human UDP-Glucuronosyltransferase 2B7 Gene Expression by Cytotoxic Anticancer Drugs in Liver Cancer HepG2 Cells

Dong Gui Hu, Peter I. Mackenzie, Lu Lu, Robyn Meech and Ross A. McKinnon
Drug Metabolism and Disposition May 2015, 43 (5) 660-668; DOI: https://doi.org/10.1124/dmd.114.062380
Dong Gui Hu
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, Australia (D.G.H., P.I.M., L.L., R.M., R.A.M.)
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Peter I. Mackenzie
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, Australia (D.G.H., P.I.M., L.L., R.M., R.A.M.)
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Lu Lu
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, Australia (D.G.H., P.I.M., L.L., R.M., R.A.M.)
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Robyn Meech
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, Australia (D.G.H., P.I.M., L.L., R.M., R.A.M.)
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Ross A. McKinnon
Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre, Bedford Park, Australia (D.G.H., P.I.M., L.L., R.M., R.A.M.)
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Abstract

We recently reported induction of UGT2B7 by its substrate epirubicin, a cytotoxic anthracycline anticancer drug, via activation of p53 and subsequent recruitment of p53 to the UGT2B7 promoter in hepatocellular carcinoma HepG2 cells. Using the same HepG2 model cell line, the present study assessed the possibility of a similar induction of UGT2B7 by several other cytotoxic drugs. We first demonstrated by reverse transcriptase quantitative real-time polymerase chain reaction that, as observed with epirubicin, nine cytotoxic drugs including three anthracyclines (doxorubicin, daunorubicin, and idarubicin) and six nonanthracyclines (mitomycin C, 5-fluorouracil, camptothecin, 7-ethyl-10-hydroxycamptothecin, topotecan, and etoposide) significantly increased UGT2B7 mRNA levels. To investigate a potential involvement of p53 in this induction, we conducted further experiments with four of the nine drugs (doxorubicin, daunorubicin, idarubicin, and mitomycin C). The cytotoxic drugs studied increased p53 and UGT2B7 protein levels. Knockdown of p53 expression by small interfering RNA reduced cytotoxic drug-induced UGT2B7 expression. Luciferase reporter assays showed activation of the UGT2B7 promoter by cytotoxic drugs via a previously reported p53 site. Finally, chromatin immunoprecipitation assays demonstrated p53 recruitment to the UGT2B7 p53 site upon exposure to mitomycin C, the most potent UGT2B7 inducer among the nine tested drugs. Taken together, these results provide further evidence supporting UGT2B7 as a p53 target gene. The cytotoxic drug-induced UGT2B7 activity in target liver cancer cells or possibly in normal liver cells may affect the therapeutic efficacy of co-administered cytotoxic drugs (e.g., epirubicin) and noncytotoxic drugs (e.g., morphine), which are UGT2B7 substrates.

Footnotes

    • Received December 1, 2014.
    • Accepted February 23, 2015.
  • This work was supported by funding from the National Health and Medical Research Council of Australia [ID1020931].

  • dx.doi.org/10.1124/dmd.114.062380.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (5)
Drug Metabolism and Disposition
Vol. 43, Issue 5
1 May 2015
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Research ArticleArticle

Induction of UGT2B7 by Cytotoxic Drugs

Dong Gui Hu, Peter I. Mackenzie, Lu Lu, Robyn Meech and Ross A. McKinnon
Drug Metabolism and Disposition May 1, 2015, 43 (5) 660-668; DOI: https://doi.org/10.1124/dmd.114.062380

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Research ArticleArticle

Induction of UGT2B7 by Cytotoxic Drugs

Dong Gui Hu, Peter I. Mackenzie, Lu Lu, Robyn Meech and Ross A. McKinnon
Drug Metabolism and Disposition May 1, 2015, 43 (5) 660-668; DOI: https://doi.org/10.1124/dmd.114.062380
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