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Inoculation of Human Tumor Cells Alters the Basal Expression but Not the Inducibility of Cytochrome P450 Enzymes in Tumor-Bearing Mouse Liver

Michiko Sugawara, Kiyoshi Okamoto, Tadashi Kadowaki, Kazutomi Kusano, Akiyoshi Fukamizu and Tsutomu Yoshimura
Drug Metabolism and Disposition November 2009, 37 (11) 2244-2254; DOI: https://doi.org/10.1124/dmd.109.028571
Michiko Sugawara
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Kiyoshi Okamoto
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Tadashi Kadowaki
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Kazutomi Kusano
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Akiyoshi Fukamizu
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Tsutomu Yoshimura
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Abstract

The athymic nude mouse is often used to grow tumors for in vivo oncology research, including the identification of anticancer drugs, whereas wild-type mice are usually used to assess the pharmacokinetics (PK) of new chemical entities. The relationship between PK and pharmacodynamics (PD) provides useful mechanistic information and helps guide of the clinical regimen. The aim of this study was to assess whether the inoculation of human hepatocellular carcinoma cells (PLC/PRF/5) into athymic nude mice alters the expression of genes encoding the drug-metabolizing enzymes and transporters in host liver. The livers from nontumor- and tumor-bearing mice were initially subjected to drug metabolism gene microarray analysis. Microarray analysis indicated that tumor inoculation had little effect on drug metabolism-related genes, including several cytochrome P450s: Cyp1a, Cyp2b, and Cyp3a. This result was further confirmed by reverse transcription-polymerase chain reaction (RT-PCR). However, immunoreactive proteins of Cyp1a, Cyp2b, and Cyp3a were suppressed by tumor inoculation. RT-PCR and Western immunoblotting analysis showed that the inducibility of Cyp1a, Cyp2b, and Cyp3a by 3-methylcholanthrene, phenobarbital, and dexamethasone, respectively, was similar between nontumor- and tumor-bearing mice. These results suggest that inoculation of human tumor cells into athymic nude mice suppresses the expression of certain drug-metabolizing enzymes, which may alter the PK and PD of antitumor drugs.

  • PK, pharmacokinetics
  • PD, pharmacodynamics
  • DME, drug-metabolizing enzymes
  • ADME, absorption, distribution, metabolism and excretion
  • P450, cytochrome P450
  • AhR, arylhydrocarbon receptor
  • CAR, constitutive androstane receptor
  • PXR, pregnane X receptor
  • MC, 3-methylcholanthrene
  • PB, phenobarbital
  • PTX, paclitaxel
  • Dex, dexamethasone
  • PCR, polymerase chain reaction
  • GAPDH, glyceraldehyde-3-phosphate dehydrogenase
  • SSC, standard saline citrate
  • PVDF, polyvinylidene difluoride
  • HRP, horseradish peroxidase
  • ANOVA, analysis of variance
  • RT, reverse transcription.

Footnotes

  • This work was supported by Eisai Co., Ltd.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.028571

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received June 2, 2009.
    • Accepted August 6, 2009.
  • Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (11)
Drug Metabolism and Disposition
Vol. 37, Issue 11
November 2009
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Inoculation of Human Tumor Cells Alters the Basal Expression but Not the Inducibility of Cytochrome P450 Enzymes in Tumor-Bearing Mouse Liver

Michiko Sugawara, Kiyoshi Okamoto, Tadashi Kadowaki, Kazutomi Kusano, Akiyoshi Fukamizu and Tsutomu Yoshimura
Drug Metabolism and Disposition November 1, 2009, 37 (11) 2244-2254; DOI: https://doi.org/10.1124/dmd.109.028571

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Inoculation of Human Tumor Cells Alters the Basal Expression but Not the Inducibility of Cytochrome P450 Enzymes in Tumor-Bearing Mouse Liver

Michiko Sugawara, Kiyoshi Okamoto, Tadashi Kadowaki, Kazutomi Kusano, Akiyoshi Fukamizu and Tsutomu Yoshimura
Drug Metabolism and Disposition November 1, 2009, 37 (11) 2244-2254; DOI: https://doi.org/10.1124/dmd.109.028571
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