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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Enhanced Delivery of Drugs to the Liver by Adenovirus-Mediated Heterologous Expression of the Human Oligopeptide Transporter PEPT1

Hidekazu Toyobuku, Yoshimichi Sai, Ikumi Tamai and Akira Tsuji
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 812-819; DOI: https://doi.org/10.1124/jpet.301.3.812
Hidekazu Toyobuku
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Yoshimichi Sai
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Ikumi Tamai
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Akira Tsuji
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Abstract

To explore the feasibility of drug delivery to the liver by the use of adenovirus-mediated human oligopeptide transporter (hPEPT1) gene transfer, we examined the accumulation ofl-[3H]carnosine in the hepatoma cell line (HepG2 and WIFB9) and mouse liver. We constructed a recombinant adenovirus encoding hPEPT1-enhanced yellow fluorescent protein (EYFP) fusion gene (AdhPEPT1-EYFP). In vitro uptake ofl-[3H]carnosine was determined in HepG2 and WIFB9 cells transduced with AdhPEPT1-EYFP. In vivo, the accumulation ofl-[3H]carnosine in mouse liver was evaluated after transduction of AdhPEPT1-EYFP. At pH 6.0, the uptake ofl-[3H]carnosine by HepG2 and WIFB9 cells transduced with AdhPEPT1-EYFP was increased 15- and 2-fold, respectively, compared with the cells without transduction. At pH 7.4, uptake of l-[3H]carnosine in AdhPEPT1-EYFP transduced HepG2 cells was 3 times greater than that of nontransduced cells. In the presence of carnosine or glycylsarcosine as an inhibitor at 20 mM, the uptake of l-[3H]carnosine was reduced to a level comparable to that of nontransduced cells. At 30 min after intravenous administration ofl-[3H]carnosine to mice transduced with AdhPEPT1-EYFP at 1 × 1010 plaque-forming units/mouse, the tissue-to-plasma concentration ratio (Kp) ofl-[3H]carnosine in the liver was significantly increased to 7 times that of nontransduced mice. In contrast, the Kp value of [14C]inulin, a marker for extracellular fluid space, remained unchanged after adenoviral transduction suggesting minimal pathological damage of tissues. hPEPT1-EYFP was localized at both the basolateral and apical membranes in HepG2 cells, WIFB9 cells, and mouse liver. In conclusion, our results suggest that delivery of oligopeptide to the liver by adenovirus-mediated heterologous expression of hPEPT1 in vivo is feasible.

Footnotes

  • This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology and by the Uehara Memorial Foundation and Takeda Science Foundation.

  • Abbreviations:
    OATP
    organic anion transporting polypeptide
    hPEPT1
    human intestinal H+/peptide cotransporter
    FCS
    fetal calf serum
    GlySar
    glycylsarcosine
    RT-PCR
    reverse transcription-polymerase chain reaction
    EYFP
    enhanced yellow fluorescent protein
    bp
    base pair
    PFU
    plaque-forming units
    MOI
    multiplicity of infection
    HBSS
    Hanks' balanced salt solution
    MES
    4-morpholineethanesulfonic acid
    GFP
    green fluorescent protein
    PBS
    phosphate-buffered saline
    Kp
    tissue-to-plasma concentration ratio
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    • Received December 19, 2001.
    • Accepted February 20, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Enhanced Delivery of Drugs to the Liver by Adenovirus-Mediated Heterologous Expression of the Human Oligopeptide Transporter PEPT1

Hidekazu Toyobuku, Yoshimichi Sai, Ikumi Tamai and Akira Tsuji
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 812-819; DOI: https://doi.org/10.1124/jpet.301.3.812

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Research ArticleCHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Enhanced Delivery of Drugs to the Liver by Adenovirus-Mediated Heterologous Expression of the Human Oligopeptide Transporter PEPT1

Hidekazu Toyobuku, Yoshimichi Sai, Ikumi Tamai and Akira Tsuji
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 812-819; DOI: https://doi.org/10.1124/jpet.301.3.812
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