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The Pharmaceutical Society of Korea (대한약학회)
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Interferon Signal Transduction of Biphenyl Dimethyl Dicarboxylate/Amantadine and Anti-HBV Activity in HepG2 2.2.15

  • Joo Seong-Soo (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Won Tae-Joon (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Kim Min-Jung (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Hwang Kwang-Woo (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Lee Do-Ik (Department of Immunology, College of Pharmacy, Chung-Ang University)
  • Published : 2006.05.01
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Abstract

Biphenyl dimethyl dicarboxylate (DDB) is a hepatoprotectant, which is used as an adjuvant agent in a treatment for chronic hepatitis. Amantadine is an antiviral agent, which is utilized primarily in the treatment of influenza, but also, occasionally in the treatment of hepatitis C. In a previous study, we reported that DDB, coupled with amantadine, would exert an anti-HBV effect, via the induction of interferon-inducible gene expression in the HepG2 2.2.15 cell line. The primary objective of the present study was to determine whether or not DDB and/or amantadine exhibit anti-HBV properties, and what mechanisms of action might be involved in such properties. In our study, we were able to determine that DDB stimulates Jak/Stat signaling, and induces the expression of interferon alpha $(IFN-\alpha)$ stimulated genes, most notably 6-16 and ISG12. In addition, the antiviral effectors induced by $IFN-\alpha$, PKR, OAS, and MxA, were regulated in the presence of DDB at its optimal concentration $(250{\mu}g/mL)$, to a degree commensurate with the degree of induction associated with the $IFN-\alpha$ treated group. Finally, we determined that the replication of pregenomic RNA and HBeAg was inhibited by DDB treatment, and this inhibition was maximized when coupled with the administration of amantadine $(25{\mu}g/mL)$. In conclusion, the results of this study demonstrated clearly that DDB, as well as the combination of DDB/amantadine, directly inhibited $IFN-\alpha$ signaling-mediated replication of HBV in infected hepatocytes, and thus may represent a novel treatment for chronic hepatitis B, which would be characterized principally by its improved safety over other treatment strategies.

Keywords

References

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