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-α) stimulated genes, most notably 6–16 and ISG12. In addition, the antiviral effectors induced by IFN-α, PKR, OAS, and MxA, were regulated in the presence of DDB at its optimal concentration (250 μg/mL), to a degree commensurate with the degree of induction associated with the IFN-α 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 μg/mL). In conclusion, the results of this study demonstrated clearly that DDB, as well as the combination of DDB/amantadine, directly inhibited IFN-α 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.
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References
Acs, G., Sells, M. A., Purcell, R. H., Price, P., Engle, R., Shapiro, M., and Popper, H., Hepatitis B virus produced by transfected HepG2 cells causes hepatitis in chimpanzees.Proc. Natl. Acad. U.S.A., 84, 4641–4644 (1987).
Doong, S. L., Tsai, C. H., Schinazi, R. F., Liotta, D. C., and Cheng, Y. C., Inhibition of the replication of hepatitis B virus in vitro by 2′,3′-dideoxy-3′-thiacytidine and related analogues.Proc. Natl. Acad. Sci. U.S.A., 88, 8495–8499 (1991).
Fernandez, M., Quiroga, J. A., and Carreno, V., Hepatitis B virus downregulates the human interferon-inducible MxA promoter through direct interaction of precore/core proteins.J. Gen. Virol., 84, 2073–2083 (2003).
Gao, M., Zhang, J., and Liu, G., Effect of diphenyl dimethyl bicarboxylate on concanavalin A-induced liver injury. Liver Int., 25, 904–912 (2005).
Gjermandersen, I. M., Justesen, J., and Martenen, P. M., The interferon induced gene ISG12 is regulated by various cytokines as the gene 6–16 in human cell line.Cytokine, 12, 233–238 (2000).
Guidotti, L. G., Guilhot, S., and Chisari, F. V., Interleukin-2 and alpha/beta interferon down-regulate hepatitis B virus gene expression in vivo by tumor necrosis factor-dependent and-independent pathways.J. Virol., 68, 1265–1270 (1994).
Hershey, J. H., Schowalter, L., and Baily, S., Public health perspective on vaccine-preventable hepatitis: integrating hepatitis A and B vaccines into public health settings.Am. J. Med., 118, 100S-108S (2005).
Jacobs, B. L. and Langland, J. O., When two strands are better than one: the mediators and modulators of the cellular responses to double stranded RNA.Virology, 219, 339–349 (1996).
Joo, S. S., and Lee, D. I., The potential anti-HBV effect of amantadine in combination with ursodeoxycholic acid and biphenyl dimethyl dicarboxylate in HepG2 2.2.15 cells.Arch. Pharm. Res., 28, 451–457 (2005).
Lee, W. M., Hepatitis B virus infection.N. Engl. J. Med., 337, 1733–1745 (1997).
Leung, N., Treatment of chronic hepatitis B: case selection and duration of therapy.J. Gastroen. Hepatol., 17, 409–414 (2002).
Liaw, Y. F., Leung, N. W., Chang, T. T., Guan, R., Tai, D. I., Ng, K. Y., Chien, R. N., Dent, J., Roman, L., Edmundson, S., and Lai, C. L., Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.Gastroenterology, 119, 172–180 (2000).
Lim, Y. S. and Suh, D. J., Current antiviral therapy for chronic hepatitis B.J. Korean Med. Sci., 19, 489–494 (2004).
Lok, A. S., Chronic hepatitis B.N. Engl. J. Med., 346, 1682–1683 (2002).
Malik, A. H. and Lee, W. M., Chronic hepatitis B virus infection: treatment strategies for the next millennium.Ann. Intem. Med., 132, 723–731 (2000).
Morita, K., Tanaka, K., Saito, S., Kitamura, T., Kondo, T., Sakaguchi, T., Morimoto, M., and Sekihara, H., Expression of interferon receptor genes (IFNAR1 and IFNAR2 mRNA) in the liver may predict outcome after interferon therapy in patients with chronic genotype 2a or 2b hepatitis C virus infection.J. Clin. Gastroenterol., 26, 135–140 (1998).
Nassal, M. and Schaller, H., Hepatitis B virus replication — an update.J. Viral. Hep., 3, 217–226 (1996).
Parkin, D. M., Bray, F., Ferlay, J., and Pisani, P., Estimating the world cancer burden: Globocan 2000.Int. J. Cancer., 94, 153–156 (2001).
Perrillo, R., Schiff, E., Yoshida, E., Statler, A., Hrsch, K., Wright, T., Gutfreund, K., Lamy, P., and Murray, A., Adefovir dipivoxil for the treatment of lamivudine-resistance hepatitis B mutants.Hepatology, 32, 129–134 (2000).
Samuel, C. E., Antiviral actions of interferons.Clin. Microbiol. Rev., 14, 778–809 (2001).
Younger, H. M., Bathgate, A. J., and Hayes, P. C., Review article: nucleoside analogues for the treatment of chronic hepatitis B.Aliment. Pharmacol. Ther., 20, 1211–1230 (2004).
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Joo, S.S., Won, T.J., Kim, M.J. et al. Interferon signal transduction of biphenyl dimethyl dicarboxylate/amantadine and anti-HBV activity in HepG2 2.2.15. Arch Pharm Res 29, 405–411 (2006). https://doi.org/10.1007/BF02968591
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DOI: https://doi.org/10.1007/BF02968591