Effect of dipterinyl calcium pentahydrate on hepatitis B virus replication in transgenic mice

J Transl Med. 2010 Mar 31;8:32. doi: 10.1186/1479-5876-8-32.

Abstract

Background: Dipterinyl calcium pentahydrate (DCP) has previously been shown to inhibit MDA-MB-231 human breast cancer xenographs in nude mice in a manner correlated with increases in plasma IL-12 and IL-4 concentrations, and decreases in plasma IL-6 levels. DCP also inhibits indoleamine 2,3-dioxygenase (IDO), an immuno-inhibitory enzyme, in human PBMCs (Peripheral Blood Mononuclear Cells).

Methods: In the present study, DCP was administered per os, once daily for 14 days to hepatitis B virus (HBV) transgenic mice at 23, 7.3, and 2.3 mg/(kg d). Multivariate stepwise regression and MANOVA analyses, by gender and treatment, of liver HBV DNA and RNA measures, liver core and serum HBe antigen assays, serum cytokine/chemokine profiles, and IDO metabolite measurements were performed.

Results: DCP caused a significant dose-response reduction of log liver HBV DNA as measured by PCR in the female HBV mice. The gender dependence of the anti-HBV DNA activity was explained by the DCP Effects Model (DCP-EM) (p = .001) which includes three serum biomarker changes caused by DCP: 1) decreased MCP-1; 2) decreased Kyn/Trp (an estimation of IDO activity); and 3) increased GM-CSF.

Conclusions: Immunomodulation via IDO or TDO (tryptophan 2,3-dioxygenase) pathways, along with serum MCP-1 and GM-CSF are proposed to play roles in the anti-HBV mechanism of DCP based upon their coordinated modulation in the reduction of viral DNA replication in HBV mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Compounds / chemistry
  • Calcium Compounds / pharmacology*
  • DNA, Viral / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Hepatitis B virus* / drug effects
  • Hepatitis B virus* / genetics
  • Hepatitis B virus* / physiology
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Liver / drug effects
  • Liver / virology
  • Male
  • Mice
  • Mice, Transgenic
  • Molecular Structure
  • Tryptophan Oxygenase / metabolism
  • Virus Replication / drug effects*

Substances

  • Calcium Compounds
  • DNA, Viral
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Tryptophan Oxygenase