Ribavirin inhibits angiogenesis by tetrahydrobiopterin depletion.
Ribavirin is a broad-spectrum antiviral drug that is used to treat hepatitis C virus (HCV)-infected patients. The virological response after ribavirin treatment appears to be insufficient to fully explain ribavirin-induced beneficial effects. Angiogenesis plays a pathogenic role in HCV-induced liver damage. Here, we investigated the influence of therapeutic ribavirin concentrations on angiogenesis. Ribavirin inhibited endothelial cell tube formation in vitro and vessel formation in the chick chorioallantoic membrane assay in vivo. Ribavirin inhibits inosine monophosphate dehydrogenase, which causes depletion of cellular GTP and in turn reduction of cellular tetrahydrobiopterin levels. The availability of tetrahydrobiopterin limits NO production by endothelial NO synthase. Ribavirin reduced levels of tetrahydrobiopterin (as revealed by HPLC), NO (as revealed by electron spin resonance spectroscopy), and cGMP (as revealed by RIA) in endothelial cells. Addition of tetrahydrobiopterin or NO prevented ribavirin-induced tube formation inhibition. In conclusion, angiogenesis inhibition by ribavirin has not been described before. This inhibition may contribute to ribavirin-induced pharmacological effects including adverse events.
Michaelis
Martin
M
Institut für Medizinische Virologie, Klinikum der Johann Wolfgang Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
Michaelis
Ruth
R
Suhan
Tatyana
T
Schmidt
Helmut
H
Mohamed
Annisuddin
A
Doerr
Hans Wilhelm
HW
Cinatl
Jindrich
J
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002645:Chickens; D002851:Chromatography, High Pressure Liquid; D006152:Cyclic GMP / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011863:Radioimmunoassay; D012254:Ribavirin / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D001708:Biopterins; D009569:Nitric Oxide; D012254:Ribavirin; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin; D006152:Cyclic GMP