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Research Topics, Division of Biological Chemistry, Biocentre,  Innsbruck Medical University 

Pharmacological effects of tetrahydrobiopterin

In analogy to folates and antifolates, we designed the H₄-biopterin-analogue 4-amino-H₄-biopterin and showed that it is an effective inhibitor of all three NO synthase isoenzymes with a preference for the cytokine-induced enzyme. In vivo, 4-amino-H₄-biopterin prolonged allograft survival in a mouse heart transplantation model with an efficacy comparable to cyclosporine A (1) and rescued rats from septic shock (2). However, the immunosuppressive effect of 4-amino-H₄-biopterin cannot be entirely explained by its capacity to inhibit NO synthase because in different experimental settings, the cofactor of NO synthase, i.e. H₄-biopterin, and the inhibitor of NO synthase, i.e. 4-amino-H₄-biopterin have similar effects. In mouse macrophages, we showed that H₄-biopterin and its amino-analogue added to culture media suppressed NO synthase gene expression via hydrogen peroxide formation and induced apoptosis. In a mouse model, cardiac allograft survival was prolonged by both H₄-pteridines independently from their effect on NO synthase expression or activity (3), whereas on dendritic cells only the amino analogon selectively suppressed  MHC class II protein content and antigen response (4).

1. Brandacher G, Zou Y, Obrist P, Steurer W, Werner-Felmayer G, Margreiter R, Werner ER (2001) The 4-amino analogue of tetrahydrobiopterin efficiently prolongs murine cardiac-allograft survival. J Heart Lung Transplant 20:747-749
2. Bahrami S, Fitzal F, Peichl G, Gasser H, Fürst W, Banerjee A, Strohmaier W, Redl H, Werner-Felmayer G, Werner ER (2000). Protection against endotoxemia in rats by a novel tetrahydrobiopterin analogue. Shock 13:386-391
3. Brandacher G, Maglione M, Schneeberger S, Obrist P, Thoeni G, Wrulich OA, Werner-Felmayer G, Margreiter R, Werner ER (2006) Tetrahydrobiopterin compounds prolong allograft rejection independently of their effect on nitric oxide synthase activity.Transplantation 81:583-589
4. Thoeni, G, Stoitzner, P, Brandacher, G, Romani, N, Heufler, C, Werner-Felmayer, G, Werner  ER (2005) Tetrahydro-4-aminobiopterin attenuates dendritic cell induced T cell priming independently from inducible nitric oxide synthase. J Immunol 174:7584-7591