Neopterin derivatives together with cyclic guanosine monophosphate induce c-fos gene expression.

We have previously shown that neopterin enhances hydrogen peroxide and chloramine T activity in a luminol-dependent chemiluminescence assay and strengthens toxicity of these agents against bacteria at slightly alkaline pH (pH 7.5), while 7,8-dihydroneopterin was shown to be a scavenger independent of the pH value. Besides various oxidants, phenolic antioxidants were shown to specifically induce expression of the c-fos and c-jun mRNAs. Using an inducible cfosCAT reporter transactivation system we studied the function of the pteridine derivatives on c-fos transactivation. For the first time, we demonstrate that neopterin and 7,8-dihydroneopterin, particularly together with cyclic guanosine monophosphate, induce c-fos gene expression. In humans, interferon-gamma induces the release of neopterin and 7,8-dihydroneopterin and also the synthesis of nitric oxide radical which in turn stimulate the formation of cGMP. Thus, in certain situations all three substances, namely neopterin, 7,8-dihydroneopterin and cGMP, may be present locally and even in the circulation at the same time. Based on our findings this constellation would significantly enhance the risk of c-fos gene expression and therefore promote tumour growth and development.