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

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Abstract
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‐γ 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.