NEOPTERIN MODULATES TOXICITY MEDIATED BY REACTIVE OXYGEN AND CHLORIDESPECIES

Neopterin, a pyrazino-pyrimidine derivative, is synthesized in excess by human monocytes/macrophages upon stimulation with interferon-gamma, a cytokine derived from activated T-cells. Neopterin is furthermore p roduced constitutively. A relatively constant ratio between neopterin and its reduced form, 7,8-dihydroneopterin, has been described in huma n serum. In the study presented here we tested the ability of neopteri n and its reduced form to modulate the effects of cytotoxic substances like hydrogen peroxide or hypochlorous acid and N-chloramine derivati ves. We show that 7,8-dihydroneopterin potently reduces biological and chemical effects of these substances independently from the pH value. In contrast, at slightly alkaline pH (pH 7.5) neopterin enhances hydr ogen peroxide and chloramine-T activity. This is demonstrated by incre ase of signal intensity in a luminol assay and also by enhancement of toxicity towards bacteria. Thus, the macrophage derived substance neop terin is able both to enhance and to reduce cytotoxicity in dependence of pH value and its oxidation state, and it may have a pivotal role i n modulation of macrophage mediated effector mechanism.