Kinetics and Mechanism of Bioreduction of Nitrimidazoles as Hypoxia Probes

Jess Pacheco-Torres¹, Paloma Ballesteros², Pilar Lopez-Larrubia¹, Sebastin Cerdn¹

2-Nitroimidazole derivatives have been traditionally used as molecular markers of hypoxia due to their preferential reduction and subsequent trapping in vivo under hypoxic conditions. However, the reduction mechanism and its rate determining steps remained largely unexplored. We show that it is the intracellular redox state (NADP/NADPH, GSSG/GSH), rather than the oxygen tension by itself, what determines the reduction rate of these compounds, the reaction rate being limited mainly by the GSH concentration. This is a general mechanism occurring in all 2-Nitroimidazole derivatives investigated. Also, we report the appearance and the kinetics of new signals belonging to reaction intermediates.