Ferredoxin-NADP reductases constitute a family of hydrophilic, monomeric enzymes that contain noncovalently bound flavin adenine dinucleotide as a prosthetic group. These ubiquitous flavoenzymes are present in animals, plants, parasites and prokaryotes, where they catalyze the reversible exchange of electrons between two molecules of a variety of obligatory one-electron carriers, such as ferredoxins and flavodoxins, and a single molecule of NADP. Although FNRs are present in all kingdoms, plant isoforms are 200–500 times more active than their animal or prokaryote counterparts, BYL719 1217486-61-7 property that could explain their notable competency as antioxidants in bacterial models. FNRs have demonstrated to protect proteobacteria and cyanobacteria from oxidative stress. Pisum sativum FNR accomplishes functional complementation of mutant Escherichia coli defective for mrvA gene that are unable to grow aerobically in the presence of the radical propagator methyl viologen. The NADP dependent activities of the reductase were necessary and sufficient for detoxification, without participation of either Fd or Fld in the process. Transgenic tobacco plants expressing knocked down levels of FNR are abnormally prone to photooxidative injury. When grown under autotrophic conditions for 3 weeks, specimens with 20–40% extant reductase underwent leaf bleaching, elevated malondialdehyde levels and membrane damage. Given these antecedents, we hypothesized that pea FNR could be beneficial in the protection of mammalian cells from the oxidative injury produced by cold ischemia/reperfusion. In a previous work, we applied FNR gene transfection to isolated hepatocytes preserved in University of Wisconsin solution and then transplanted into recipient animals. We observed that, after cold preservation, transplanted hepatocytes expressing pea FNR were found in the parenchyma of recipient rat livers in quantities 20–50 times greater than controls and were devoid of the surrounding inflammatory infiltrates normally present when hepatocyte engraftment occurs. These results were indicative of an advantage of FNR-expressing cells during implantation. Two facts were already known: 1- donor hepatocytes show a burst of reactive oxygen species soon after transplantation ; and 2- the obstruction of sinusoids produced by donor hepatocyte arrival through portal circulation recruits Kuppfer cells that exert their local action by releasing of ROS. Consequently, it seemed that FNR transfected hepatocytes could overcome these challenges better and engraft more effectively in the receptor liver than control cells. Since our original hypothesis was that an advantage of FNRexpressing hepatocytes should be due to an antioxidant effect of this transgene, we became interested to assess whether pea FNR protects mammalian cells from oxidative insults in a less complex in vitro model that allowed a direct challenge to oxidants and nonambiguous interpretation of the results. Flavodoxins, on the other hand, are small acidic proteins that transfer electrons at low potentials and contain a non-covalently bound flavin mononucleotide.