Medicinal Chemistry, 2006, 2, 407-413 407 1573-4064/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd. Folic Acid as a Fenton-modulator: Possible Physiological Implication Birija S. Patro 1 , Soumyakanti Adhikari 2 , Tulsi Mukherjee 2 , and Subrata Chattopadhyay 1, * 1 Bio-Organic Division, 2 Radiation Chemistry and Chemical Dynamics Division, Bhabha Atomic Research Centre, Mumbai - 400 085, India Abstract: Acting as a redox switch, folic acid (1) might be a promising iron modulator to protect cellular machinery against oxidative stress and iron overload. The vitamin 1 can directly control the iron concentration by oxidizing it even if present in chelated forms. In addition, during its role as a reducing agent for the biologically relevant reactive oxygen spe- cies (ROS), it furnishes 6-formyl pterin. This folate-derived intermediate possesses a stronger Fe 2+ -oxidizing capacity than 1. Thus, compound 1 can reduce the iron toxicity in two ways. Although, the Fe 2+ -oxidizing capacity is nullified in the presence of a strong biological reductant like ascorbic acid, this property may play a predominant role during pathogene- sis when the cellular ascorbic acid levels deplete significantly. The iron-modulatory property of 1 was also confirmed with the L929 mouse fibroblast cell line. INTRODUCTION Folic acid (1) and its derivatives are essential cofactors for de novo synthesis of amino acids and nucleic acids and are also important for cell division. Folate deficiency is known to cause numerous genetic abnormalities, promote cardiovascular disease [1] and neural defects [2] via hyper- homocysteinemia and lead to carcinogenesis and apoptosis [3] due to the increased level of uracil. Its supplementation has been suggested as a preventive measure against these ailments [4,5]. Given that oxidative stress has been impli- cated for many of the diseases, we recently studied the anti- oxidant activity of 1 and found it to scavenge a diverse array of reactive oxygen species (ROS) efficiently [6]. This, in part, might account for its therapeutic potential. It is well recognized that the essential element, iron po- tentiates oxygen toxicity causing enhancement of hepatocar- cinoma occurrence [7], repurfusion injury [8], liver damage [9] etc. Proper regulation of iron assimilation would prevent oxidative stress and diseases related to iron overload. Evolu- tion of new strategies for control of iron assimilation and metabolism, thus, has assumed great importance. To this end, exploration of natural dietary antioxidants as iron modulators is appealing because of their possible non- toxicity. The present study was specifically aimed at assess- ing the potential of 1 in controlling the iron-mediated oxida- tive reactions. The results, as discussed in this paper, clearly support for the first time, its positive role as an effective iron modulator via a mechanism involving oxidation of Fe 2+ by 1 itself, or one of its oxidized metabolites. RESULTS AND DISCUSSION The Fenton mediated oxidation of 2-deoxyribose is a reliable method for assessing the capacity of a test com- pound in modulating cellular iron even at a very low concen *Address correspondence to this author at the Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai - 400 085, India; Fax: 91-22- 25505151; E. Mail: schatt@apsara.barc.ernet.in tration [10] and was extensively used in the present study. Fig. (1) shows the comparative protective activities of 1 and mannitol against Fe 2+ -H 2 O 2 mediated oxidation of 2- deoxyribose. Compound 1 could prevent the 2-deoxyribose Fig. (1). Concentration dependent protective activities of 1 and mannitol against Fe 2+ (80 M)-H 2 O 2 (200 M) induced oxidation of 2-deoxyribose (2.8 mM) in KH 2 PO 4 -KOH (100 mM) buffer at pH 7.4 in the absence and presence of EDTA (100 M). The reac- tions were conducted for 60 min. The concentrations of 1 and man- nitol were x 10 -3 and x 10 -2 respectively. -1 (with EDTA), -1 (without EDTA), -mannitol (with EDTA) and -mannitol (with- out EDTA). Values are mean+ S.E (n = 4). oxidation concentration dependently, both in the presence and absence of a strong iron chelator, EDTA. The protec- tive activity of 1 was better in the presence of EDTA than its absence. In the absence of EDTA, Fe 2+ gets com- plexed with 2-deoxyribose, leading to the generation of