In Vitro Interaction Between Homocysteine and Copper Ions: Potential Redox Implications

Abstract

Homocysteine (Hcys) has been implicated in various oxidativestress–related disorders. The presence of a thiol on its structureallows Hcys to exert a double-edge redox action. Depending onwhether Cu2þions occur concomitantly, Hcys can either promoteor prevent free radical generation and its consequences. Wehave addressed in vitro the interaction between Hcys and Cu2þions, in terms of the consequences that such interaction mayhave on the free radical scavenging properties of Hcys and onthe redox state and redox activity of the metal. To this end, weinvestigated the free radical–scavenging, O2-generating, andascorbate-oxidizing properties of the interacting species byassessing the bleaching of ABTSþ radicals, the reduction ofO2-dependent cytochrome c, and the copper-dependent oxidationof ascorbate, respectively. In addition, electron paramagneticresonance and Cu(I)-bathocuproine formation were appliedto assess the formation of paramagnetic complexes and themetal redox state. Upon a brief incubation, the Hcys/Cu2þinteraction led to a decrease in the free radical–scavengingproperties of Hcys, and to a comparable loss of the thiol density.Both effects were partial and were not modified by increasing theincubation time, despite the presence of Cu2þexcess. Dependingon the molar Hcys:Cu2þ ratio, the interaction resulted in theformation of mixtures that appear to contain time-stable andascorbate-reducible Cu(II) complexes (for ratios up to 2:1), andascorbate- and oxygen-redox–inactive Cu(I) complexes (forratios up to 4:1). Increasing the interaction ratio beyond 4:1was associated with the sudden appearance of an O2-generatingactivity. The data indicate that depending on the molar ratioof interaction, Hcys and Cu2þ react to form copper complexesthat can promote either antioxidant or pro-oxidant actions. Wespeculate that the redox activity arising from a large molar Hcysexcess may partially underlie the association between hyperhomocysteinemiaand a greater risk of developing oxidativerelatedcardiovascular diseases.