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5TH INTERNATIONAL CONFERENCE ON METALLOTHIONEIN SYMPOSIUM PAPERS

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

Catalina Carrasco-Pozo^*,, Alejandro Álvarez-Lueje, Claudio Olea-Azar, Camilo López-Alarcón and Hernán Speisky^*,,1

^* Micronutrients Unit, Nutrition and Food Technology Institute; Department of Pharmacological and Toxicological Chemistry; and Department of Analytical Chemistry, Faculty of Chemical & Pharmaceutical Sciences; University of Chile, Santiago, Chile

To whom requests for reprints should be addressed at ¹ Miconutrients Unit, Nutrition and Food Technology Institute (INTA), University of Chile, El Líbano 5524, Macul, P.O. Box 138–11, Santiago, Chile. E-mail: hspeisky{at}inta.cl

Abstract

Homocysteine (Hcys) has been implicated in various oxidative stress–related disorders. The presence of a thiol on its structure allows Hcys to exert a double-edge redox action. Depending on whether Cu²⁺ ions occur concomitantly, Hcys can either promote or prevent free radical generation and its consequences. We have addressed in vitro the interaction between Hcys and Cu²⁺ ions, in terms of the consequences that such interaction may have on the free radical scavenging properties of Hcys and on the redox state and redox activity of the metal. To this end, we investigated the free radical–scavenging, O₂^·–-generating, and ascorbate-oxidizing properties of the interacting species by assessing the bleaching of ABTS^·+ radicals, the reduction of O₂^·–-dependent cytochrome c, and the copper-dependent oxidation of ascorbate, respectively. In addition, electron paramagnetic resonance and Cu(I)-bathocuproine formation were applied to assess the formation of paramagnetic complexes and the metal redox state. Upon a brief incubation, the Hcys/Cu²⁺ interaction led to a decrease in the free radical–scavenging properties of Hcys, and to a comparable loss of the thiol density. Both effects were partial and were not modified by increasing the incubation time, despite the presence of Cu²⁺ excess. Depending on the molar Hcys:Cu²⁺ ratio, the interaction resulted in the formation of mixtures that appear to contain time-stable and ascorbate-reducible Cu(II) complexes (for ratios up to 2:1), and ascorbate- and oxygen-redox–inactive Cu(I) complexes (for ratios up to 4:1). Increasing the interaction ratio beyond 4:1 was associated with the sudden appearance of an O₂^·–-generating activity. The data indicate that depending on the molar ratio of interaction, Hcys and Cu²⁺ react to form copper complexes that can promote either antioxidant or pro-oxidant actions. We speculate that the redox activity arising from a large molar Hcys excess may partially underlie the association between hyper-homocysteinemia and a greater risk of developing oxidative-related cardiovascular diseases.

Key Words: homocysteine • copper ions • free radicals • antioxidants • complex formation • redox consequences