Cu²⁺-Induced Isoproterenol Oxidation into Isoprenochrome in Adult Rat Calcium-Tolerant Cardiomyocytes

Abstract

Sustained high levels of circulating catecholamines may induce cardiotoxicity. There is increasing evidence that this could result from catecholamine oxidation into aminochromes, which is catalyzed by transition metals. In fact, it has already been shown that copper-induced oxidation of the beta-agonist isoproterenol decreases the viability of isolated cardiomyocytes. Thus, the aim of this work was to contribute for the clarification of the mechanisms underlying the toxic effects of isoproterenol, Cu2+ and their concomitant effect in isolated rat cardiomyocytes. Freshly isolated calcium-tolerant cardiomyocytes from adult rat were incubated with 1 mM isoproterenol, 20 microM Cu2+ or with both during 4 h. Isoproterenol and its aminochrome (isoprenochrome), and reduced and oxidized glutathione were measured at each hour in the incubation medium and in the cells. The intracellular activities of the selenium-dependent glutathione peroxidase, glutathione reductase, and glutathione-S-transferase were determined after 4 h of incubation. Isoprenochrome was found in both cells and incubation medium in samples incubated with isoproterenol alone. However, in the isoproterenol plus Cu2+ samples, a greater depletion of isoproterenol accompanied by a proportional increase of isoprenochrome was observed. This higher ISO oxidation resulted in the depletion of intracellular glutathione and in the release of oxidized glutathione to the incubation medium. The content of total glutathione (intra- and extracellular) and the intracellular activity of the selenium-dependent glutathione peroxidase, glutathione reductase, and glutathione-S-transferase were also decreased in the isoproterenol plus Cu2+ samples. These results seem to indicate that the oxidative stress resulting from catecholamine/transition metal association may contribute to catecholamine cardiotoxicity.

Neurotoxicity of Ecstasy Metabolites in Rat Cortical Neurons, and Influence of Hyperthermia

“…OrthoQuinones, aminochromes, and GSH conjugates are known to cause irreversible inhibition of enzymes that possess either a GSH binding site and/or cysteine residues critical for enzyme function (Monks et al, 2004). Likewise, inhibition of glutathione reductase and glutathione S-transferase by quinones, as well as glutathione reductase, selenium-dependent glutathione peroxidase, and glutathione S-transferase by aminochromes has been reported (Remiã o et al, 2002). Quinone thioethers have the ability to interfere with redox cycle, produce ROS, and arylate tissue macromolecules (Kleiner et al, 1998).…”

“…MDMA and MDA are O-demethylenated to N-methyl-␣-methyldopamine (N-Me-␣-MeDA) and ␣-methyldopamine (␣-MeDA), respectively (Lim and Foltz, 1988;Kumagai et al, 1991), both of which are catechols that can undergo oxidation to the corresponding o-quinones. These quinones are highly redox-active molecules that can undergo redox cycling, which originates semiquinone radicals and leads to the generation of ROS and RNS (Bolton et al, 2000;Remiã o et al, 2002). The catecholamine oxidation process can be catalyzed under physiological conditions by oxidative enzymes, such as xanthine oxidase, peroxidases, lipoxygenase, several copper-containing catechol oxidases, or in the presence of metal ions such as Cu 2ϩ , Mn 2ϩ , Fe 3ϩ , and several copper and ferric chelates (Bindoli et al, 1992).…”

Synthesis and Cyclic Voltammetry Studies of 3,4-Methylenedioxymethamphetamine (MDMA) Human Metabolites

“…8,9) These quinones are highly active redox molecules, which can enter redox cycles with their semiquinone radicals, leading to formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). 10,11) The toxicity of these metabolites has been corre- lated with electron transfer (ET), ROS formation and consequent oxidative stress (OS). 12,13) A cyclic voltammetry study on the oxidation-reduction behavior of bioactive catecholamines 14,15) showed the straightforward formation of the corresponding oquinones via electro-oxidation (a two electron transfer process).…”

Hepatotoxicity of 3,4-methylenedioxyamphetamine and ?-methyldopamine in isolated rat hepatocytes: formation of glutathione conjugates

“…The activity of GR, which catalyzes the NADPH-dependent reduction of GSSG to GSH, is crucial to maintain a high cellular GSH/GSSG ratio. Inhibition of GR and GST by quinones, as well as GR, GPX and GST by aminochromes, has been reported (Remia˜o et al 1999(Remia˜o et al , 2002.…”