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Different Mechanisms Between Copper and Iron in Catecholamines-Mediated Oxidative DNA Damage and Disruption of Gene Expression In Vitro

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Abstract

Catechols produce reactive oxygen species (ROS) and induce oxidative DNA damage through reduction–oxidation reactions with metals such as copper. Here, we examined oxidative DNA damage by neurotransmitter catecholamines in the presence of copper or iron and evaluated the effects of this damage on gene expression in vitro. Dopamine induced strand breaks and base oxidation in calf thymus DNA in the presence of Cu(II) or Fe(III)-NTA (nitrilotriacetic acid). The extent of this damage was greater for Cu(II) than for Fe(III)-NTA. For the DNA damage induced by dopamine, the responsible reactive species were hydrogen peroxide and Cu(I) for Cu(II) and hydroxyl radicals and Fe(II) for Fe(III)-NTA. Cu(II) induced DNA conformational changes, but Fe(III)-NTA did not in the presence of dopamine. These differences indicate different modes of action between Cu and Fe-NTA with regard to the induction of DNA damage. Expression of the lacZ gene coded on plasmid DNA was inhibited depending on the extent of the oxidative damage and strand breaks. Endogenous catecholamines (dopamine, adrenaline, and noradrenaline) were more potent than catechols (no aminoalkyl side chains) or 3,4-dihydroxybenzylamine (aminomethyl side chain). These results suggest that the metal-mediated DNA damage induced by dopamine disrupts gene expression, and leukoaminochromes (further oxidation products of O-quinones having aminoethyl side chain) are involved in the DNA damage. These findings indicate a possibility that metal (especially iron and copper)-mediated oxidation of catecholamines plays an important role in the pathogenesis of neurodegenerative disorders including Parkinson’s disease.

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Acknowledgments

The authors thank Dr. T. Ezure of Shimadzu Corporation for the gift of pTD1-Gal; Ms. Haruka Murase and Ms. Saori Maeda for their technical assistances. This research was supported in part by Academic Frontier Project for Private Universities; matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology).

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  1. Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 468-8503, Japan

    Yoshihiko Nishino, Motozumi Ando, Rena Makino, Koji Ueda, Yoshinori Okamoto & Nakao Kojima

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  1. Yoshihiko Nishino
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  2. Motozumi Ando
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  3. Rena Makino
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  4. Koji Ueda
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  5. Yoshinori Okamoto
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Correspondence to Nakao Kojima.

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Nishino, Y., Ando, M., Makino, R. et al. Different Mechanisms Between Copper and Iron in Catecholamines-Mediated Oxidative DNA Damage and Disruption of Gene Expression In Vitro. Neurotox Res 20, 84–92 (2011). https://doi.org/10.1007/s12640-010-9226-7

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