Serial review: oxidative DNA damage and repair
The role of metals in site-specific DNA damage with reference to carcinogenesis1, 2

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Abstract

We reviewed the mechanism of oxidative DNA damage with reference to metal carcinogenesis and metal-mediated chemical carcinogenesis. On the basis of the finding that chromium (VI) induced oxidative DNA damage in the presence of hydrogen peroxide (H2O2), we proposed the hypothesis that endogenous reactive oxygen species play a role in metal carcinogenesis. Since then, we have reported that various metal compounds, such as cobalt, nickel, and ferric nitrilotriacetate, directly cause site-specific DNA damage in the presence of H2O2. We also found that carcinogenic metals could cause DNA damage through indirect mechanisms. Certain nickel compounds induced oxidative DNA damage in rat lungs through inflammation. Endogenous metals, copper and iron, catalyzed ROS generation from various organic carcinogens, resulting in oxidative DNA damage. Polynuclear compounds, such as 4-aminobiphenyl and heterocyclic amines, appear to induce cancer mainly through DNA adduct formation, although their N-hydroxy and nitroso metabolites can also cause oxidative DNA damage. On the other hand, mononuclear compounds, such as benzene metabolites, caffeic acid, and o-toluidine, should express their carcionogenicity through oxidative DNA damage. Metabolites of certain carcinogens efficiently caused oxidative DNA damage by forming NADH-dependent redox cycles. These findings suggest that metal-mediated oxidative DNA damage plays important roles in chemical carcinogenesis.

Introduction

A number of metals have carcinogenic potentials. The mechanism of metal carcinogenesis has been extensively investigated. In 1986, we proposed the hypothesis that metal carcinogenesis involves endogenous reactive oxygen species (ROS) generation (Fig. 1), since we discovered that chromium (VI), which has been confirmed to be a human carcinogen, induced oxidative DNA damage in the presence of hydrogen peroxide (H2O2) [1]. Thereafter, we have reported that various carcinogenic metal compounds are capable of causing oxidative DNA damage in the presence of H2O2 [2], [3], [4], [5]. This hypothesis has been supported by a number of studies on oxidative DNA damage in vivo induced by carcinogenic metal compounds. These metal compounds showed different site specificity depending on reactive species causing DNA damage. In addition, we have also found that lead and nickel compounds can induce site-specific DNA damage in vivo through indirect mechanisms.

Metals are considered to act as not only carcinogens but also co-carcinogens that activate carcinogenic chemicals. We have also demonstrated that a number of organic carcinogens induce oxidative DNA damage through metal-catalyzed ROS generation. Here we discuss the mechanisms of (i) metal carcinogenesis through oxidative DNA damage and (ii) the role of metals, particularly copper and iron, in carcinogenesis induced by aromatic hydrocarbons and aromatic nitro and amino compounds through oxidative DNA damage.

Section snippets

Metal carcinogenesis

Carcinogenic risks of metal compounds to humans have been evaluated by the International Agency for Research on Cancer (IARC). Chromium (VI), nickel (II), beryllium, cadmium, and arsenic compounds have been confirmed to be human carcinogens. Cobalt (II) and ferric nitrilotriacetate [Fe(III)-NTA] have shown carcinogenic effects in animal studies and are possibly carcinogenic to humans [6]. We found that DNA damage could be induced by carcinogenic metal compounds through ROS generation. On the

The role of metals in chemical carcinogenesis

We demonstrated that a large part of weakly mutagenic and nonmutagenic carcinogens appear to induce carcinogenesis through metal-mediated oxidative DNA damage. Particularly, endogenous metal ions, such as copper and iron, play an important role in ROS generation from various carcinogens, leading to DNA damage. In view of the very tightly controlled physiological uptake and turnover of copper and iron, it is difficult to consider any presence of free copper and iron ions available for the

Role of oxidative DNA damage in chemical carcinogenesis

We have investigated the mechanism of metal-induced carcinogenesis and the role of metals in carcinogenesis induced by various organic chemicals. Transition metal ions catalyze the formation of highly reactive species causing DNA damage, and its site specificity is determined by the chemical property of reactive species. Therefore, metal-catalyzed ROS generation may play a critical role for carcinogenesis induced by a wide variety of chemicals in humans. It is generally accepted that DNA adduct

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    Guest Editor: Miral Dizdaroglu

    2

    This article is part of a series of reviews on “Oxidative DNA Damage and Repair.” The full list of papers may be found on the homepage of the journal.

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