Role of DNA Repair Systems Inhibition in Carcinogenicity of Metal Compounds
Abstract:Several metals have been shown to be carcinogenic to humans and/or experimental animals. The mechanisms of their carcinogenicity are not completely understood, even if DNA repair inhibition seems to be the most probable. Current evidence suggests that DNA repair systems are very sensitive target for nickel (II), cadmium (II), cobalt (II) and arsenic (III) leading to a diminished removal of endogenous and exogenously induced DNA damage, which increase the risk of tumor formation. Metal compounds inhibit DNA repair probably by oxidative damage and direct interactions of metal-ions with reparative enzyme. Metals carcinogenic potential depends from their solubility and oxidation state. Oxidative DNA damage by metal compounds is due to ROS generation by Fenton-type reactions and inactivation of anti-oxidative enzymes. DNA repair inhibition seems to depend on the ability of metal ions to compete with magnesium ions or to displace zinc ions in zinc finger structures of DNA repair enzymes with consequent their inactivation. The DNA repair inhibition has been shown for low non-cytotoxic metal concentrations. DNA repair systems inhibited by metal compounds include essentially base-excision repair (BER) including Formamidopyrimidinglycosilase (Fpg)-oxidized base excision repair and nucleotide excision repair (NER). Several studies on metal inhibition activity use prevalently the comet test, a rapid and sensitive technique, to evaluate direct and oxidative DNA damage and its repair in human cells. Comet test consents to study the influence of metals on the different steps involved in DNA repair, evaluating the recovery of DNA damage induced by exposure to different genotoxic agents in absence or presence of metal compounds. This technique and its modifications can clarify the mechanisms of inhibitory processes of enzymes involved in carcinogenesis and could be a useful tool in the development of new anticancer drugs.
Document Type: Review Article
Affiliations: Department of Occupational Health, ISPESL National Institute for Occupational Safety and Prevention, Via Fontana Candida, 1 - 00040 Monteporzio Catone, Rome, Italy.
Publication date: November 1, 2005
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