Application of UV-Induced Unscheduled DNA-Synthesis Measurements in Human Genotoxicological Risk Assessment

Abstract

Cancer development is a long-term, multistep process with a complex interplay between genes and environment. The magnitude of environmental effects depends on the presence or absence of genetic susceptibility of the subjects to certain cancer types. Molecular epidemiological studies in cancer have proved, that besides target cell genetic instability, the presence of triggering environmental exposure is critical in cancer development [Albertini & Hayes 1997, Newby &Howard 2005]. The biomarker responses, exposure character and the route of exposure of different environmental factors (chemicals, physical agents and biological agents) are also important in causing tumors especially in the cases of occupational cancer [Ward 1995]. The EPA Guidelines for carcinogen Risk Assessment [EPA 2005] is based on the mode of action of chemicals, such as interaction with DNA, cytotoxicity, or binding to the receptors modifying signal pathways. There are several natural compounds – so called chemopreventive agents- which are able to modify the genotoxic or mutagenic response (Ames 1983) in different organisms. These vitamins, antioxidants, phytochemicals, micro nutrients are available on the market without knowing their mode of action. Mutagenesis caused by environmental chemicals or physical agents can be prevented by protection of the cell’s DNA replication, increasing the repair capacity or delaying cell replication to allow enough time to make a complete repair of damaged cells.  Antioxidants are able to protect the cells from oxidative stress, and stimulate the phase I reactions including oxidation, reduction, and hydrolysis of xenobiotics by the monoxigenase detoxicating key enzymes, such as CYP450 [Xu et al.1996, Poulsen &Loft]. These changes increase the polarity of these molecules and help to conjugate them in phase II to glucuronic acid, acetic acid and sulfuric acid which are the physiological ways to eliminate active metabolites that are genotoxic to the target cells. The best studied crucial early event in carcinogenesis is chromosomal aberration, including microsatellite instability, abnormal number of chromosomes (aneuploidy), gene amplification or the loss of heterozygosity of tumor suppressor genes. By reducing chromosomal mutation via chemoprevention, the cell may be able to survive the genotoxic effects without any permanent damage, or it is able to go through the physiological pathway of apoptosis, without mutation occurring in the P53 gene [Lowe&Lin 2000].