The cellular response to the genotoxic insult: the question of threshold for genotoxic carcinogens

Genotoxic carcinogens can lead to DNA mutations with the potential to cause cancer. Typically, a series of mutation events are needed before malignancy occurs so a single, small exposure may not result in disease. Also, cells have anarmoury of defence mechanisms which, to a degree, counter the effects of mutagens. Distinguishing the point at which exposure to a carcinogen increases mutation rates beyond the background level is challenging. In fact, there is now general agreement that, for genotoxic carcinogens, no specific threshold can be identified. However, NOAELs (No Observed Adverse Effect Levels) may be used in the process of establishing a dose-response relationship. These denote the level of exposure at which there is no significant increase in adverse effectsin the exposed population when compared to an appropriate control. Such a scientifically defendable threshold allows us to propose health based exposure limits for genotoxic carcinogens. This book describes the various cellular defence mechanisms individually and explains how they are regulated. The processes covered include metabolic inactivation, epigenetic regulation, scavenging mechanisms, DNA-repair and apoptosis. It also considers dose-dependent threshold mechanisms of carcinogenesis and the rate limiting parameters. Aimed at graduate level and above, the book discusses the consequences of genotoxic evaluationand urges readers to question the idea that even low exposures present a cancer risk. ÍNDICE: Introduction: The rationale for thresholds for genotoxic carcinogens; Part 1. Threshold effects observed in experimental studies: Mechanisms responsible for the chromosome and gene mutations driving carcinogenesis: implications for dose-response characteristics of mutagenic carcinogens; Dose-effect relationships of DANN-reactive liver carcinogens; DNA alkylation and repair after EEMS exposure: Where do the thresholds for mutagenic/clastogenic effects arise? Part 2. Metabolic inactivation of genotoxic reactants: Enzymatic detoxification of endogenously produced mutagenic carcinogens maintaining cellular homeostasis; Phase 2 detoxifying enzymes and anti-oxygen defense mechanisms in the inactivation of genotoxic carcinogens; Part 3. DNA repair: Consequences andRepair of oxidative DNA damage; The plasticity of DNA damage response during cell differentiation: pathways and consequences; Tumor suppressor protein-mediated regulation of base excision repair in response to DNA damage; Part 4. Apoptosis: Survival and death strategies in cells exposed to genotoxin; Differentmodes of cell death induced by DNA damage; Transcriptional inhibition by DNA damage as a trigger of cell death; Part 5. Epigenetic mechanisms: The interplay

• ISBN: 978-1-84973-177-5
• Editorial: Royal Society of Chemistry
• Encuadernacion: Cartoné
• Páginas: 480
• Fecha Publicación: 31/07/2012
• Nº Volúmenes: 1
• Idioma: Inglés