Hanspeter Naegeli Libri

In response to a plethora of genotoxic reactions, all forms of life ranging from bacteria to man possess multiple systems for either repairing damage inflicted on DNA or, alternatively, increasing their tolerance to it. This book summarizes existing knowledge on how these DNA damage processing pathways are selectively targeted to defective sites in the mammalian genome. It discusses the biological, clinical and toxicological implications of DNA damage recognition in a comprehensive manner. For example, DNA adducts formed by the anticancer drug cisplatin are recognized by excision repair factors, transcription factors, DNA polymerases, RNA polymerases or recombination factors. The consequences of each of these molecular recognition functions are discussed in detail.

Recent findings of acrylamide in foods have sparked new interest in assessing human health hazards due to long-term exposure to this vinyl compound. Acrylamide is tumorigenic at high doses in rodents but cancer risk projections in the human population remain uncertain as the molecular pathogenesis of acrylamide at the low dietary uptake is not understood. The present work addresses the question whether transcriptional responses amplify the known genotoxicity of acrylamide. Using DNA microarrays and PCR validations, we assessed genome-wide messenger profiles induced in human cells by acrylamide and glycidamide, its more reactive metabolite. The expression changes are characterized by the up-regulation of cytoprotective factors including the GSH system and multiple antioxidants. Low-dose experiments indicate that EPHX1 represents the most sensitive biomarker for glycidamide exposure. At higher concentrations, glycidamide induces markers of tumor progression, while growth suppressors and cell adhesion molecules are down-regulated. These findings indicate that tumor-promoting transcriptional signatures may be expected only at higher doses that exceed the ordinary dietary exposure.