EXSPub Date : 2009-01-01DOI: 10.1007/978-3-7643-8336-7_6
Andreas Luch
{"title":"On the impact of the molecule structure in chemical carcinogenesis.","authors":"Andreas Luch","doi":"10.1007/978-3-7643-8336-7_6","DOIUrl":"https://doi.org/10.1007/978-3-7643-8336-7_6","url":null,"abstract":"<p><p>Cancer is as a highly complex and multifactorial disease responsible for the death of hundreds of thousands of people in the western countries every year. Since cancer is clonal and due to changes at the level of the genetic material, viruses, chemical mutagens and other exogenous factors such as short-waved electromagnetic radiation that alter the structure of DNA are among the principal causes. The focus of this present review lies on the influence of the molecular structure of two well-investigated chemical carcinogens from the group of polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP). Although there is only one additional benzo ring present in the latter compound, DBP exerts much stronger genotoxic and carcinogenic effects in certain tumor models as compared to BP. Actually, DBP has been identified as the most potent tumorigen among all carcinogenic PAHs tested to date. The genotoxic effects of both compounds investigated in mammalian cells in culture or in animal models are described. Comparison of enzymatic activation, DNA binding levels of reactive diol-epoxide metabolites, efficiency of DNA adduct repair and mutagenicity provides some clues on why this compound is about 100-fold more potent in inducing tumors than BP. The data published during the past 20 years support and strengthen the idea that compound-inherent physicochemical parameters, along with inefficient repair of certain kinds of DNA lesions formed upon metabolic activation, can be considered as strong determinants for high carcinogenic potency of a chemical.</p>","PeriodicalId":77125,"journal":{"name":"EXS","volume":"99 ","pages":"151-79"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27936180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EXSPub Date : 2009-01-01DOI: 10.1007/978-3-7643-8336-7_4
David H Phillips, Volker M Arlt
{"title":"Genotoxicity: damage to DNA and its consequences.","authors":"David H Phillips, Volker M Arlt","doi":"10.1007/978-3-7643-8336-7_4","DOIUrl":"https://doi.org/10.1007/978-3-7643-8336-7_4","url":null,"abstract":"<p><p>A genotoxin is a chemical or agent that can cause DNA or chromosomal damage. Such damage in a germ cell has the potential to cause a heritable altered trait (germline mutation). DNA damage in a somatic cell may result in a somatic mutation, which may lead to malignant transformation (cancer). Many in vitro and in vivo tests for genotoxicity have been developed that, with a range of endpoints, detect DNA damage or its biological consequences in prokaryotic (e.g. bacterial) or eukaryotic (e.g. mammalian, avian or yeast) cells. These assays are used to evaluate the safety of environmental chemicals and consumer products and to explore the mechanism of action of known or suspected carcinogens. Many chemical carcinogens/mutagens undergo metabolic activation to reactive species that bind covalently to DNA, and the DNA adducts thus formed can be detected in cells and in human tissues by a variety of sensitive techniques. The detection and characterisation of DNA adducts in human tissues provides clues to the aetiology of human cancer. Characterisation of gene mutations in human tumours, in common with the known mutagenic profiles of genotoxins in experimental systems, may provide further insight into the role of environmental mutagens in human cancer.</p>","PeriodicalId":77125,"journal":{"name":"EXS","volume":"99 ","pages":"87-110"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/978-3-7643-8336-7_4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27936178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EXSPub Date : 2009-01-01DOI: 10.1007/978-3-7643-8336-7_8
Roberto Sánchez-Olea, Mónica R Calera, Alexei Degterev
{"title":"Molecular pathways involved in cell death after chemically induced DNA damage.","authors":"Roberto Sánchez-Olea, Mónica R Calera, Alexei Degterev","doi":"10.1007/978-3-7643-8336-7_8","DOIUrl":"https://doi.org/10.1007/978-3-7643-8336-7_8","url":null,"abstract":"<p><p>DNA damage is at the center of the genesis, progression and treatment of cancer. We review here the molecular mechanisms of the DNA damage inducing small molecules most commonly used in cancer therapy. Cell cycle control and DNA repair mechanisms are known to be activated after DNA damage. Here, we revise recent discoveries related to the cell cycle control and DNA repair processes and how these findings are being utilized for the more efficient, powerful and selective therapies for cancer treatment.</p>","PeriodicalId":77125,"journal":{"name":"EXS","volume":"99 ","pages":"209-30"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27936182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EXSPub Date : 2009-01-01DOI: 10.1007/978-3-7643-8336-7_12
Tong Zhou, Jeff Chou, Paul B Watkins, William K Kaufmann
{"title":"Toxicogenomics: transcription profiling for toxicology assessment.","authors":"Tong Zhou, Jeff Chou, Paul B Watkins, William K Kaufmann","doi":"10.1007/978-3-7643-8336-7_12","DOIUrl":"https://doi.org/10.1007/978-3-7643-8336-7_12","url":null,"abstract":"<p><p>Toxicogenomics, the application of transcription profiling to toxicology, has been widely used for elucidating the molecular and cellular actions of chemicals and other environmental stressors on biological systems, predicting toxicity before any functional damages, and classification of known or new toxicants based on signatures of gene expression. The success of a toxicogenomics study depends upon close collaboration among experts in different fields, including a toxicologist or biologist, a bioinformatician, statistician, physician and, sometimes, mathematician. This review is focused on toxicogenomics studies, including transcription profiling technology, experimental design, significant gene extraction, toxicological results interpretation, potential pathway identification, database input and the applications of toxicogenomics in various fields of toxicological study.</p>","PeriodicalId":77125,"journal":{"name":"EXS","volume":"99 ","pages":"325-66"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/978-3-7643-8336-7_12","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27934497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EXSPub Date : 2009-01-01DOI: 10.1007/978-3-7643-8336-7_14
Willem G E J Schoonen, Walter M A Westerink, G Jean Horbach
{"title":"High-throughput screening for analysis of in vitro toxicity.","authors":"Willem G E J Schoonen, Walter M A Westerink, G Jean Horbach","doi":"10.1007/978-3-7643-8336-7_14","DOIUrl":"https://doi.org/10.1007/978-3-7643-8336-7_14","url":null,"abstract":"<p><p>The influence of combinatorial chemistry and high-throughput screening (HTS) technologies in the pharmaceutical industry during the last 10 years has been enormous. However, the attrition rate of drugs in the clinic due to toxicity during this period still remained 40-50%. The need for reduced toxicity failure led to the development of early toxicity screening assays. This chapter describes the state of the art for assays in the area of genotoxicity, cytotoxicity, carcinogenicity, induction of specific enzymes from phase I and II metabolism, competition assays for enzymes of phase I and II metabolism, embryotoxicity as well as endocrine disruption and reprotoxicity. With respect to genotoxicity, the full Ames, Ames II, Vitotox, GreenScreen GC, RadarScreen, and non-genotoxic carcinogenicity assays are discussed. For cytotoxicity, cellular proliferation, calcein uptake, oxygen consumption, mitochondrial activity, radical formation, glutathione depletion as well as apoptosis are described. For high-content screening (HCS), the possibilities for analysis of cytotoxicity, micronuclei, centrosome formation and phospholipidosis are examined. For embryotoxicity, endocrine disruption and reprotoxicity alternative assays are reviewed for fast track analysis by means of nuclear receptors and membrane receptors. Moreover, solutions for analyzing enzyme induction by activation of nuclear receptors, like AhR, CAR, PXR, PPAR, FXR, LXR, TR and RAR are given.</p>","PeriodicalId":77125,"journal":{"name":"EXS","volume":"99 ","pages":"401-52"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/978-3-7643-8336-7_14","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27934498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EXSPub Date : 2009-01-01DOI: 10.1007/978-3-7643-8336-7_5
Ulrike Camenisch, Hanspeter Naegeli
{"title":"Role of DNA repair in the protection against genotoxic stress.","authors":"Ulrike Camenisch, Hanspeter Naegeli","doi":"10.1007/978-3-7643-8336-7_5","DOIUrl":"https://doi.org/10.1007/978-3-7643-8336-7_5","url":null,"abstract":"<p><p>The genome of all organisms is constantly attacked by a variety of environmental and endogenous mutagens that cause cell death, apoptosis, senescence, genetic diseases and cancer. To mitigate these deleterious endpoints of genotoxic reactions, living organisms have evolved one or more mechanisms for repairing every type of naturally occurring DNA lesion. For example, double-strand breaks are rapidly religated by non-homologous end-joining. Homologous recombination is used for the high-fidelity repair of interstrand cross-links, double-strand breaks and other DNA injuries that disrupt the replication fork. Some genotoxic lesions inflicted by alkylating agents can be repaired by direct reversal of DNA damage. The base excision repair pathway takes advantage of multiple DNA glycosylases to remove modified or incorrect bases. Finally, the nucleotide excision repair machinery provides a versatile strategy to monitor DNA quality and eliminate all forms of helix-distorting DNA lesions, including a wide diversity of carcinogen adducts. The efficiency of DNA repair responses is enhanced by their coupling to transcription and coordination with the cell cycle circuit.</p>","PeriodicalId":77125,"journal":{"name":"EXS","volume":"99 ","pages":"111-50"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/978-3-7643-8336-7_5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27936179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EXSPub Date : 2009-01-01DOI: 10.1007/978-3-7643-8336-7_7
Johan Högberg, Ilona Silins, Ulla Stenius
{"title":"Chemical induced alterations in p53 signaling.","authors":"Johan Högberg, Ilona Silins, Ulla Stenius","doi":"10.1007/978-3-7643-8336-7_7","DOIUrl":"https://doi.org/10.1007/978-3-7643-8336-7_7","url":null,"abstract":"<p><p>The p53 protein is one of the most important tumor suppressors. The present review summarizes aspects of p53 function and its role in cancer development. Some of the most well-characterized molecular mechanisms affecting p53 regulation, stabilization, inactivation and downstream events are described. A major focus is on how xenobiotics can interfere with p53 function and on its role in chemical carcinogenesis. In the final section of this chapter we discuss future aspects on how knowledge about p53 can be used in testing of carcinogens and in risk assessment.</p>","PeriodicalId":77125,"journal":{"name":"EXS","volume":"99 ","pages":"181-208"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27936181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EXSPub Date : 2009-01-01DOI: 10.1007/978-3-7643-8336-7_10
Jennifer Marlowe, Soon-Siong Teo, Salah-Dine Chibout, François Pognan, Jonathan Moggs
{"title":"Mapping the epigenome--impact for toxicology.","authors":"Jennifer Marlowe, Soon-Siong Teo, Salah-Dine Chibout, François Pognan, Jonathan Moggs","doi":"10.1007/978-3-7643-8336-7_10","DOIUrl":"https://doi.org/10.1007/978-3-7643-8336-7_10","url":null,"abstract":"<p><p>Recent advances in technological approaches for mapping and characterizing the epigenome are generating a wealth of new opportunities for exploring the relationship between epigenetic modifications, human disease and the therapeutic potential of pharmaceutical drugs. While the best examples for xenobiotic-induced epigenetic perturbations come from the field of non-genotoxic carcinogenesis, there is growing evidence for the relevance of epigenetic mechanisms associated with a wide range of disease areas and drug targets. The application of epigenomic profiling technologies to drug safety sciences has great potential for providing novel insights into the molecular basis of long-lasting cellular perturbations including increased susceptibility to disease and/or toxicity, memory of prior immune stimulation and/or drug exposure, and transgenerational effects.</p>","PeriodicalId":77125,"journal":{"name":"EXS","volume":"99 ","pages":"259-88"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27936184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EXSPub Date : 2009-01-01DOI: 10.1007/978-3-7643-8336-7_2
David Kim, Leena A Nylander-French
{"title":"Physiologically based toxicokinetic models and their application in human exposure and internal dose assessment.","authors":"David Kim, Leena A Nylander-French","doi":"10.1007/978-3-7643-8336-7_2","DOIUrl":"https://doi.org/10.1007/978-3-7643-8336-7_2","url":null,"abstract":"<p><p>Human populations may exhibit large interindividual variation in toxicokinetic response to chemical exposures. Rapid developments in dosimetry research have brought medicine and public health closer to understanding the biological basis of this heterogeneity. The toxicokinetic behavior of chemicals is, in part, controlled by the properties of the epithelium surrounding organs, some of which are effective barriers to penetration into the systemic circulation. Physiologically based toxicokinetic (PBTK) models have been developed and used to simulate the mechanism of uptake into the systemic circulation, to extrapolate between doses and exposure routes, and to estimate internal dosimetry and sources of heterogeneity in animals and humans. Recent improvements to PBTK models include descriptions of active transport across biological membranes, carrier-mediated clearance, and fractal kinetics. The expanding area of toxicogenetics has provided valuable insight for delineating toxicokinetic differences between individuals; genetic differences include inherited single nucleotide polymorphisms, copy number variants, and dynamic changes in the methylation pattern of imprinted genes. This chapter discusses the structure of PBTK models and how toxicogenetic information and newer biological descriptions have improved our understanding of variability in response to toxicant exposures.</p>","PeriodicalId":77125,"journal":{"name":"EXS","volume":"99 ","pages":"37-55"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/978-3-7643-8336-7_2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27935672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EXSPub Date : 2009-01-01DOI: 10.1007/978-3-7643-8336-7_9
Ci Ma, Jennifer L Marlowe, Alvaro Puga
{"title":"The aryl hydrocarbon receptor at the crossroads of multiple signaling pathways.","authors":"Ci Ma, Jennifer L Marlowe, Alvaro Puga","doi":"10.1007/978-3-7643-8336-7_9","DOIUrl":"https://doi.org/10.1007/978-3-7643-8336-7_9","url":null,"abstract":"<p><p>The aryl hydrocarbon receptor (AHR) has long been recognized as a ligand-activated transcription factor responsible for the induction of drug-metabolizing enzymes. Its role in the combinatorial matrix of cell functions was established long before the first report of an AHR cDNA sequence was published. It is only recently that other functions of this protein have begun to be recognized, and it is now clear that the AHR also functions in pathways outside of its well-characterized role in xenobiotic enzyme induction. Perturbation of these pathways by xenobiotic ligands may ultimately explain much of the toxicity of these compounds. This chapter focuses on the interactions of the AHR in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, differentiation and apoptosis. Ultimately, the effect of a particular AHR ligand on the biology of the organism will depend on the milieu of critical pathways and proteins expressed in specific cells and tissues with which the AHR itself interacts.</p>","PeriodicalId":77125,"journal":{"name":"EXS","volume":"99 ","pages":"231-57"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/978-3-7643-8336-7_9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"27936183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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