Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT238
Ludmila V. Danilova, M. Ochs
{"title":"Biomarkers of System Response to Therapeutic Intervention","authors":"Ludmila V. Danilova, M. Ochs","doi":"10.1002/9780470744307.GAT238","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT238","url":null,"abstract":"","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"35 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128931897","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT225
Lei Guo, J. Fuscoe, P. Fu, N. Mei
Herbal dietary supplements are used extensively worldwide and the consumption has dramatically increased in the United States in recent years. Although side effects of many herbal dietary supplements have been reported, safety assurance has not been addressed adequately and toxicological data on most herbal dietary supplements are lacking. To address the issue of human health protection, there are currently more than 30 herbal dietary supplements or active ingredients under study by the US National Toxicology Program (NTP). Herbal products often exhibit great variability in quality because of different processing methods, cultivation conditions, and harvest time, as well as the strain and species differences. Authentication of plant species used for preparation of herbal dietary supplements is a critical step of safety assurance. Botanical extracts differ from drugs in that they are mixtures of many active constituents. At present, there are no well-established methodologies for evaluating the toxicity or determining the toxic mechanisms of herbal plant extracts due to the complexity of chemical components. In this chapter, we describe the applications of DNA microarray for plant authentication and mechanistic studies of herbal dietary supplements. Keywords: authentication of plant species; gene expression; herbal dietary supplements; microarray; pathway analysis; toxicity
{"title":"Application of DNA Microarray in Studies of Herbal Dietary Supplements","authors":"Lei Guo, J. Fuscoe, P. Fu, N. Mei","doi":"10.1002/9780470744307.GAT225","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT225","url":null,"abstract":"Herbal dietary supplements are used extensively worldwide and the consumption has dramatically increased in the United States in recent years. Although side effects of many herbal dietary supplements have been reported, safety assurance has not been addressed adequately and toxicological data on most herbal dietary supplements are lacking. To address the issue of human health protection, there are currently more than 30 herbal dietary supplements or active ingredients under study by the US National Toxicology Program (NTP). Herbal products often exhibit great variability in quality because of different processing methods, cultivation conditions, and harvest time, as well as the strain and species differences. Authentication of plant species used for preparation of herbal dietary supplements is a critical step of safety assurance. Botanical extracts differ from drugs in that they are mixtures of many active constituents. At present, there are no well-established methodologies for evaluating the toxicity or determining the toxic mechanisms of herbal plant extracts due to the complexity of chemical components. In this chapter, we describe the applications of DNA microarray for plant authentication and mechanistic studies of herbal dietary supplements. \u0000 \u0000 \u0000Keywords: \u0000 \u0000authentication of plant species; \u0000gene expression; \u0000herbal dietary supplements; \u0000microarray; \u0000pathway analysis; \u0000toxicity","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"118 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115596281","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT201
P. Joseph
Human exposure to toxic chemicals is almost unavoidable. The toxicity owing to human exposure to chemicals may result in adverse health effects such as illnesses and even death. It is therefore important to determine whether human exposure to chemicals may result in toxicity and, if so, to obtain a full understanding of the mechanism(s) underlying the toxicity. Recent developments in genomics and their application in toxicology (toxicogenomics) have facilitated a better understanding of chemical toxicity. Unlike traditional toxicity studies, toxicogenomics studies have the potential to detect toxicity pre-clinically (before the onset of clinical manifestations of toxicity) and this may have implications even in predicting the toxicity of chemicals. Recent studies have demonstrated the potential application of genomics-based toxicity determination in surrogate tissues such as blood, for monitoring human exposure to toxic chemicals. The potential of toxicogenomics in determining the toxicity of chemicals is best illustrated in the case of hepatotoxic chemicals. It is anticipated that toxicogenomics studies, in conjunction with the traditional toxicity determination approaches, may be useful to determine the systems toxicity of chemicals. Keywords: blood; gene expression; hepatotoxicity; microarray; surrogate tissue; toxicogenomics
{"title":"Toxicogenomics — Applications in Systems Toxicology","authors":"P. Joseph","doi":"10.1002/9780470744307.GAT201","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT201","url":null,"abstract":"Human exposure to toxic chemicals is almost unavoidable. The toxicity owing to human exposure to chemicals may result in adverse health effects such as illnesses and even death. It is therefore important to determine whether human exposure to chemicals may result in toxicity and, if so, to obtain a full understanding of the mechanism(s) underlying the toxicity. Recent developments in genomics and their application in toxicology (toxicogenomics) have facilitated a better understanding of chemical toxicity. Unlike traditional toxicity studies, toxicogenomics studies have the potential to detect toxicity pre-clinically (before the onset of clinical manifestations of toxicity) and this may have implications even in predicting the toxicity of chemicals. Recent studies have demonstrated the potential application of genomics-based toxicity determination in surrogate tissues such as blood, for monitoring human exposure to toxic chemicals. The potential of toxicogenomics in determining the toxicity of chemicals is best illustrated in the case of hepatotoxic chemicals. It is anticipated that toxicogenomics studies, in conjunction with the traditional toxicity determination approaches, may be useful to determine the systems toxicity of chemicals. \u0000 \u0000 \u0000Keywords: \u0000 \u0000blood; \u0000gene expression; \u0000hepatotoxicity; \u0000microarray; \u0000surrogate tissue; \u0000toxicogenomics","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"27 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122835515","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT215
M. Sepúlveda, K. Ralston-Hooper, Brian C. Sanchez, Amber Hopf-jannasch, S. D. Baker, N. Diaz, J. Adamec
Over the last decade, the environmental sciences have witnessed an incredible movement towards the utilization of high through-put molecular tools that are capable of detecting simultaneous changes of hundreds and even thousands of molecules and molecular components after exposure of organisms to different environmental stressors. These techniques have received lots of attention because they not only offer the potential to unravel novel mechanisms of physiological and toxic action, but they also are amenable for the discovery of biomarkers of exposure and effects. In this chapter we will review the state of knowledge of two of these holistic tools in ecotoxicological research: Proteomics and metabolomics. We will follow this review with a presentation of three of our own case studies utilizing proteomic and metabolomic tools: (i) Analysis of proteomic responses in fish exposed to different types of contaminants using GeneGo™; (ii) Comparison of proteomic and metabolomic responses in aquatic invertebrates exposed to herbicides; and (ii) Use of metabolomics to characterize egg quality in fish eating birds exposed to persistent organic pollutants. We will end with some ideas for future studies and research needs. Keywords: proteomics; metabolomics; ecotoxicology; fish; invertebrates; birds; aquatic; wildlife; biomarkers; contaminants; toxicity; pollution
{"title":"Use of Proteomic and Metabolomic Techniques in Ecotoxicological Research","authors":"M. Sepúlveda, K. Ralston-Hooper, Brian C. Sanchez, Amber Hopf-jannasch, S. D. Baker, N. Diaz, J. Adamec","doi":"10.1002/9780470744307.GAT215","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT215","url":null,"abstract":"Over the last decade, the environmental sciences have witnessed an incredible movement towards the utilization of high through-put molecular tools that are capable of detecting simultaneous changes of hundreds and even thousands of molecules and molecular components after exposure of organisms to different environmental stressors. These techniques have received lots of attention because they not only offer the potential to unravel novel mechanisms of physiological and toxic action, but they also are amenable for the discovery of biomarkers of exposure and effects. In this chapter we will review the state of knowledge of two of these holistic tools in ecotoxicological research: Proteomics and metabolomics. We will follow this review with a presentation of three of our own case studies utilizing proteomic and metabolomic tools: (i) Analysis of proteomic responses in fish exposed to different types of contaminants using GeneGo™; (ii) Comparison of proteomic and metabolomic responses in aquatic invertebrates exposed to herbicides; and (ii) Use of metabolomics to characterize egg quality in fish eating birds exposed to persistent organic pollutants. We will end with some ideas for future studies and research needs. \u0000 \u0000 \u0000Keywords: \u0000 \u0000proteomics; \u0000metabolomics; \u0000ecotoxicology; \u0000fish; \u0000invertebrates; \u0000birds; \u0000aquatic; \u0000wildlife; \u0000biomarkers; \u0000contaminants; \u0000toxicity; \u0000pollution","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"121 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132020826","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT243
Jinsong Zhang, J. Spallholz
Selenium is a necessary dietary constituent of at least 25 human selenoproteins and enzymes all containing selenocysteine. In excessive amounts, all selenium compounds become toxic in a dose-dependent fashion to cells in vitro and to the primary target tissue of chronic selenium toxicity, the liver. Elemental selenium of zero valence state has long been considered to be biologically inert. With bovine serum albumin or other dispersant agents such as polysaccharide, biologically active nano-selenium particles (Nano-Se) are formed from sodium selenite and glutathione. Different from the biologically inert black elemental selenium with coarse size, red Nano-Se manifests toxicity which conforms to the concern of nanotoxicity. However, compared with selenium compounds such as sodium selenite, selenomethionine and Se-methylselenocysteine, Nano-Se is not compromised in increasing the activities of selenoenzymes including glutathione peroxidase and thioredoxin reductase at nutritional levels and phase 2 detoxification enzymes such as glutathione S-transferase at supranutritional levels, but exhibits much lower toxicities. Nano-Se is thus a potential selenium source with a prominent characteristic of lower toxicity for supplementation. Keywords: toxicity; selenite; selenomethionine; Se-methylselenocysteine; nano-selenium particles
{"title":"Toxicity of Selenium Compounds and Nano‐Selenium Particles","authors":"Jinsong Zhang, J. Spallholz","doi":"10.1002/9780470744307.GAT243","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT243","url":null,"abstract":"Selenium is a necessary dietary constituent of at least 25 human selenoproteins and enzymes all containing selenocysteine. In excessive amounts, all selenium compounds become toxic in a dose-dependent fashion to cells in vitro and to the primary target tissue of chronic selenium toxicity, the liver. Elemental selenium of zero valence state has long been considered to be biologically inert. With bovine serum albumin or other dispersant agents such as polysaccharide, biologically active nano-selenium particles (Nano-Se) are formed from sodium selenite and glutathione. Different from the biologically inert black elemental selenium with coarse size, red Nano-Se manifests toxicity which conforms to the concern of nanotoxicity. However, compared with selenium compounds such as sodium selenite, selenomethionine and Se-methylselenocysteine, Nano-Se is not compromised in increasing the activities of selenoenzymes including glutathione peroxidase and thioredoxin reductase at nutritional levels and phase 2 detoxification enzymes such as glutathione S-transferase at supranutritional levels, but exhibits much lower toxicities. Nano-Se is thus a potential selenium source with a prominent characteristic of lower toxicity for supplementation. \u0000 \u0000 \u0000Keywords: \u0000 \u0000toxicity; \u0000selenite; \u0000selenomethionine; \u0000Se-methylselenocysteine; \u0000nano-selenium particles","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"15 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133649698","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT220
Athina Zira, S. Theocharis
The report and understanding of interactions among genes, proteins and metabolites is of crucial importance in the classification of mechanisms involved in chemical/drug-induced toxicity. Consequently, the application of the “omics” technologies (genomics, proteomics and metabonomics), and mainly metabonomics, is imperative in toxicological studies. Metabonomics has been widely used in established models of target organ toxicity in order to monitor the effect of the toxic agents and possibly identify novel biomarkers of toxicity. In the present review, the applications of metabonomics in toxicological studies have been reported. Although limitations from the use of this technology in toxicology still exist, its combination with genomics and proteomics could provide valuable information for the underlying mechanisms of target organ toxicity. Keywords: brain; heart; kidney; liver; metabolomics; toxicity
{"title":"Application of Metabonomic Approach in Target Organ Toxicity","authors":"Athina Zira, S. Theocharis","doi":"10.1002/9780470744307.GAT220","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT220","url":null,"abstract":"The report and understanding of interactions among genes, proteins and metabolites is of crucial importance in the classification of mechanisms involved in chemical/drug-induced toxicity. Consequently, the application of the “omics” technologies (genomics, proteomics and metabonomics), and mainly metabonomics, is imperative in toxicological studies. Metabonomics has been widely used in established models of target organ toxicity in order to monitor the effect of the toxic agents and possibly identify novel biomarkers of toxicity. In the present review, the applications of metabonomics in toxicological studies have been reported. Although limitations from the use of this technology in toxicology still exist, its combination with genomics and proteomics could provide valuable information for the underlying mechanisms of target organ toxicity. \u0000 \u0000 \u0000Keywords: \u0000 \u0000brain; \u0000heart; \u0000kidney; \u0000liver; \u0000metabolomics; \u0000toxicity","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122786994","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT248
J. Sina, F. Sistare
The concept of integrating molecular and biochemical data from new technologies with more traditional endpoints to develop a more complete understanding of risks and benefits in drug development has gained wide acceptance as a reasonable way to advance human health. However, actual implementation of this systems approach is not straightforward. While technology keeps advancing, our ability to accurately interpret the complexity of human biology has not kept pace. Indeed, sometimes the case seems to be one of the deeper we investigate, the more we realize what we do not understand. Additionally, in developing ethical pharmaceuticals, a major issue is establishing the necessary level of confidence to extrapolate from a series of endpoint measurements to accurately predict beneficial and/or potentially adverse responses in the diverse population of patients. The evidentiary standard for acceptance of new models and biomarkers in clinical practice is necessarily high, although the concept of “fit-for-purpose” may help expedite the application of new knowledge in specific clinical situations. This chapter will present a view of both the progress and hurdles to applying systems toxicology to drug development in a regulated environment. Keywords: systems toxicology; drug development; biomarkers; clinical translation; pre-clinical; pathways; review; genomics; metabolomics; proteomics
{"title":"Implementing Systems Toxicology in Drug Development for Regulatory Decision Making","authors":"J. Sina, F. Sistare","doi":"10.1002/9780470744307.GAT248","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT248","url":null,"abstract":"The concept of integrating molecular and biochemical data from new technologies with more traditional endpoints to develop a more complete understanding of risks and benefits in drug development has gained wide acceptance as a reasonable way to advance human health. However, actual implementation of this systems approach is not straightforward. While technology keeps advancing, our ability to accurately interpret the complexity of human biology has not kept pace. Indeed, sometimes the case seems to be one of the deeper we investigate, the more we realize what we do not understand. Additionally, in developing ethical pharmaceuticals, a major issue is establishing the necessary level of confidence to extrapolate from a series of endpoint measurements to accurately predict beneficial and/or potentially adverse responses in the diverse population of patients. The evidentiary standard for acceptance of new models and biomarkers in clinical practice is necessarily high, although the concept of “fit-for-purpose” may help expedite the application of new knowledge in specific clinical situations. This chapter will present a view of both the progress and hurdles to applying systems toxicology to drug development in a regulated environment. \u0000 \u0000 \u0000Keywords: \u0000 \u0000systems toxicology; \u0000drug development; \u0000biomarkers; \u0000clinical translation; \u0000pre-clinical; \u0000pathways; \u0000review; \u0000genomics; \u0000metabolomics; \u0000proteomics","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"5 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129905689","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}
Pub Date : 2011-09-15DOI: 10.1002/9780470744307.GAT236
T. Knudsen, R. Dewoskin
High-throughput or high-content studies are now providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential in vivo toxicity. EPA's ToxCast™ project, and the broader Tox21 consortium, as well as other projects worldwide, are providing high-throughput and high-content screening data (HTS-HCS) focusing on the in vitro targets and cellular bioactivity profiles for thousands of chemical compounds in commerce or entering the environment. A goal of chemical profiling is to rapidly identify and efficiently classify signatures of biological activity that are potentially diagnostic of in vivo toxicities using automated technologies. Predictive modeling of developmental toxicity faces several challenges: correlating in vitro concentration–response with internal dose–response kinetics; understanding how in vitro bioactivity profiles extrapolate from one cell-type or technology platform to another; and linking individual targets of in vitro bioactivity to complex signatures associated with pathways of in vivo toxicity. Toxicity in the intact organism is an expression of complex and interwoven events that follow from cellular perturbations. As such, multicellular computer models known as ‘virtual tissues’ that recapitulate developmental events can provide a technology platform to simulate non-linear behaviors of dynamical systems and to model perturbations. A virtual embryo, for example, might be envisaged as a toolbox of computational (in silico) models that execute morphogenetic programs to simulate developmental toxicity. Keywords: computational toxicology; high-throughput; screening; developmental toxicity; chemical profiling; toxicity pathways; predictive models; risk assessment; mechanistic models; systems biology; virtual tissues
{"title":"Systems Modeling in Developmental Toxicity","authors":"T. Knudsen, R. Dewoskin","doi":"10.1002/9780470744307.GAT236","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT236","url":null,"abstract":"High-throughput or high-content studies are now providing a rich source of data that can be applied to in vitro profiling of chemical compounds for biological activity and potential in vivo toxicity. EPA's ToxCast™ project, and the broader Tox21 consortium, as well as other projects worldwide, are providing high-throughput and high-content screening data (HTS-HCS) focusing on the in vitro targets and cellular bioactivity profiles for thousands of chemical compounds in commerce or entering the environment. A goal of chemical profiling is to rapidly identify and efficiently classify signatures of biological activity that are potentially diagnostic of in vivo toxicities using automated technologies. Predictive modeling of developmental toxicity faces several challenges: correlating in vitro concentration–response with internal dose–response kinetics; understanding how in vitro bioactivity profiles extrapolate from one cell-type or technology platform to another; and linking individual targets of in vitro bioactivity to complex signatures associated with pathways of in vivo toxicity. Toxicity in the intact organism is an expression of complex and interwoven events that follow from cellular perturbations. As such, multicellular computer models known as ‘virtual tissues’ that recapitulate developmental events can provide a technology platform to simulate non-linear behaviors of dynamical systems and to model perturbations. A virtual embryo, for example, might be envisaged as a toolbox of computational (in silico) models that execute morphogenetic programs to simulate developmental toxicity. \u0000 \u0000 \u0000Keywords: \u0000 \u0000computational toxicology; \u0000high-throughput; \u0000screening; \u0000developmental toxicity; \u0000chemical profiling; \u0000toxicity pathways; \u0000predictive models; \u0000risk assessment; \u0000mechanistic models; \u0000systems biology; \u0000virtual tissues","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126986048","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}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT177
R. Olson, B. Cusack
Cardiotoxicity of anthracyclines limits their therapeutic potential. In the in vitro acute model, anthracyclines produce cardiotoxicity in minutes or hours at concentrations near 100 μM, through a mechanism involving impairment of sarcoplasmic reticulum (SR) function and requiring the quinone moiety, most likely through a non-free-radical process. The chronic cardiotoxicity is more complex, but may also involve SR. Additional mechanisms in the chronic model of anthracycline cardiotoxicity may include impairment of triiodothyronine function, cardiac protein degradation, free-radical generation, apoptosis, cardiac metabolite formation, impairment of iron metabolism and oestrogen-dependent up-regulation of nitric oxide synthase (NOS). Thus, prevention or attenuation of anthracycline cardiotoxicity may be achieved by favourably manipulating these mechanisms.Keywords:anthracyclines;cardiotoxicity;heart failure;calcium;free radicals;ageing
{"title":"Cardiac Toxicity of Anthracyclines","authors":"R. Olson, B. Cusack","doi":"10.1002/9780470744307.GAT177","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT177","url":null,"abstract":"Cardiotoxicity of anthracyclines limits their therapeutic potential. In the in vitro acute model, anthracyclines produce cardiotoxicity in minutes or hours at concentrations near 100 μM, through a mechanism involving impairment of sarcoplasmic reticulum (SR) function and requiring the quinone moiety, most likely through a non-free-radical process. The chronic cardiotoxicity is more complex, but may also involve SR. Additional mechanisms in the chronic model of anthracycline cardiotoxicity may include impairment of triiodothyronine function, cardiac protein degradation, free-radical generation, apoptosis, cardiac metabolite formation, impairment of iron metabolism and oestrogen-dependent up-regulation of nitric oxide synthase (NOS). Thus, prevention or attenuation of anthracycline cardiotoxicity may be achieved by favourably manipulating these mechanisms.Keywords:anthracyclines;cardiotoxicity;heart failure;calcium;free radicals;ageing","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"119 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"117222758","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}
Pub Date : 2009-12-15DOI: 10.1002/9780470744307.GAT018
S. Kitamura, K. Sugihara, Kazuo Nakamura, Y. Kotake, A. Kashiwagi, N. Fujimoto
Many endocrine-disrupting agents, including industrial materials, pesticides, pharmaceuticals and phytochemicals, have been identified with their use by in vitro assay systems and in vivo studies in laboratory animals. These chemicals are widely distributed in the environment, and are able to mimic or antagonize the biological functions of natural hormones. Indeed, abnormalities thought to be due to such agents have been found in animals throughout the world. There is also thought to be a risk to humans, for example, DES syndrome. Xenoestrogens can accumulate in our environment, and may play a role in the increasing incidences of breast cancer, testicular cancer and other problems of the reproductive system in humans. Risks due to endocrine disruptors in the environment are discussed in this chapter. Keywords: endocrine disrupting activity; oestrogen; antiandrogen; reproductive system; central nervous system; immune system
{"title":"Endocrine Disruption in Toxic Responses","authors":"S. Kitamura, K. Sugihara, Kazuo Nakamura, Y. Kotake, A. Kashiwagi, N. Fujimoto","doi":"10.1002/9780470744307.GAT018","DOIUrl":"https://doi.org/10.1002/9780470744307.GAT018","url":null,"abstract":"Many endocrine-disrupting agents, including industrial materials, pesticides, pharmaceuticals and phytochemicals, have been identified with their use by in vitro assay systems and in vivo studies in laboratory animals. These chemicals are widely distributed in the environment, and are able to mimic or antagonize the biological functions of natural hormones. Indeed, abnormalities thought to be due to such agents have been found in animals throughout the world. There is also thought to be a risk to humans, for example, DES syndrome. Xenoestrogens can accumulate in our environment, and may play a role in the increasing incidences of breast cancer, testicular cancer and other problems of the reproductive system in humans. Risks due to endocrine disruptors in the environment are discussed in this chapter. \u0000 \u0000 \u0000Keywords: \u0000 \u0000endocrine disrupting activity; \u0000oestrogen; \u0000antiandrogen; \u0000reproductive system; \u0000central nervous system; \u0000immune system","PeriodicalId":325382,"journal":{"name":"General, Applied and Systems Toxicology","volume":"15 2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2009-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125916660","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：