PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Toxicogenetics”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 199 records · Page 11Linked to original sources
PubMed2004

Biokinetics and subchronic toxic effects of oral arsenite, arsenate, monomethylarsonic acid, and dimethylarsinic acid in v-Ha-ras transgenic (Tg.AC) mice.

Previous research demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment increased the number of skin papillomas in v-Ha-ras transgenic (Tg.AC) mice that had received sodium arsenite [(As(III)] in drinking water, indicating that this model is useful for studying the toxic effects of arsenic in vivo. Because the liver is a known target of arsenic, we examined the pathophysiologic and molecular effects of inorganic and organic arsenical exposure on Tg.AC mouse liver in this study. Tg.AC mice were provided drinking water containing As(III), sodium arsenate [As(V)], monomethylarsonic acid [(MMA(V)], and 1,000 ppm dimethylarsinic acid [DMA(V)] at dosages of 150, 200, 1,500, or 1,000 ppm as arsenic, respectively, for 17 weeks. Control mice received unaltered water. Four weeks after initiation of arsenic treatment, TPA at a dose of 1.25 microg/200 microL acetone was applied twice a week for 2 weeks to the shaved dorsal skin of all mice, including the controls not receiving arsenic. In some cases arsenic exposure reduced body weight gain and caused mortality (including moribundity). Arsenical exposure resulted in a dose-dependent accumulation of arsenic in the liver that was unexpectedly independent of chemical species and produced hepatic global DNA hypomethylation. cDNA microarray and reverse transcriptase-polymerase chain reaction analysis revealed that all arsenicals altered the expression of numerous genes associated with toxicity and cancer. However, organic arsenicals [MMA(V) and DMA(V)] induced a pattern of gene expression dissimilar to that of inorganic arsenicals. In summary, subchronic exposure of Tg.AC mice to inorganic or organic arsenicals resulted in toxic manifestations, hepatic arsenic accumulation, global DNA hypomethylation, and numerous gene expression changes. These effects may play a role in arsenic-induced hepatotoxicity and carcinogenesis and may be of particular toxicologic relevance.

Administration, Oral↗
PubMed2004

The intelligent data management system for toxicogenomics.

Toxicogenomics is now emerging as one of the most important genomic application because the toxicity test based on gene expression profiles is expected to be more precise and efficient than current histopathological approaches in a pre-clinical phase. One of the challenging issues in toxicogenomics is the construction of intelligent database management system which can deal with heterogeneous and complex data from many different experimental and information sources. TEST(Toxicogenomics for Efficient Safety Test) database is especially focused on the connectivity of heterogeneous data and the intelligent query system which enable users to obtain relevant useful information from the complex data sets. The database deals with four kinds of information; compound, histopathology, gene expression, and annotation information. Currently, TEST database maintains toxicogenomics information for 16 compounds, 45 microarrays, 190 animal experiments, and customized 4.8 K rat clone set. Our presented system is expected to be a good information source for studying of toxicology mechanism in the genome-wide level and can also be applied to the designing toxicity test chip.

Animals↗
PubMed2004

cDNA microarray gene expression analysis and toxicological phenotype for anticancer drug.

Toxicogenomics, the subdiscipline that merges genomics with toxicology, hold the promise to contributing toward the goal of elucidating mechanism by studying genomic profiling related with various drugs. The application of gene expression profiling technology to examine multiple genes and signaling pathways promises a significant advance in understanding the toxic mechanisms of various drugs and prediction of new drug candidate. Toxicogenomics is emerging field combining genomics and bioinformatics to identify and characterize mechanisms of toxicity of drug and various compounds. The principal hypothesis underlying on this field is that chemical-specific pattern of altered gene expression is related with each chemicals properties, especially toxicological property, and it will be revealed using high-density microarray analysis of sample from exposed organisms. So, in this study we compare the gene expression pattern of two anticancer drugs paclitaxel and orally absorbable paclitaxel, using the cDNA microarray. And from the result of this study, it is possible to provide the new possibility for genome-wide insight into mechanism of their anticancer activity and toxicological phenotype.

Administration, Oral↗
PubMed2003

Application of toxicogenomics in drug development.

The recognition of toxicological potential in new chemical entities early on in development would be highly desirable in streamlining and reducing the cost of drug development. Analysis of gene expression profiles using microarrays is one of the most fashionable methods for achieving this objective. The procedure relies on developing a gene expression profile related to compound exposure and then matching this against a database of profiles associated with known mechanisms of toxicity. Studies profiling tumors and associating these with pathology and phenotype have shown the potential of the technique. However, application of the technique in toxicology is only at the preliminary stage. This article examines current state of development in toxicology and its future potential.

Antineoplastic Agents↗
PubMed2005

Gene expression profiling to characterize anticancer drug sensitivity.

This chapter presents a protocol for using cDNA microarrays to acquire gene expression profiles that characterize anticancer drug sensitivity. The protocol includes steps for drug exposure, RNA isolation, preparation of fluorescently labeled samples, microarray hybridization, data processing, and data analysis. In addition to the detailed protocol, important experimental design issues are discussed, and some preliminary experiments are recommended.

Antineoplastic Agents↗
PubMed2004

Genomics, proteomics and metabonomics in toxicology: hopefully not 'fashionomics'.

Genomics, proteomics and metabonomics are applied to toxicology either as stand-alone technologies or in combination, with the intention of providing a more efficient assessment of the potential side effects of new chemical entities. Two different approaches are taken: a predictive/proactive strategy based on a statistical analogy of 'signatures' of drugs to many known toxicant gene or metabolite fingerprints; and a mechanistic/reactive strategy based on the in-depth biological analysis of the gene, protein or metabolite profiles induced by one or a few compounds of interest. This article focuses on the advantages and disadvantages of these technologies, as well as the many hurdles associated with both these approaches in toxicology that have to be considered before applying them to the assessment of future drugs.

Animals↗
PubMed2005

Gene expression profile analysis: an emerging approach to investigate mechanisms of genotoxicity.

The response to stress triggers transcriptional activation of genes involved in cell survival and/or cell death. Thus, the monitoring of gene expression levels in large gene sets or whole genomes in response to various agents (toxicogenomics) has been proposed as a tool for investigating mechanisms of toxicity. Although standard in vitro genetic toxicity testing provides relatively simple and accurate hazard detection, interpretation of positive findings, i.e., in vitro chromosome aberrations, in terms of relevant risk to humans is difficult, due to the limited insight into the underlying mechanisms. Therefore, the development of experimental approaches capable of differentiating a wide range of genotoxic mechanisms is expected to significantly improve risk assessment. The goal of this review is to summarize current developments in toxicogenomic analysis of genotoxic stress, and to provide a perspective on the application of gene expression profile analysis in genetic toxicology.

Animals↗
PubMed2005

Predictive ADME-Tox London, UK, 27 -- 28 April 2005.

The Predictive ADME-Tox conference brought together scientists responsible for innovative in vitro and in silico screens to predict particular chemical liabilities. Oral bioavailability without adverse effects requires good absorption, distribution, metabolism and excretion (ADME) and minimal toxicity. Traditionally, these properties are measured late in development, when sufficient material is available for classical assays. Although these assays remain the gold standard, the conference focused on novel methods to predict liabilities early in the development pipeline, when a course change has less impact in the development timeline. Emerging themes from the meeting were i) integration - of data from a number of predictive assays into a 'profile' of a new class, and of safety scientists into discovery teams, in order to guide interpretation of the profile and identify tests to include in the hit-to-lead process; and ii) collaboration. As in silico predictive models are increasingly accepted, from reactivity and genetic toxicity to models for hERG inhibition, kinase crossreactivity and cytochrome P450 reactivity, increasing amounts of high-quality data will be needed to 'feed' the models. Such data will soon be beyond the capabilities of individual organisations to generate, and methods for pooling data are needed to advance the generation of predictive models for new toxicities. In addition, collaboration to apply novel methods such as metabonomics profiling to withdrawn drugs may permit the identification of new safety biomarkers to prevent such costly failures.

Biotransformation↗
PubMed2005

Precision-cut organ slices to investigate target organ injury.

Drug-induced organ injury is a multifaceted process, involving numerous cell types and mediators, and remains a significant safety issue in pharmaceutical development and clinical therapy. Organ slices, an in vitro model representing the multicellular, structural and functional features of in vivo tissue, is a promising model for elucidating mechanisms of drug-induced organ injury and for characterising species susceptibilities. Time- and concentration-dependent drug-induced effects on organ slice gene expression, function and morphology are providing insight into the molecular and biochemical pathways leading to organ dysfunction, an altered morphology and the induction of repair pathways. Human organ slice studies are valuable for bridging the extrapolation of animal-derived data and for identifying mechanisms relevant for humans. The liver is the major organ used in organ slice studies; however, the utility of extrahepatic-derived slices, as well as cocultures for investigating multiple organ involvement in tissue injury is increasing. Organ slice investigations can further our understanding of the cell types and cell interactions involved in drug-induced injury and the consequences of drug-induced off-target effects for identifying compound liabilities that will impact safety.

Animals↗
PubMed2006

Genomic-based biomarkers of drug-induced nephrotoxicity.

Typical drug development timelines are 10 - 15 years, with high attrition rates that make it difficult for companies to sustain productive pipelines. Investigational and discovery toxicology are novel and revolutionary extensions of the field of general toxicology, which has been created to fulfil the growing need for generating higher throughput, and integrative and predictive toxicological information, in an effort to reduce attrition. Included in this new paradigm is transcript profiling, and recent innovations have led some to speculate that genomics would help revolutionise drug development, as more better predictive biomarkers of organ damage would be identified. The kidney has been a focus of toxicogenomics investigations, and candidate genomic-based biomarkers of renal damage have been identified for rodent as well as nonhuman primate models of nephrotoxicity. This review highlights published results that have led to the preliminary identification of candidate genomic-based markers of nephrotoxicity and provides insight into the future of toxicogenomics.

Animals↗
PubMed2006

Cross-species comparative toxicogenomics as an aid to safety assessment.

Cross-species comparative toxicogenomics has the potential for improving the understanding of the different responses of animal models to toxicants at a molecular level. This understanding could then lead to a more accurate extrapolation of the risk posed by these toxicants to humans. Cross-species comparative studies have been carried out at the genomic sequence level and using microarrays to examine changes in global mRNA profiles. However, these studies face considerable bioinformatic challenges in terms of identifying which genes are truly orthologous across species. The resources to analyse such studies, in the context of such orthologues, beg improvement. Finally, the experimental design of such studies needs to be carefully considered to make their results fully interpretable. These issues are discussed, along with the current state-of-the-art cross-species comparative toxicogenomics in this review.

Animals↗
PubMed2004

Gentronix.

Gentronix is an innovative biotechnology company with the aim of providing cell-based assays and systems to ease or remove some of the current bottlenecks in preclinical drug discovery and development. Gentronix's first product, GreenScreen trade mark GC, is a combined genotoxicity and cytotoxicity test designed for high-throughput screening of new pharmaceutical lead compounds, giving drug development scientists a cost-effective preview of the battery of mandatory regulatory genotoxicity tests. Future products based on the company's extensive intellectual property rights portfolio will combine the company's expertise in cellular biosensor systems with novel optical detection technology to deliver a range of products for other applications within drug discovery, as well as industrial and environmental monitoring of toxic chemicals.

Biosensing Techniques↗
PubMed2005

Systems toxicology: applications of toxicogenomics, transcriptomics, proteomics and metabolomics in toxicology.

Toxicogenomics can facilitate the identification and characterization of toxicity, as illustrated in this review. Toxicogenomics, the application of the functional genomics technologies (transcriptomics, proteomics and metabolomics) in toxicology enables the study of adverse effects of xenobiotic substances in relation to structure and activity of the genome. The advantages and limitations of the different technologies are evaluated, and the prospects for integration of the technologies into a systems biology or systems toxicology approach are discussed. Applications of toxicogenomics in various laboratories around the world show that the crucial steps and sequence of events at the molecular level can be studied to provide detailed insights into mechanisms of toxic action. Toxicogenomics allowed for more sensitive and earlier detection of adverse effects in (animal) toxicity studies. Furthermore, the effects of exposure to mixtures could be studied in more detail. This review argues that in the (near) future, human health risk assessment will truly benefit from toxicogenomics (systems toxicology).

Animals↗
PubMed2004

Application of DNA microarray to toxicological research.

DNA microarray technology is becoming increasingly popular in the field of toxicological research. Information on the global gene expression profile may provide clues to understanding biological actions of toxic substances at the molecular, cellular, tissue, and individual animal levels. This review focuses on the practical aspects of DNA microarray experiments and their applications to relatively small sizes of research projects in toxicology. First, different types of DNA microarrays and their characters are reviewed. Then, two fundamental concepts of DNA microarray data analysis--supervised and unsupervised methods--and their applications to toxicological research projects are discussed. Typical pitfalls of DNA microarray experiments are examined. Finally, strategies of experimental design and data analysis of minimum scale DNA microarray project are provided.

Animals↗
PubMed2006

Utilization of a one-dimensional score for surveying chemical-induced changes in expression levels of multiple biomarker gene sets using a large-scale toxicogenomics database.

A large-scale toxicogenomcis database has now been constructed in the Toxicogenomics Project in Japan (TGP). To facilitate the analytical procedures for such large-scale microarray data, we developed a simple one-dimensional score, named TGP1 which expresses the trend of the changes in expression of biomarker genes as a whole. To evaluate the usefulness of the TGP1 score, microarray data of rat liver and rat hepatocytes deposited in the TGP database were scored for three biomarker gene sets, i.e., carcinogenesis-related, PPARalpha-regulated and glutathione depletion-related gene sets. The TGP1 scoring system gave reasonable results, i.e., the scores for carcinogenesis-related genes were high in omeprazole-, chlorpromazine-, hexachlorobenzene-, sulfasalazine- and Wy-14,643-treated rat livers, that for PPARalpha-regulated genes were high in clofibrate-, Wy-14,643-, gemfibrozil-, benzbromarone- and aspirin-treated rat livers as well as rat hepatocytes, and for glutathione deficiency-related genes were high in omeprazole-, bromobenzene-, acetaminophen- and coumarin-treated rat liver. We concluded that the TGP1 score is useful for surveying the expression changes in multiple biomarker gene sets for a large-scale toxicogenomics database, which would reduce the time of doing conventional multivariate statistical analysis. In addition, the TGP1 score can be applied to screening of compatible biomarker gene sets between rat liver and rat hepatocytes, like PPARalpha-regulated gene sets, which will allow us to develop an appropriate in vitro system for drug safety assessment in vivo.

Animals↗
PubMed2004

DNA microarrays as a tool in toxicogenomics.

Toxicogenomics is an emerging technology that defines the use of novel genomic techniques to investigate the adverse effects of xenobiotic on gene expression. Toxicogenomics is based on the fact that most of relevant toxicological effects of a compound affect directly or indirectly the gene expression. The most common methods to profile gene expression at the transcript level are Northern Blotting and the real-time PCR. While commonly used and well accepted, these techniques are now superseded by new technologies allowing the analysis of the expression for multiple genes simultaneously. DNA microarrays are now developed for simultaneous gene analysis but inherent to such multiple assays, their quantitative aspect and their relevance for toxicogenomics have been questioned. We will review here recent studies on their use for toxicogenomics and examine the possible future of such technology in complementation with the other toxicology methods.

Animals↗
PubMed2006

Reactive intermediates and the pathogenesis of adverse drug reactions: the toxicology perspective.

Severe adverse drug responses are infrequent but occasionally serious events that are not readily predictable at the preclinical development level using only non-human or in vitro models. A common characteristic of the more serious toxicities is generation of short-lived and highly reactive electrophilic species in some individuals. The objective here is to review the literature for toxicological mechanisms that underlie known adverse drug reactions and then categorize the biological consequences of reactive chemical intermediates and radicals in terms of human risk factors and known metabolic variables. Xenobiotics described as being associated with rare but potentially serious adverse events affecting liver, skin, or causing blood dyscrasias tend to have three of four essential characteristics, (1) they are capable of forming short-lived reactive intermediates (RI) or free radicals in target tissues under ideal conditions that are distinct from primary metabolic products, (2) these RI escape/overwhelm the detoxification mechanisms associated with the site of origin or form toxic conjugates, (3) the unconjugated RI must either selectively damage critical proteins or other key macromolecules or (4) the RI acts as a hapten and stimulates an immunological (hypersensitivity) response or overcomes tolerance. Some risk factors may increase the probability of susceptibility, but this remains an active area of research. Because of the complexity of the pathogenesis of some injuries and the role of individual factors, no highly predictive in vitro screening methods are available; however, several methods are evolving that may be used to reveal mechanisms of action when a serious adverse effect is encountered.

Animals↗