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At least 145 records · Page 8Linked to original sources
PubMed2006

Comparison of coumarin-induced toxicity between sandwich-cultured primary rat hepatocytes and rats in vivo: a toxicogenomics approach.

Sandwich-cultured primary rat hepatocytes are often used as an in vitro model in toxicology and pharmacology. However, loss of liver-specific functions, in particular, the decline of cytochrome P450 (P450) enzyme activity, limits the value of this model for prediction of in vivo toxicity. In this study, we investigated whether a hepatic in vitro system with improved metabolic competence enhances the predictability for coumarin-induced in vivo toxicity by using a toxicogenomics approach. Therefore, primary rat hepatocytes were cultured in sandwich configuration in medium containing a mixture of low concentrations of P450 inducers, phenobarbital, dexamethasone, and beta-naphthoflavone. The toxicogenomics approach used enabled comparison of similar mechanistic end-points at the molecular level between in vitro and in vivo conditions, namely, compound-induced changes in multiple genes and signaling pathways. Toxicant-induced cytotoxic effects and gene expression profiles observed in hepatocytes cultured in modified medium and hepatocytes cultured in standard medium (without inducers) were compared with results from a rat in vivo study. Coumarin was used as a model compound because its toxicity depends on bioactivation by P450 enzymes. Metabolism of coumarin toward active metabolites, coumarin-induced cytotoxicity, and gene expression modulation were more pronounced in hepatocytes cultured in modified medium compared with hepatocytes cultured in standard medium. In addition, more genes and biological pathways were similarly affected by coumarin in hepatocytes cultured in modified medium and in vivo. In conclusion, these experiments showed that for coumarin-induced toxicity, sandwich-cultured hepatocytes maintained in modified medium better represent the situation in vivo compared with hepatocytes cultured in standard medium.

Alanine Transaminase↗
PubMed2005

EDGE: a centralized resource for the comparison, analysis, and distribution of toxicogenomic information.

Transcriptional profiling via microarrays holds great promise for toxicant classification and hazard prediction. Unfortunately, the use of different microarray platforms, protocols, and informatics often hinders the meaningful comparison of transcriptional profiling data across laboratories. One solution to this problem is to provide a low-cost and centralized resource that enables researchers to share toxicogenomic data that has been generated on a common platform. In an effort to create such a resource, we developed a standardized set of microarray reagents and reproducible protocols to simplify the analysis of liver gene expression in the mouse model. This resource, referred to as EDGE, was then used to generate a training set of 117 publicly accessible transcriptional profiles that can be accessed at http://edge.oncology.wisc.edu/. The Web-accessible database was also linked to an informatics suite that allows on-line clustering and K-means analyses as well as Boolean and sequence-based searches of the data. We propose that EDGE can serve as a prototype resource for the sharing of toxicogenomics information and be used to develop algorithms for efficient chemical classification and hazard prediction.

Animals↗
PubMed2004

INVITOX 2004: 13th Workshop of the European Society of Toxicology In Vitro, organised in cooperation with the Scandinavian Society for Cell Toxicology.

INVITOX 2004, the 13th Workshop of the European Society of Toxicology In Vitro, was held on 8-11 September 2004, in Zegrze, Poland, in cooperation with the Scandinavian Society for Cell Toxicology. The workshop was attended by 112 participants from 19 countries. The programme included 11 main sessions and two round table discussions. The lectures of the invited speakers, together with short oral presentations and posters, covered the most important aspects of current research in the field of in vitro toxicology. ECVAM's strategies for the replacement of animal testing for toxic chemicals by alternative test systems were discussed.

Animal Testing Alternatives↗
PubMed2005

The emergence of toxicogenomics: a case study of molecularization.

This paper described the efforts of scientists at the National Institute of Environmental Health Sciences (NIEHS) and their allies in the National Toxicology Program to molecularize toxicology by fostering the emergence of a new discipline: toxicogenomics. I demonstrate that the molecularization of toxicology at the NIEHS began in a process of 'co-construction'. However, the subsequent emergence of the discipline of toxicogenomics has required the deliberate development of communication across the myriad disciplines necessary to produce toxicogenomic knowledge; articulation of emergent forms, standards, and practices with extant ones; management of the tensions generated by grounding toxicogenomics in traditional toxicological standards and work practices even it transforms those standards and practices; and identification and stabilization of roles for toxicogenomic knowledge in markets and service sites, such as environmental health risk assessment and regulation. This paper describes the technological, institutional, and inter-sectoral strategies that scientists have pursued in order to meet these challenges. In so doing, this analysis offers a vista into both the means and meanings of molecularization.

Animals↗
PubMed2004

Pharmacogenetics and pharmacogenomics as new tools to optimise cancer chemotherapy.

Pharmacogenetics takes into account the individual variability of the genome and its relationships with drug activity. Numerous gene polymorphisms occurring at the level of drug metabolising enzymes, drug transporters or drug targets have been identified; they may be responsible for an alteration of the phenotype, and of individual changes in drug efficacy and/or toxicity. Pharmacogenomics takes into account the genetic alterations present in tumours and their role in drug activity. It may be possible to establish correlations between the activity of a drug and the level of expression of tumour genes, and thus select the most appropriate drugs to prescribe for the treatment of individual tumours. Pharmacogenetics and pharmacogenomics are acting synergistically for the personalisation of treatments, on the basis of the constitutive singularity of patients and of the molecular characteristics of tumours.

Antineoplastic Agents↗
PubMed2004

Uridine diphosphoglucuronosyl transferase and methylenetetrahydrofolate reductase polymorphisms as genomic predictors of toxicity and response to irinotecan-, antifolate- and fluoropyrimidine-based chemotherapy.

Pharmacogenetics could be a useful tool for performing tailored anticancer chemotherapy. Several polymorphisms potentially affecting enzymes responsible for metabolism, transport and mechanism of action of irinotecan, fluoropyrimidines and antifolate agents have been investigated and sometimes associated with toxicity and response. In particular, uridine diphosphoglucuronosyl transferase 1A1 (UGT1A1) enzyme is responsible for detoxification of irinotecan active metabolite, SN38. A polymorphic structure in the promoter region (UGT1A1*28) may affect irinotecan toxicity and SN38 plasma level. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the folate cycle, presenting two common polymorphisms (677C>T and 1298 A>C) which have impact on toxicity and efficacy of methotrexate and 5-fluorouracil.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

MicroGen: a MIAME compliant web system for microarray experiment information and workflow management.

BACKGROUND: Improvements of bio-nano-technologies and biomolecular techniques have led to increasing production of high-throughput experimental data. Spotted cDNA microarray is one of the most diffuse technologies, used in single research laboratories and in biotechnology service facilities. Although they are routinely performed, spotted microarray experiments are complex procedures entailing several experimental steps and actors with different technical skills and roles. During an experiment, involved actors, who can also be located in a distance, need to access and share specific experiment information according to their roles. Furthermore, complete information describing all experimental steps must be orderly collected to allow subsequent correct interpretation of experimental results. RESULTS: We developed MicroGen, a web system for managing information and workflow in the production pipeline of spotted microarray experiments. It is constituted of a core multi-database system able to store all data completely characterizing different spotted microarray experiments according to the Minimum Information About Microarray Experiments (MIAME) standard, and of an intuitive and user-friendly web interface able to support the collaborative work required among multidisciplinary actors and roles involved in spotted microarray experiment production. MicroGen supports six types of user roles: the researcher who designs and requests the experiment, the spotting operator, the hybridisation operator, the image processing operator, the system administrator, and the generic public user who can access the unrestricted part of the system to get information about MicroGen services. CONCLUSION: MicroGen represents a MIAME compliant information system that enables managing workflow and supporting collaborative work in spotted microarray experiment production.

Computational Biology↗
PubMed2005

Toxicogenomics: regulatory perspective on current position.

Published studies on the utility of toxicogenomic approaches (transcriptomics, proteomics and metabonomics) in screening for toxicological mechanisms and evaluation of dose response effects have been reviewed. The information supports the use of transcriptomics to screen for specific toxicological mechanisms for which there is an a priori hypothesis, although in some areas such as mutagenicity testing, toxicogenomics appear to have limited value for identifying mutagens. Data from such screening approaches cannot be used to exclude the possibility of toxicity. Targeted transcriptomics might be valuable for screening for specific mechanisms of toxicity considered to be irrelevant for assessing risk to humans, which would help to reduce the need for detailed testing of some chemicals. An integrated approach is suggested where data from more than one toxicogenomic approach could be used as an adjunct to conventional toxicology to assess dose-response in toxicological tests. An outline preliminary proposal for use by regulators is suggested although it is noted that more data are required before this could be formally used in a decision-making process.

Animals↗