Expression Levels of GABA-A Receptor Subunit Alpha 3, Gabra3 and Lipoprotein Lipase, Lpl Are Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity

Drug-induced liver injury (DILI) is the serious and fatal drug-associated adverse effect, but its incidence is very low and individual variation in severity is substantial. Acetaminophen (APAP)-induced liver injury accounts for >50% of reported DILI cases but little is known for the cause of individual variations in the severity. Intrinsic genetic variation is considered a key element but the identity of the genes was not well-established. Here, pre-biopsy method and microarray technique was applied to uncover the key genes for APAP-induced liver injury in mice, and a cause and effect experiment employing quantitative real-time PCR was conducted to confirm the correlation between the uncovered genes and APAP-induced hepatotoxicity. We identified the innately and differentially expressed genes of mice susceptible to APAP-induced hepatotoxicity in the pre-biopsied liver tissue before APAP treatment through microarray analysis of the global gene expression profiles (Affymetrix GeneChip® Mouse Gene 1.0 ST for 28,853 genes). Expression of 16 genes including Gdap10, Lpl, Gabra3 and Ccrn4l were significantly different (t-test: FDR <10%) more than 1.5 fold in the susceptible animals than resistant. To confirm the association with the susceptibility to APAP-induced hepatotoxicity, another set of animals were measured for the expression level of selected 4 genes (higher two and lower two genes) in the liver pre-biopsy and their sensitivity to APAP-induced hepatotoxicity was evaluated by post hoc. Notably, the expressions of Gabra3 and Lpl were significantly correlated with the severity of liver injury (p<0.05) demonstrating that these genes may be linked to the susceptibility to APAP-induced hepatotoxicity.

Establishment and validation of classifiers to predict genotoxic and non-genotoxic carcinogens / 中国药学杂志

OBJECTIVE: To establish classifiers to predict genotoxic and non-genotoxic carcinogens using toxicogenomics methods, explore the effect of exposure time and validated the prediction performance of the classifiers. METHODS: The primary mouse hepatocyte model was treated for 24 and 48 h with two genotoxic carcinogens, aflatoxin Bl (AFB1), benzo(a) pyrene (BAP) and two non-genotoxic carcinogens, thioacetamide (TAA), wyeth-14643 (WY). The differentially expressed genes were input to prediction analysis for microarray (PAM) software to screen out classifiers. The functions and interrelations of genes in classifiers were studied by gene set enrichment analysis (GSEA) and the protein-protein interactions were predicted using STRING database. Two additional carcinogens to validate the prediction performance of the classifiers were used. Finally, the experiment of QuantiGene Multiplex assay (Q-GP) to validate the microarray data was used. RESULTS: Forty-eight h classifiers had a better predicted capability than that of 24 h classifiers. p53 pathway, TNF-α signaling pathway, fatty acid metabolism, PPAR signaling pathway involved in the classifires were enriched by GSEA. Carcinogenic protein-protein interaction network and metabolism-related protein-protein interaction network are obtained using STRING database. The predicted probability of the two additional carcinogens using 48 h classifiers was nearly 100% and data between QuantiGene Multiplex assay and microarray assay had a high conformity. CONCLUSION: The classifiers which could be used to discriminate the potential genotoxic carcinogens and non-genotoxic carcinogens and to predict modes of action for unknown compounds, are successfully established and validated. This might be a promising candidate in vitro method for carcinogenicity study in the field of nonclinical safety evaluation of drugs.

La medicina genómica: un cambio de paradigma de la medicina moderna retos para la bioética y el derecho / Genomic medicine; a paradigm shift in modern medicine challenges for bioethics an the law / A medicina genômica: uma mudança de paradigma da medicina moderna desafios para a bioética e para o direito

La medicina genómica y sus diferentes formas de aplicación medicinas personalizada o individualizada, de la que hacen parte la farmacogenómica, toxicogenómica y nutrigenómica; y la medicina predictiva, regenerativa o de reemplazo, molecular y reproductiva), sin lugar a dudas han transformado a la medicina moderna y se constituyen en un nuevo paradigma. Este artículo pretende hacer una revisión de las distintas formas de la medicina genómica, desde sus beneficios para la salud humana y cambios sustanciales en el abordaje del proceso salud-enfermedad, así como de las problemáticas y paradojas asociadas que deben ser abordadas desde la Bioética y el Derecho...

Genomic medicine and its different application forms, such as personalized (to which pharmacogenomics, toxicogenomics, nutrigenomics and predictive medicine belong), regenerative, molecular and reproductive medicines, have undoubtedly transformed modern medicine, becoming a new paradigm. The present study aims at reviewing the different forms of genomic medicine, from its benefits to human health, up to the problems and paradoxes that must be approached from bioethics and law...

A medicina genômica e suas diferentes formas de aplicação (medicinas personalizada ou individualizada, da qual fazem parte a farmacogenômica, a toxicogenômica e a nutrigenômica; e a medicina preditiva, regenerativa ou de substituição, molecular e reprodutiva) sem dúvidas têm transformado a medicina moderna e constituem um novo paradigma. Este artigo pretende fazer uma revisão das distintas formas da medicina genômica, desde seus benefícios para a saúde humana e mudanças substanciais na abordagem do processo saúde-doença, bem como das problemáticas e paradoxos associados que devem ser abordados a partir da Bioética e do Direito...

XPERNATO-TOX: an Integrated Toxicogenomics Knowledgebase

Toxicogenomics combines transcriptome, proteome and metabolome profiling with conventional toxicology to investigate the interaction between biological molecules and toxicant or environmental stress in disease caution. Toxicogenomics faces the problems of comparison and integration across different sources of data. Cause of unusual characteristics of toxicogenomic data, researcher should be assisted by data analysis and annotation for getting meaningful information. There are already existing repositories which claim to stand for toxicogenomics database. However, those just contain limited abilities for toxicogenomic research. For supporting toxicologist who comes up against toxicogenomic data flood, now we propose novel toxicogenomics knowledgebase system, XPERANTO-TOX. XPERANTO-TOX is an integrated system for toxicogenomic data management and analysis. It is composed of three distinct but closely connected parts. Firstly, Data Storage System is for reposit many kinds of '-omics' data and conventional toxicology data. Secondly, Data Analysis System consists of analytical modules for integrated toxicogenomics data. At last, Data Annotation System is for giving extensive insight of data to researcher.

GraPT: Genomic InteRpreter about Predictive Toxicology

Toxicogenomics has recently emerged in the field of toxicology and the DNA microarray technique has become common strategy for predictive toxicology which studies molecular mechanism caused by exposure of chemical or environmental stress. Although microarray experiment offers extensive genomic information to the researchers, yet high dimensional characteristic of the data often makes it hard to extract meaningful result. Therefore we developed toxicant enrichment analysis similar to the common enrichment approach. We also developed web-based system graPT to enable considerable prediction of toxic endpoints of experimental chemical.

Contribution of genomics, proteomics, and single-nucleotide polymorphism in toxicology research and Indian scenario.

Advancement in the molecular tools used in toxicology has provided immense information about the cellular and global structure and function of toxicant-responsive genes. Now, it has become possible to assess the functional activity of genes and proteins involved in various toxicological pathways, which were not possible with the conventional methods. Many genes are known to have a greater influence on the susceptibility to environmental agents than others; therefore, identification and characterization of polymorphism in such genes for the determination of early, late, or no response of an individual for the toxicant-induced diseases has also become mandatory. Toxicogenomics, a newly born discipline of toxicology, comprises of two major facets, one, how various genes in the genome respond to environmental toxicants and stressors and second, how toxicants modify the function and expression of specific genes in the genome. Toxicogenomics play an important role in the identification and characterization of molecular biomarkers to predict cellular toxicity and to determine the efficacy and exposure in the toxicity trials at an early stage. Genome and proteome-wide expression profiles in combination with conventional toxicology are being used to classify compounds, predict the mechanism of toxicity of newer compounds and determine the susceptibility of an individual for the toxic responses. Single-nucleotide polymorphism in toxicant-responsive genes is being used to obtain basic information of the genetic variation and its role in the functional protein expression. Various national and international government and private organizations have launched several programs on gene-environment interactions. Council of Scientific and Industrial Research (CSIR), New Delhi, India, has also launched a program on 'toxicogenomics of genetic polymorphism in Indian population to industrial chemicals for development of biomarkers' to provide better ventures and facilities to researchers in order to understand the environment-genome interactions. In this review, the contribution of genomics, proteomics, and SNPs in toxicology along with its current status in India has been discussed3.

Application of Microarray Technique in Toxicology / 环境与健康杂志

Toxicogenomics is a new undertaking in the pursuit of human genomics relevant to health risk from environmental toxicants and related stress, and also is a new scientific subdiscipline derived from a combination of the fields of toxicology and genomics. Microarray technique, i. e. gene-chip technique includes gene-chip development, pretreatment of detected samples, probe hybridization, detection data analysis. The microarray technique in toxicology mainly was applied to identification of potential hazardous substances, screening for mechanism of action, dose-response relationship assessment, identification of interaction among chemical mixtures, biomarker of exposure and biomarker of susceptibility. Microarray technique has been used to study biomarker for human bladder cancer, to study fingerprints of gene regulation associated with cadmium chloride, benzo(a) pyrene and trichloroethylene. fn this paper, a new automated and multi-applied molecular biology workstation, NanoChip biomolecular system was introduced .

Systems Toxicology:a New Orientation of Toxicological Research / 环境与健康杂志

With the development of systems biology and high-throughput molecular technologies, systems toxicology has come into being. The up-date understanding of systems toxicology is the study of the perturbation of biological systems by using chemicals and stressors, monitoring changes in molecular expression (transcript, protein and metabolite profiling), conventional toxicological parameters and iteratively integrating response data to describe the functioning organism. The background, research framework, supporting tools and the main applications of systems toxicology were discussed in detail in the present paper. Although in its infancy, systems toxicology will play an important role in advancing the study of environmental stress and heath impact definitely.