| In modern medicine science, not only have the great progress witnessed in applying new techniques such as the computer aided drug design, .high throughput screening and combination chemistry, but some important changes have occurred in the paradigm and the development chain of new drug research and development (R&D). Previously, the drug safety evaluation and research were been carried out in pre-clinic and clinic stages. Presently, to discover and filter as early as possible the compounds unsuitable for further development for their toxicity, the pharmas have changed the drug toxicology research strategy. The New Chemical Entities (NCEs) were optimized and screened based on the integrated results of toxicology, pharmacology and pharmacokinetics, which formed a new subject of discovery toxicology.The study paradigms of discovery toxicology are to engage drug toxicity screening and optimization in the whole course of R&D, i.e. new drug discovery, preclinical and clinic safety evaluation, to speed the R&D progress, to reduce the innovation cost and to increase the success rate. One of the main technologies of discovery toxicology is '-omics' technique such as genomic and metabonomic technologies. Using the '-omics' techniques, we could study toxic mechanisms of lead, to find the biomarkers related to the lead toxicity and to globally analyze all kinds of dynamic processes of the organisms on the physiological, pathological and toxicological conditions. Toxicgenomic techniques are used to predict the potential toxicity of drug candidates based on the changes of gene expressions. Metabonomics defined as the quantitative measurement of the dynamic multiparametric metabolic response of living systems to pathophysiolgical stimuli or genetic modification. Metabonomics is now recognized as an independent and widely used technique for evaluating the toxicity of drug candidates. It is used to screen of NCEs toxicity, to identify the target organ of the toxicity, and to determine the biochemical biomarkers for the onset, progression and regression of the toxic lesions.Z24 series compounds are designed and developed by Professor Li Song and his colleages, and are promised to become a first class antineoplastic drug. Based oncomputer model of BCL-2 and targeting on VEGF and BCL-2 protein, these compounds have antiangiogenesis effects on tumor mass. We have preliminarily studied the Z24 toxicology using toxicogenomic, metabonomic techniques and the bioinformatics tools. At the same time, we have explored the application of toxicogenomics and metabonomics in pharmatoxicology. The main results are as follows:Chapter 1 Studies of Z24 Toxic Mechanisms to Liver with Toxicogenomic ChipsSection 1 Toxicity screening of Z24 series compoundsThe acute toxicity of Z24 series was compared by MTT colorimetry and up-and-down procedures. Combined with the results of pharmacology and pharmacokinetics screening, Z24 was choosed as drug-candidate to further study its toxicicy and mode of toxic action. Section 2 Assessment of the liver toxicity of Z24Twenty female Kunming mice were oral administrated with 0, 40, 80 or 120mg/kg Z24 for one month, respectively. After dosing, all animals were euthanized and bled for blood biochemical analysis and liver histopathology examination. Results shown that the plasma level of ALT, AST and Tbil of 120mg/kg group were increased by 97%, 281% and 179 % respectively, compared to controls. There were clear necrosis foci in liver histopathology of 120 and 80mg/kg groups. Section 3 In vitro analyses of Z24 toxicity to HepG2 cells using high-densitygenechipsWe used cDNA microarray to analyze Z24 liver toxicity. The mRNA from HepG2 cells of both controls and those treated with 0.248mM (IC20) or 0.78 mM (IC50) Z24 for 24h were reversely transcribed to cDNA by incorporation of fluorescent-labeld ddUTP, hybridized then with a cDNA microarray representing the 1153 human genes. The hybridization fluorescent signals of Cy3 and Cy5 were scanned and analyzed to find the genes with altered expression. Hierarchi...
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