Human Gene Set: HU_GENOTOXIN_ACTION_DIRECT_VS_INDIRECT_4HR

For the Mouse gene set with the same name, see HU_GENOTOXIN_ACTION_DIRECT_VS_INDIRECT_4HR

Standard name HU_GENOTOXIN_ACTION_DIRECT_VS_INDIRECT_4HR
Systematic name M1516
Brief description Genes discriminating between direct (cisplatin, MMS, mitomycin C [PubChem=2767;4156;5746]) and indirect (paclitaxel, hydroxyurea, etoposide [PubChem=4666;3657;36462]) acting genotoxins at 4 h time point.
Full description or abstract During the safety evaluation process of new drugs and chemicals, a battery of genotoxicity tests is conducted starting with in vitro genotoxicity assays. Obtaining positive results in in vitro genotoxicity tests is not uncommon. Follow-up studies to determine the biological relevance of positive genotoxicity results are costly, time consuming, and utilize animals. More efficient methods, especially for identifying a putative mode of action like an indirect mechanism of genotoxicity (where DNA molecules are not the initial primary targets), would greatly improve the risk assessment for genotoxins. To this end, we are participating in an International Life Sciences Institute (ILSI) project involving studies of gene expression changes caused by model genotoxins. The purpose of the work is to evaluate gene expression tools in general, and specifically for discriminating genotoxins that are direct-acting from indirect-acting. Our lab has evaluated gene expression changes as well as micronuclei (MN) in L5178Y TK(+/-) mouse lymphoma cells treated with six compounds. Direct-acting genotoxins (where DNA is the initial primary target) that were evaluated included the DNA crosslinking agents, mitomycin C (MMC) and cisplatin (CIS), and an alkylating agent, methyl methanesulfonate (MMS). Indirect-acting genotoxins included hydroxyurea (HU), a ribonucleotide reductase inhibitor, taxol (TXL), a microtubule inhibitor, and etoposide (ETOP), a DNA topoisomerase II inhibitor. Microarray gene expression analysis was conducted using Affymetrix mouse oligonucleotide arrays on RNA samples derived from cells which were harvested immediately after the 4 h chemical treatment, and 20 h after the 4 h chemical treatment. The evaluation of these experimental results yields evidence of differentially regulated genes at both 4 and 24 h time points that appear to have discriminating power for direct versus indirect genotoxins, and therefore may serve as a fingerprint for classifying chemicals when their mechanism of action is unknown.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 15120960   Authors: Hu T,Gibson DP,Carr GJ,Torontali SM,Tiesman JP,Chaney JG,Aardema MJ
Exact source Table 4
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Source species Mus musculus
Contributed by John Newman (University of Washington)
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identifier namespace		 MOUSE_SEQ_ACCESSION
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Version history 3.1: First introduced

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