Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro.
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Thompson KL, Sistare FD
Selection of drugs to test the specificity of the Tg.AC assay by screening for induction of the gadd153 promoter in vitro.
Toxicol Sci. 2003 Aug;74(2):260-70. Epub 2003 May 2.
- PubMed ID
- 12730611 [ View in PubMed]
- Abstract
Short-term assays for carcinogenicity testing of chemicals that use transgenic mice designed to have altered expression of genes mechanistically relevant to carcinogenesis are attractive alternatives to two-year dosing studies in rodents. The models that have been the received the greatest level of performance evaluation include p53(+/-), rasH2, Xpa/p53(+/-), and Tg.AC mice. For use of these models in a regulatory setting to evaluate the carcinogenic potential of pharmaceuticals, it is important to establish an assurance of assay specificity and positive predictivity based on studies using drugs with a wide spectrum of pharmacologic activity. For this purpose, 99 noncarcinogenic drugs were prioritized based on their activity in an in vitro induction assay correlative with a positive response in the Tg.AC assay (induction of the gadd153 promoter in HepG2 cells). Activities in two assays less predictive of Tg.AC activity (induction of c-fos and zeta-globin gene promoters) were also measured. Nine percent of the screened drugs induced the gadd153 promoter by at least fourfold. Several criteria were used to select candidates for subsequent in vivo testing in the Tg.AC assay: (1) sufficient drug solubility in appropriate skin paint vehicles to elicit systemic toxicity, (2) the level of induction of the gadd153 promoter by the drug, (3) the in vitro potency of the drug, and (4) the cost of the drug required for a 6-month study. Based on these criteria, amiloride, dipyridamole, and pyrimethamine were selected from 99 rodent noncarcinogens in a drug database for testing the specificity of the Tg.AC assay.
DrugBank Data that Cites this Article
- Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Acebutolol Approved Investigational FOS 2353 upregulated Acebutolol results in increased expression of FOS mRNA 14q24.3 Acrivastine Approved FOS 2353 upregulated acrivastine results in increased expression of FOS mRNA 14q24.3 Allopurinol Approved FOS 2353 upregulated Allopurinol results in increased expression of FOS mRNA 14q24.3 Amiloride Approved FOS 2353 upregulated Amiloride results in increased expression of FOS mRNA 14q24.3 Chlorpropamide Approved Investigational FOS 2353 upregulated Chlorpropamide results in increased expression of FOS mRNA 14q24.3 Diclofenac Approved Vet Approved FOS 2353 upregulated Diclofenac results in increased expression of FOS mRNA 14q24.3 Diflunisal Approved Investigational FOS 2353 upregulated Diflunisal results in increased expression of FOS mRNA 14q24.3 Dipyridamole Approved FOS 2353 upregulated Dipyridamole results in increased expression of FOS mRNA 14q24.3 Ephedrine Approved FOS 2353 upregulated Ephedrine results in increased expression of FOS mRNA 14q24.3 Flecainide Approved Withdrawn FOS 2353 upregulated Flecainide results in increased expression of FOS mRNA 14q24.3 Mebendazole Approved Vet Approved FOS 2353 upregulated Mebendazole results in increased expression of FOS mRNA 14q24.3 Mycophenolic acid Approved Investigational FOS 2353 upregulated Mycophenolic Acid results in increased expression of FOS mRNA 14q24.3 Nabumetone Approved FOS 2353 upregulated nabumetone results in increased expression of FOS mRNA 14q24.3 Nimodipine Approved Investigational FOS 2353 upregulated Nimodipine results in increased expression of FOS mRNA 14q24.3 Pyrimethamine Approved Investigational Vet Approved FOS 2353 upregulated Pyrimethamine results in increased expression of FOS mRNA 14q24.3 Verapamil Approved FOS 2353 upregulated Verapamil results in increased expression of FOS mRNA 14q24.3