Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants
| Autor: | Angelique Leone, S. Jim Proctor, Geert R. Verheyen, Mark D. Johnson, Michael McMillian, L. Mark Kao, Leigh-Anne Piechta, Michael F. Kelley, Alex Nie, J. Brandon Parker, Peter G. Lord, Sharmilee Sawant |
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| Rok vydání: | 2013 |
| Předmět: |
Genetic Markers
Male Methapyrilene Pharmacology Toxicology Toxicogenetics Felbamate Flutamide Rats Sprague-Dawley chemistry.chemical_compound Databases Genetic medicine Animals Oligonucleotide Array Sequence Analysis Valproic Acid Gene Expression Profiling Cyproterone acetate Rats Oxidative Stress chemistry Gene Expression Regulation Liver Disulfiram Phenobarbital Chemical and Drug Induced Liver Injury medicine.drug Nimesulide |
| Zdroj: | Toxicology and applied pharmacology. 275(3) |
| ISSN: | 1096-0333 |
| Popis: | Previously we reported a gene expression signature in rat liver for detecting a specific type of oxidative stress (OS) related to reactive metabolites (RM). High doses of the drugs disulfiram, ethinyl estradiol and nimesulide were used with another dozen paradigm OS/RM compounds, and three other drugs flutamide, phenacetin and sulindac were identified by this signature. In a second study, antiepileptic drugs were compared for covalent binding and their effects on OS/RM; felbamate, carbamazepine, and phenobarbital produced robust OS/RM gene expression. In the present study, liver RNA samples from drug-treated rats from more recent experiments were examined for statistical fit to the OS/RM signature. Of all 97 drugs examined, in addition to the nine drugs noted above, 19 more were identified as OS/RM-producing compounds-chlorpromazine, clozapine, cyproterone acetate, dantrolene, dipyridamole, glibenclamide, isoniazid, ketoconazole, methapyrilene, naltrexone, nifedipine, sulfamethoxazole, tamoxifen, coumarin, ritonavir, amitriptyline, valproic acid, enalapril, and chloramphenicol. Importantly, all of the OS/RM drugs listed above have been linked to idiosyncratic hepatotoxicity, excepting chloramphenicol, which does not have a package label for hepatotoxicity, but does have a black box warning for idiosyncratic bone marrow suppression. Most of these drugs are not acutely toxic in the rat. The OS/RM signature should be useful to avoid idiosyncratic hepatotoxicity of drug candidates. |
| Databáze: | OpenAIRE |
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