Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants.
Toxicol Appl Pharmacol
; 275(3): 189-97, 2014 Mar 15.
Article
in En
| MEDLINE
| ID: mdl-24486436
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oxidative Stress
/
Gene Expression Profiling
/
Toxicogenetics
/
Chemical and Drug Induced Liver Injury
/
Liver
Limits:
Animals
Language:
En
Journal:
Toxicol Appl Pharmacol
Year:
2014
Document type:
Article
Affiliation country:
Estados Unidos