Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants

Area of Science:

• Toxicology
• Pharmacology
• Genomics

Background:

• A previously identified gene expression signature detects oxidative stress (OS) related to reactive metabolites (RM) in rat liver.
• Initial studies identified OS/RM-producing drugs including disulfiram, ethinyl estradiol, nimesulide, flutamide, phenacetin, and sulindac.
• Antiepileptic drugs like felbamate, carbamazepine, and phenobarbital were also found to induce OS/RM gene expression.

Purpose of the Study:

• To validate and expand the use of the OS/RM gene expression signature in identifying new drug candidates.
• To assess a broader range of drugs for their potential to induce OS/RM and associated hepatotoxicity.
• To determine the utility of the OS/RM signature in predicting idiosyncratic hepatotoxicity.

Main Methods:

• Analysis of liver RNA samples from rats treated with 97 different drugs.
• Statistical fitting of gene expression data to the established OS/RM signature.
• Correlation of identified OS/RM-producing drugs with known instances of idiosyncratic hepatotoxicity.

Main Results:

• The OS/RM signature identified 19 additional drugs, bringing the total to 28 compounds.
• Notable identified drugs include chlorpromazine, clozapine, tamoxifen, and valproic acid.
• All identified OS/RM-producing drugs, except chloramphenicol, are linked to idiosyncratic hepatotoxicity.

Conclusions:

• The OS/RM gene expression signature is a valuable tool for identifying drugs that cause oxidative stress and reactive metabolites.
• This signature can help predict and potentially avoid idiosyncratic hepatotoxicity in drug development.
• The findings support the use of this signature to screen drug candidates for liver toxicity risks.