Toxicological characterization of N-methyl-N-nitrosourea-induced cataract in rats by LC/MS-based metabonomic analysis

Abstract

Cataract is one of the most serious drug-induced side effects that can terminate the development of drug candidates, and pharmaceutical companies consider it important to evaluate cataract-inducing potential in the early phases. Metabonomics is expected to be a powerful approach for the safety evaluation of drug candidates. In this study, we conducted a toxicological characterization of N-methyl-N-nitrosourea (MNU)-induced cataract in rats by LC/MS-based metabonomic analysis. MNU was intraperitoneally administered once to 15-day old rats at 70 mg kg(-1) . After that, animals were kept for 3 weeks waiting for cataract formation. Lens samples for metabonomic analysis were collected on 7, 14 and 21 days after MNU administration. Comprehensive analyses of lens metabolites were conducted using an LC/MS system, and multivariate data for each sample were compared by principal component analysis (PCA) to find any changes in lens metabolites. Lens opacity was confirmed by ophthalmoscopy 14 days after dosing, and even by gross observation 21 days after dosing. PCA of the lens samples for the control and MNU-treated groups revealed that the metabolite profiles of lens differed from each other, and several lens metabolites, such as lots of α-amino acids and gluthathione, decreased after MNU treatment. In conclusion, metabonomic analysis enabled us to identify new marker candidates for cataract and provided a better understanding of the mechanism related to MNU-induced cataract. It was considered that metabonomics is a useful approach for the characterization of drug-induced toxicity.