Evaluation of the Genotoxicity of Aristolochic Acid in the Kidney and Liver of F344 gpt delta Transgenic Rat Using a 28-Day Repeated-dose Protocol: A Collaborative Study of the gpt delta Transgenic Rat Mutation Assay

Abstract

Transgenic rat gene-mutation assays can be used to assess genotoxicity of chemicals in target organs for carcinogenicity. Since gene mutations in transgenes are genetically neutral and thus accumulate along with treatment periods, the assays are suitable for genotoxicity risk assessment of chemicals using repeated-dose treatment methodologies. However, few studies have been conducted to examine the suitability of the assays in repeat-dose treatment protocols. In order to prove the utility of the transgenic rat assays, we treated gpt delta rats with aristolochic acid at 0.3 and 1 mg/kg by gavage daily for 28 days, and autopsied the rats 3 days after the final treatment, which is a protocol recommended by the International Workshop on Genotoxicity Testing (IWGT). Aristolochic acid exists in herbs and some other plants, and is carcinogenic in the kidney, bladder and stomach in rats. The mutant frequency (MF) in both the kidney and the liver increased significantly in a dose-dependent manner when the rats were treated with aristolochic acid. We concluded that the gpt delta rat assay is sensitive enough to detect gene mutations induced by aristolochic acid and also that the 28-day repeated-dose protocol is suitable for assessing genotoxicity of chemicals.