2,6-and 3,5-dimethylaniline-induced mutagenesis in Chinese hamster ovary cells expressing human cytochrome P450 1A2 and sulfotransferase

ABSTRACT

Aim: The aim of this study was to test the hypothesis that human cytochrome P450 1A2 (CYP1A2) and sulfotransferase (SULT) contribute to the phase I and II bioactivation of 2,6-dimethylaniline (2,6-DMA) and 3,5-dimethylaniline (3,5-DMA) in affecting the incidence of genotoxicity.Methodology: 5P3H1 cells carrying cytochrome P450 1A2 (CYP1A2) and SULT cells were treated with various concentrations of 2,6-and 3,5-DMA for 48 hr or their N-hydroxyl and aminophenol metabolites for 1 hr in the absence or presence of 2,6-Dichloro-4-nitrophenol (DCNP). Cell lethality was assayed by trypan blue exclusion and induced mutagenesis of adenine phosphoribosyl transferase (aprt) gene was also evaluated. Results: A significant dose-dependent increase in cytotoxicity and mutant fraction was observed after treatment with 2,6- and 3,5-DMA, and their metabolites; N-hydroxy and aminophenol metabolites are more potent than the parent compounds. Addition of sulfotransferase inhibitor DCNP decreased the cytotoxic and mutagenic effects of 2,6- and 3,5-DMA, and their metabolites in a dose-dependent manner. Interpretation: This research indicate that 2,6 and 3,5-DMA are mutagenic, and their toxicity in model systems depend on metabolic activation. This activation is mediated by CYP1A2 and SULT enzymes