In vitro metabolism of permethrin and two metabolites by human primary hepatocytes
Résumé
Permethrin, an insecticide of the pyrethroid family, is suspected to induce hormonal and neuronal disorders. Permethrin is usually sold and found in the environment as a mixture of two isomers cis/trans. In a previous study, Scollon et al. (2009) characterized the metabolism of permethrin in human hepatic microsomes and observed that the metabolism of isomers was altered when incubated together. In this study, we propose to determine the metabolism of isomers of permethrin alone and as a mixture in primary human hepatocytes, recognized as the most suitable in vitro model for such studies. The formation of two metabolites, 3-phenoxybenzoic acid (3-PBA) and cis/trans 3-(2,2-dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (DCCA), was also assessed. Platted primary human hepatocytes were incubated with either cis or trans-permethrin at 7 concentrations (5–125 μM) for 10 min, 30 min, 1 h and 3 h. The depletion of permethrin and the formation of two metabolites were analysed using the Michaelis Menten model. Metabolism was also evaluated at low concentrations below Km to estimate the intrinsic clearance when cells are exposed to both isomers. As observed in previous studies, the metabolism of cis-permethrin is slower than trans-permethrin one. Michaelis–Menten parameters were estimated for all compounds except DCCA because the saturation phase was not reached at the highest exposure concentration. No significant differences for the metabolic rates of parent compounds and metabolites were observed for cis- and trans-isomers incubated alone or in mixture. Our results could be integrated in physiologically based pharmacokinetic models.