title: In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes.
abstract: In vitro metabolism of permethrin, a pyrethroid insecticide, was assessed in primary human hepatocytes. In vitro kinetic experiments were performed to estimate the Michaelis-Menten parameters and the clearances or formation rates of the permethrin isomers (cis- and trans-) and three metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA) and 3-phenoxybenzoic acid (3-PBA). Non-specific binding and the activity of the enzymes involved in permethrin's metabolism (cytochromes P450 and carboxylesterases) were quantified. Trans-permethrin was cleared more rapidly than cis-permethrin with a 2.6-factor (25.7±0.6 and 10.1±0.3 μL/min/10(6) cells respectively). A 3-factor was observed between the formation rates of DCCA and 3-PBA obtained from trans- and cis-permethrin. For both isomers, the rate of formation of DCCA was higher than the one of 3-PBA. The metabolism of the isomers in mixture was also quantified. The co-incubation of isomers at different ratios showed the low inhibitory potential of cis- and trans-permethrin on each other. The estimates of the clearances and the formation rates in the co-incubation condition did not differ from the estimates obtained with a separate incubation. These metabolic parameters may be integrated in physiologically based pharmacokinetic (PBPK) models to predict the fate of permethrin and metabolites in the human body.
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité Modèles pour l'Ecotoxicologie et la Toxicologie (METO), Parc ALATA BP2, 60550 Verneuil en Halatte, France; Sorbonne University, Université de Technologie de Compiègne, CNRS, UMR 7338, Biomechanics and Bioengineering, Centre de recherche Royallieu, CS 60 319, 60 203 Compiègne cedex, France.
authors.forename: M-E
authors.initials: ME
authors.lastname: Willemin
authors.affiliation: Institut de Recherche sur l'Agronomie (INRA), UMR 1331 TOXALIM, 400 route des Chappes, BP167, 06903 Sophia Antipolis, France.
authors.forename: A
authors.initials: A
authors.lastname: Kadar
authors.affiliation: Institut de Recherche sur l'Agronomie (INRA), UMR 1331 TOXALIM, 400 route des Chappes, BP167, 06903 Sophia Antipolis, France.
authors.forename: G
authors.initials: G
authors.lastname: de Sousa
authors.affiliation: Sorbonne University, Université de Technologie de Compiègne, CNRS, UMR 7338, Biomechanics and Bioengineering, Centre de recherche Royallieu, CS 60 319, 60 203 Compiègne cedex, France.
authors.forename: E
authors.initials: E
authors.lastname: Leclerc
authors.affiliation: Institut de Recherche sur l'Agronomie (INRA), UMR 1331 TOXALIM, 400 route des Chappes, BP167, 06903 Sophia Antipolis, France.
authors.forename: R
authors.initials: R
authors.lastname: Rahmani
authors.affiliation: Institut National de l'Environnement Industriel et des Risques (INERIS), Unité Modèles pour l'Ecotoxicologie et la Toxicologie (METO), Parc ALATA BP2, 60550 Verneuil en Halatte, France. Electronic address: celine.brochot@ineris.fr.
authors.forename: C
authors.initials: C
authors.lastname: Brochot
mesh_terms: D001711:Biotransformation; D015925:Cryopreservation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism*; D007536:Isomerism; D008297:Male; D015233:Models, Statistical; D026023:Permethrin / Q000737:chemistry / Q000378:metabolism*; D061251:Primary Cell Culture; D066007:Toxicokinetics
chemical_list: D007306:Insecticides; D026023:Permethrin; D003577:Cytochrome P-450 Enzyme System; D004950:Esterases
keywords: 3-Phenoxybenzoic acid; Interaction; Michaelis–Menten parameters; Primary human hepatocytes; cis/trans-3-(2,2 Dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid; cis/trans-Permethrin