In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes

Marie-Emilie Willemin; Ali Kadar; Georges de Sousa; E. Leclerc; Roger Rahmani; Céline Brochot

In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes

Marie-Emilie Willemin ^{1, 2} Ali Kadar ³ Georges de Sousa ³ E. Leclerc ² Roger Rahmani ³ Céline Brochot ¹

1 INERIS - Institut National de l'Environnement Industriel et des Risques

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 mu L/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.

Keywords : CIS/TRANS-PERMETHRIN CIS/TRANS-3-(2 2 DICHLOROVINYL)-2 2DIMETHYL-(1-CYCLOPROPANE) CARBOXYLIC ACID 3-PHENOXYBENZOIC ACID PRIMARY HUMAN HEPATOCYTES INTERACTION MICHAELIS-MENTEN PARAMETERS

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Toxicology

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https://hal-ineris.archives-ouvertes.fr/ineris-01855035
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Submitted on : Tuesday, August 7, 2018 - 1:40:18 PM
Last modification on : Friday, June 14, 2019 - 6:31:19 PM

In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes

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In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes

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