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

•We estimated the Michaelis–Menten parameters of permethrin and its main metabolites.•Metabolic rates were estimated with the isomers incubated separately and in mixture.•Non-specific binding of permethrin was negligible or corrected.•The rate of formation of DCCA is higher than the one of 3-PBA.•We...

Full description

Saved in:
Bibliographic Details
Published in:Toxicology in vitro 2015-06, Vol.29 (4), p.803-812
Main Authors: Willemin, M.-E., Kadar, A., de Sousa, G., Leclerc, E., Rahmani, R., Brochot, C.
Format: Article
Language:English
Subjects:
3-Phenoxybenzoic acid
Biotransformation
cis/trans-3-(2,2 Dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid
cis/trans-Permethrin
Cryopreservation
Cytochrome P-450 Enzyme System - metabolism
Esterases - metabolism
Female
Hepatocytes - metabolism
Humans
Insecticides - chemistry
Insecticides - metabolism
Interaction
Isomerism
Life Sciences
Male
Michaelis–Menten parameters
Models, Statistical
Permethrin - chemistry
Permethrin - metabolism
Primary Cell Culture
Primary human hepatocytes
Toxicokinetics
Toxicology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:•We estimated the Michaelis–Menten parameters of permethrin and its main metabolites.•Metabolic rates were estimated with the isomers incubated separately and in mixture.•Non-specific binding of permethrin was negligible or corrected.•The rate of formation of DCCA is higher than the one of 3-PBA.•We observed a low inhibitory potential of cis- and trans-permethrin on each other. 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±0.3μL/min/106 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.
ISSN:0887-2333
1879-3177
DOI:10.1016/j.tiv.2015.03.003