Pyrethroids: cytotoxicity and induction of CYP isoforms in human hepatocytes.
Article Details
- CitationCopy to clipboard
Das PC, Streit TM, Cao Y, Rose RL, Cherrington N, Ross MK, Wallace AD, Hodgson E
Pyrethroids: cytotoxicity and induction of CYP isoforms in human hepatocytes.
Drug Metabol Drug Interact. 2008;23(3-4):211-36.
- PubMed ID
- 19326768 [ View in PubMed]
- Abstract
Deltamethrin [(S)-alpha-cyano-3-phenoxybenzyl-cis-(1 R,3R)-3(2,2-dibromovinyl)(2,2-dimethyl-cyclopropane-carboxylate] and permethrin [3-phenoxybenzyl(1RS)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropaneca rboxylate] are pyrethroid insecticides used in agriculture, public health and military deployments. Pyrethroids are known to be capable of inducing cytochrome P450 (CYP) 2B1/2B2, CYP1A1 and overall CYP content in rat liver. The objectives of this study were to evaluate the potential of deltamethrin and permethrin to cause cytotoxicity and to induce CYP isoforms in human hepatocytes. Permethrin and deltamethrin showed dose-dependent effects on adenylate kinase activity in HepG2 cells, in which 50 and 100 microM doses, respectively, induced a 3-5 fold increase in activity, and also induced adenylate kinase activity in primary human hepatocytes. An approximately 3-fold induction was noted at 200 microM deltamethrin and a 4-fold induction at 100 microM permethrin. Cytotoxicity was noted in HepG2 cells following 48-72 h exposure to 100 or 200 microM deltamethrin and permethrin, respectively. Dose-dependent induction of caspase-3/7 was initiated by 12.5 microM deltamethrin or by 3.125 microM permethrin. Actinomycin D, a positive control for induction of caspase 3/7, induced caspase-3/7, an effect completely abrogated by the specific inhibitor Z-DEVD-FMK. At 100 microM deltamethrin 2-3 fold induction of CYP1A1 and CYP2B6 mRNA was observed, while at the same time an approximately 25-fold induction of CYP3A4 was noted. Permethrin-mediated CYP induction was much less potent, 4-fold or less for CYP1A1, CYP3A4, CYP3A5, CYP2B6 and CYP2A6. It has also been shown that these pyrethroids are ligands for the pregnane X receptor (PXR).
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Permethrin Cytochrome P450 2B6 Protein Humans UnknownSubstrateInducerDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Permethrin Approved Investigational CYP1A1 1543 upregulated Permethrin results in increased expression of CYP1A1 mRNA 15q24.1 Permethrin Approved Investigational CYP2A6 1548 upregulated Permethrin results in increased expression of CYP2A6 mRNA 19q13.2 Permethrin Approved Investigational CYP2B6 1555 upregulated Permethrin results in increased expression of CYP2B6 mRNA 19q13.2 Permethrin Approved Investigational CYP3A4 1576 upregulated Permethrin results in increased expression of CYP3A4 mRNA 7q22.1 Permethrin Approved Investigational CYP3A5 1577 upregulated Permethrin results in increased expression of CYP3A5 mRNA 7q22.1