Pyrethroids: cytotoxicity and induction of CYP isoforms in human hepatocytes.

Article Details

Citation

Copy 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	Unknown	Substrate Inducer	Details

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