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

Authors
Das-PC; Streit-TM; Cao-Y; Rose-RL; Cherrington-N; Ross-MK; Wallace-AD; Hodgson-E
Source
Drug Metabol Drug Interact 2008 Jan; 23(3-4):211-236
NIOSHTIC No.
20036475
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-cyclopropanecarboxylate] 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).
Keywords
Cell-metabolism; Cellular-reactions; Chemical-hypersensitivity; Chemical-indicators; Chemical-reactions; Cytotoxic-effects; Environmental-exposure; Environmental-hazards; Enzymatic-effects; Hepatocytes; Hepatotoxicity; Hormone-activity; Hormones; Liver; Metabolic-disorders; Metabolic-study; Metabolism
Contact
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633
CODEN
DMDIEQ
Publication Date
20080102
Document Type
Journal Article
Funding Type
Cooperative Agreement
Fiscal Year
2008
NTIS Accession No.
NTIS Price
Identifying No.
Cooperative-Agreement-Number-U50-OH-007551
Issue of Publication
3-4
ISSN
0792-5077
Source Name
Drug Metabolism and Drug Interactions
State
MD; NC
Performing Organization
East Carolina University
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