Pyrethroids: Cytotoxicity and induction of CYP isoforms in human hepatocytes

Parikshit C. Das, Timothy M. Streit, Yan Cao, Randy L. Rose, Nathan J Cherrington, Matthew K. Ross, Andrew D. Wallace, Ernest Hodgson

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Deltamethrin [(S)-α-cyano-3-phenoxybenzyl-cis-(1R,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 μM 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 μM deltamethrin and a 4-fold induction at 100 μM permethrin. Cytotoxicity was noted in HepG2 cells following 48-72 h exposure to 100 or 200 μM deltamethrin and permethrin, respectively. Dose-dependent induction of caspase-3/7 was initiated by 12.5 μM deltamethrin or by 3.125 μM 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 μM deltamethrin 2-3 fold induction of CYP1A1 and CYP2B6 mRNA was observed, while at the same time an ∼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).

Original languageEnglish (US)
Pages (from-to)211-236
Number of pages26
JournalDrug Metabolism and Drug Interactions
Volume23
Issue number3-4
StatePublished - 2008

Fingerprint

Permethrin
Pyrethrins
Cytochrome P-450 Enzyme System
Hepatocytes
Protein Isoforms
Caspase 7
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP1A1
Caspase 3
Adenylate Kinase
Hep G2 Cells
Cytochrome P-450 CYP2B1
Dactinomycin
Insecticides
decamethrin
Agriculture
Public Health
Ligands
Messenger RNA
Liver

Keywords

  • CYP isoforms
  • Cytotoxicity
  • Deltamethrin
  • HepG2 cells
  • Human hepatocytes
  • Induction
  • Permethrin
  • PXR/SXR

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Medicine(all)

Cite this

Das, P. C., Streit, T. M., Cao, Y., Rose, R. L., Cherrington, N. J., Ross, M. K., ... Hodgson, E. (2008). Pyrethroids: Cytotoxicity and induction of CYP isoforms in human hepatocytes. Drug Metabolism and Drug Interactions, 23(3-4), 211-236.

Pyrethroids : Cytotoxicity and induction of CYP isoforms in human hepatocytes. / Das, Parikshit C.; Streit, Timothy M.; Cao, Yan; Rose, Randy L.; Cherrington, Nathan J; Ross, Matthew K.; Wallace, Andrew D.; Hodgson, Ernest.

In: Drug Metabolism and Drug Interactions, Vol. 23, No. 3-4, 2008, p. 211-236.

Research output: Contribution to journalArticle

Das, PC, Streit, TM, Cao, Y, Rose, RL, Cherrington, NJ, Ross, MK, Wallace, AD & Hodgson, E 2008, 'Pyrethroids: Cytotoxicity and induction of CYP isoforms in human hepatocytes', Drug Metabolism and Drug Interactions, vol. 23, no. 3-4, pp. 211-236.
Das, Parikshit C. ; Streit, Timothy M. ; Cao, Yan ; Rose, Randy L. ; Cherrington, Nathan J ; Ross, Matthew K. ; Wallace, Andrew D. ; Hodgson, Ernest. / Pyrethroids : Cytotoxicity and induction of CYP isoforms in human hepatocytes. In: Drug Metabolism and Drug Interactions. 2008 ; Vol. 23, No. 3-4. pp. 211-236.
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