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Title: Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor

Abstract

Endosulfan is an organochlorine pesticide commonly used in agriculture. Endosulfan has affects on vertebrate xenobiotic metabolism pathways that may be mediated, in part, by its ability to activate the pregnane X receptor (PXR) and/or the constitutive androstane receptor (CAR) which can elevate expression of cytochrome P450 (CYP) enzymes. This study examined the dose-dependency and receptor specificity of CYP induction in vitro and in vivo. The HepG2 cell line was transiently transfected with CYP2B6- and CYP3A4-luciferase promoter reporter plasmids along with human PXR (hPXR) or hCAR expression vectors. In the presence of hPXR, endosulfan-alpha exposure caused significant induction of CYP2B6 (16-fold) and CYP3A4 (11-fold) promoter activities over control at 10 {mu}M. The metabolite endosulfan sulfate also induced CYP2B6 (12-fold) and CYP3A4 (6-fold) promoter activities over control at 10 {mu}M. In the presence of hCAR-3, endosulfan-alpha induced CYP2B6 (2-fold) promoter activity at 10 {mu}M, but not at lower concentrations. These data indicate that endosulfan-alpha significantly activates hPXR strongly and hCAR weakly. Using western blot analysis of human hepatocytes, the lowest concentrations at which CYP2B6 and CYP3A4 protein levels were found to be significantly elevated by endosulfan-alpha were 1.0 {mu}M and 10 {mu}M, respectively. In mPXR-null/hPXR-transgenic mice, endosulfan-alpha exposure (2.5 mg/kg/day) caused amore » significant reduction of tribromoethanol-induced sleep times by approximately 50%, whereas no significant change in sleep times was observed in PXR-null mice. These data support the role of endosulfan-alpha as a strong activator of PXR and inducer of CYP2B6 and CYP3A4, which may impact metabolism of CYP2B6 or CYP3A4 substrates.« less

Authors:
;  [1]; ;  [2]; ;  [1]
  1. Department of Environmental and Molecular Toxicology, Box 7633, North Carolina State University, Raleigh, NC 27695 (United States)
  2. School of Biological Sciences, College of Natural and Health Sciences, University of Northern Colorado, Greeley, CO 80639 (United States)
Publication Date:
OSTI Identifier:
21460179
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 245; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2010.03.017; PII: S0041-008X(10)00114-6; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; LIVER CELLS; LUCIFERASE; PESTICIDES; PROMOTERS; RECEPTORS; TRANSGENIC MICE; ANIMAL CELLS; ANIMALS; ENZYMES; MAMMALS; MEMBRANE PROTEINS; MICE; ORGANIC COMPOUNDS; OXIDASES; OXIDOREDUCTASES; PROTEINS; RODENTS; SOMATIC CELLS; TRANSGENIC ANIMALS; VERTEBRATES

Citation Formats

Casabar, Richard C.T., Das, Parikshit C, DeKrey, Gregory K, Gardiner, Catherine S, Yan, Cao, Rose, Randy L, and Wallace, Andrew D., E-mail: andrew_wallace@ncsu.ed. Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor. United States: N. p., 2010. Web. doi:10.1016/j.taap.2010.03.017.
Casabar, Richard C.T., Das, Parikshit C, DeKrey, Gregory K, Gardiner, Catherine S, Yan, Cao, Rose, Randy L, & Wallace, Andrew D., E-mail: andrew_wallace@ncsu.ed. Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor. United States. https://doi.org/10.1016/j.taap.2010.03.017
Casabar, Richard C.T., Das, Parikshit C, DeKrey, Gregory K, Gardiner, Catherine S, Yan, Cao, Rose, Randy L, and Wallace, Andrew D., E-mail: andrew_wallace@ncsu.ed. 2010. "Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor". United States. https://doi.org/10.1016/j.taap.2010.03.017.
@article{osti_21460179,
title = {Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor},
author = {Casabar, Richard C.T. and Das, Parikshit C and DeKrey, Gregory K and Gardiner, Catherine S and Yan, Cao and Rose, Randy L and Wallace, Andrew D., E-mail: andrew_wallace@ncsu.ed},
abstractNote = {Endosulfan is an organochlorine pesticide commonly used in agriculture. Endosulfan has affects on vertebrate xenobiotic metabolism pathways that may be mediated, in part, by its ability to activate the pregnane X receptor (PXR) and/or the constitutive androstane receptor (CAR) which can elevate expression of cytochrome P450 (CYP) enzymes. This study examined the dose-dependency and receptor specificity of CYP induction in vitro and in vivo. The HepG2 cell line was transiently transfected with CYP2B6- and CYP3A4-luciferase promoter reporter plasmids along with human PXR (hPXR) or hCAR expression vectors. In the presence of hPXR, endosulfan-alpha exposure caused significant induction of CYP2B6 (16-fold) and CYP3A4 (11-fold) promoter activities over control at 10 {mu}M. The metabolite endosulfan sulfate also induced CYP2B6 (12-fold) and CYP3A4 (6-fold) promoter activities over control at 10 {mu}M. In the presence of hCAR-3, endosulfan-alpha induced CYP2B6 (2-fold) promoter activity at 10 {mu}M, but not at lower concentrations. These data indicate that endosulfan-alpha significantly activates hPXR strongly and hCAR weakly. Using western blot analysis of human hepatocytes, the lowest concentrations at which CYP2B6 and CYP3A4 protein levels were found to be significantly elevated by endosulfan-alpha were 1.0 {mu}M and 10 {mu}M, respectively. In mPXR-null/hPXR-transgenic mice, endosulfan-alpha exposure (2.5 mg/kg/day) caused a significant reduction of tribromoethanol-induced sleep times by approximately 50%, whereas no significant change in sleep times was observed in PXR-null mice. These data support the role of endosulfan-alpha as a strong activator of PXR and inducer of CYP2B6 and CYP3A4, which may impact metabolism of CYP2B6 or CYP3A4 substrates.},
doi = {10.1016/j.taap.2010.03.017},
url = {https://www.osti.gov/biblio/21460179}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 245,
place = {United States},
year = {Tue Jun 15 00:00:00 EDT 2010},
month = {Tue Jun 15 00:00:00 EDT 2010}
}