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Author Casabar, Richard C. T. ♦ Das, Parikshit C. ♦ DeKrey, Gregory K. ♦ Gardiner, Catherine S. ♦ Yan, Cao ♦ Rose, Randy L. ♦ Wallace, Andrew D.
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword 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
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 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.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2010-06-15
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 245
Issue Number 3


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