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Endosulfan induces CYP2B6 and CYP3A4 by activating the pregnane X receptor.

Authors
Casabar-RC; Das-PC; Dekrey-GK; Gardiner-CS; Cao-Y; Rose-RL; Wallace-AD
Source
Toxicol Appl Pharmacol 2010 Jun; 245(3):335-343
NIOSHTIC No.
20037063
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 microM. The metabolite endosulfan sulfate also induced CYP2B6 (12-fold) and CYP3A4 (6-fold) promoter activities over control at 10 microM. In the presence of hCAR-3, endosulfan-alpha induced CYP2B6 (2-fold) promoter activity at 10 microM, 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 microM and 10 microM, respectively. In mPXR-null/hPXR-transgenic mice, endosulfan-alpha exposure (2.5mg/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.
Keywords
Agricultural-chemicals; Agricultural-industry; Agricultural-processes; Agricultural-workers; Agriculture; Exposure-assessment; Exposure-levels; Exposure-methods; Health-hazards; Health-standards; Hepatotoxicity; Humans; Laboratory-animals; Laboratory-testing; Liver-cells; Occupational-health; Pesticides-and-agricultural-chemicals; Risk-analysis; Statistical-analysis; Author Keywords: Pesticide; Endosulfan; PXR; CAR; CYP3A4; CYP2B6; Human hepatocytes; HepG2 cell line
Contact
Andrew D. Wallace, Department of Environmental and Molecular Toxicology, 850 Main Campus Dr., Suite 1104, Raleigh, NC 27606
CODEN
TXAPA9
Publication Date
20100615
Document Type
Journal Article
Email Address
andrew_wallace@ncsu.edu
Funding Type
Cooperative Agreement
Fiscal Year
2010
NTIS Accession No.
NTIS Price
Identifying No.
Cooperative-Agreement-Number-U50-OH-007551
Issue of Publication
3
ISSN
0041-008X
Source Name
Toxicology and Applied Pharmacology
State
NC; CO
Performing Organization
East Carolina University
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