Endosulfan Induces CYP2B6 and CYP3A4 by Activating the Pregnane X Receptor

Details

• Personal Author:
  Cao Y ; Casabar RC ; Das PC ; DeKrey GK ; Gardiner CS ; Rose RL ; Wallace AD ; Cao Y ; Casabar RC ; Das PC ; DeKrey GK ; Gardiner CS ; Rose RL ; Wallace AD
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Agriculture Environmental Monitoring Hazardous Substances Insecticides Laboratories Liver Occupational Health Risk Assessment Safety
• Keywords:
  Agricultural-chemicals Agricultural-industry Agricultural-processes Agricultural-workers Author Keywords: Pesticide CAR CYP2B6 CYP3A4 Endosulfan Exposure-assessment Exposure-levels Exposure-methods Health-hazards Health-standards Hepatotoxicity HepG2 Cell Line Human Hepatocytes Humans Laboratory-animals Laboratory-testing Liver-cells Occupational-health Pesticides-and-agricultural-chemicals PXR Risk-analysis Statistical-analysis

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• ISSN:
  0041-008X
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article ; Journal Article
• Place as Subject:
  Colorado ; North Carolina ; OSHA Region 4 ; OSHA Region 8
• CIO:
  National Institute for Occupational Safety and Health (NIOSH) ; National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health ; Workplace Safety & Health
• Location:
  North America ; North America
• Pages in Document:
  335-343
• Volume:
  245
• Issue:
  3
• NIOSHTIC Number:
  nn:20037063
• Citation:
  Toxicol Appl Pharmacol 2010 Jun; 245(3):335-343
• Contact Point Address:
  Andrew D. Wallace, Department of Environmental and Molecular Toxicology, 850 Main Campus Dr., Suite 1104, Raleigh, NC 27606
• Email:
  andrew_wallace@ncsu.edu
• Federal Fiscal Year:
  2010
• Performing Organization:
  East Carolina University
• Peer Reviewed:
  True
• Start Date:
  20010930
• Source Full Name:
  Toxicology and Applied Pharmacology
• End Date:
  20080929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:452510be81dda12314aab6abcb6f0e0edd98954dcc4e96f1ad063c3d5d791a6dfe6f3bce42183ed4cae98e6b600e6f2f590f77ab5f19dce468958920b9f3504a
• Download URL:
  https://stacks.cdc.gov/view/cdc/188222/cdc_188222_DS1.pdf
• File Type:
  [PDF - 1.08 MB ]