A Labile Factor Regulates Induction of NQOR by TCDD and Phenolic Antioxidants

Details

• Personal Author:
  Kinneer De Fede K ; Ma Q
• Description:
  NAD(P)H: quinone reductase (NQOR, DT-diaphorase) catalyzes the two electron reduction of quinones and quinoid chemicals. Induction of NQOR constitutes a major mechanism of defense against toxicity of quinones, azo chemicals, and other redox-cycling chemicals. Prototypical inducers of NQOR include TCDD, a potent agonist of the Ah receptor, and tert-butylhydroquinone (tBHQ), a phenolic antioxidant. Induction of NQOR by TCDD involves binding of TCDD to AhR, AhR/Arnt dimer formation, and binding of the dimer to a dioxin response element (DRE) in the upstream region of NQOR. The anitoxidants induce NQOR through a pathway involving activation of the Nrf2 transcription factor, which dimerizes with a Maf protein and binds to an antioxidant response element (ARE). However, the molecular mechanism of the induction by these inducers is not well understood. To gain new insights into the molecular steps of the induction, we examined the effect of cycloheximide (CHX), a potent inhibitor of protein synthesis, on the transcriptional regulation of NQOR by TCDD and tBHQ. Northern blot analyses reveal that CHX blocks induction of the enzyme by both TCDD and tBHQ. The inhibition occurs in a dose- and time- dependent manner, and does not affect the mRNA stability of NQOR. These results demonstrate that CHX inhibits both DRE- and ARE-mediated transcriptional control of NQOR. The blocking involves inhibition of protein synthesis. Time course analyses of the inhibition implicate a labile factor in the induction. Taken together, our results demonstrate that a novel labile factor is required for the transcriptional regulation of NQOR by TCDD and phenolic antioxidants. These findings provide new insights into the regulation of phase II enzymes by chemical inducers. [Description provided by NIOSH]
• Subjects:
  Antioxidants Enzymes Occupational Health Quinones Safety
• Keywords:
  Phenolic Compounds Proteins
• ISSN:
  1096-6080
• Publisher:
  Oxford University Press
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  California ; OSHA Region 3 ; OSHA Region 9 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  60
• Issue:
  1
• NIOSHTIC Number:
  nn:20021372
• Citation:
  Toxicologist 2001 Mar; 60(1):364
• Federal Fiscal Year:
  2001
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:80f65b00e685b8871a6291ec855398429ddd5b694ee70db0e00d6139146b0b9c16a945323102cff6db0b57e7fdfd59e2bcab12f81a86ba8b012f911d319e90a9
• Download URL:
  https://stacks.cdc.gov/view/cdc/198723/cdc_198723_DS1.pdf
• File Type:
  [PDF - 126.22 KB ]