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A labile factor regulates induction of NQOR by TCDD and phenolic antioxidants.

Authors
Ma-Q; Kinneer De-Fede-K
Source
Toxicologist 2001 Mar; 60(1):364
NIOSHTIC No.
20021372
Abstract
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.
Keywords
Phenolic-compounds; Antioxidants; Quinones; Enzymes; Proteins
Publication Date
20010301
Document Type
Abstract
Fiscal Year
2001
NTIS Accession No.
NTIS Price
Issue of Publication
1
ISSN
1096-6080
NIOSH Division
HELD
Source Name
The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California
State
WV; CA
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