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Vol. 63, Issue 1, 119-127, January 2003
Department of Pharmacology and Toxicology, Medical College of
Virginia Campus of Virginia Commonwealth University, Richmond, Virginia
The utility of oltipraz as a cancer chemopreventive agent is thought to
depend on the induction of enzymes involved in phase 2 xenobiotic
detoxification. Although studies of some enzymes induced by oltipraz
implicate a novel transcriptional activating pathway involving Nrf2 and
antioxidant-response elements (AREs), the mechanism of phenol UGT
induction has remained unclear. Previous work showed that UGT1A6 is
transcribed from two promoters, P1 and P2, that are both induced by
oltipraz in rat liver. The effect also occurs in rat hepatocytes
treated with oltipraz (concentrations >3 µM). To investigate the
mechanism, luciferase reporter plasmids under the control of P1
[p(
1078/+27)1A6P1-luc] or P2 [p(1354/+65)1A6P2-luc] were
transfected into rat hepatocytes and tested for inducibility. P1, but
not P2, showed responsiveness to oltipraz (2- to 5-fold increase) and
3-methylcholanthrene (10- to 30-fold increase). Because P1 contained no
visible AREs, the role of a xenobiotic response element (XRE) centered
between bases 134 and 129 was evaluated. Mutation of the XRE core
reduced the effects of both oltipraz and 3-methylcholanthrene on the P1
reporter. The 1A6 XRE conferred oltipraz responsiveness on the simian
virus 40 promoter of pGL3-Promoter. Comparative effects of oltipraz and
3-methylcholanthrene on transfected cytochrome P4501A1 reporters
support the general but relatively weak XRE-stimulating activity of
oltipraz. The involvement of the aryl hydrocarbon receptor (AHR) and
aryl hydrocarbon nuclear translocator (ARNT) in mediating the effects
of oltipraz on the XRE is supported by electrophoretic mobility
supershift data and AHR/ARNT overexpression studies. These data raise
questions about the contribution of AHR and other secondary induction
pathways in the mechanism of oltipraz.
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