![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
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.
This article has been cited by other articles:
|
|
 |
|
  R. L. Yeager, S. A. Reisman, L. M. Aleksunes, and C. D. Klaassen Introducing the "TCDD-Inducible AhR-Nrf2 Gene Battery" Toxicol. Sci., October 1, 2009; 111(2): 238 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Hedge, M. J. DeVito, and K. M. Crofton In Vivo Acute Exposure to Polychlorinated Biphenyls: Effects on Free and Total Thyroxine in Rats International Journal of Toxicology, September 1, 2009; 28(5): 382 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. B. Buckley and C. D. Klaassen Induction of Mouse UDP-Glucuronosyltransferase mRNA Expression in Liver and Intestine by Activators of Aryl-Hydrocarbon Receptor, Constitutive Androstane Receptor, Pregnane X Receptor, Peroxisome Proliferator-Activated Receptor {alpha}, and Nuclear Factor Erythroid 2-Related Factor 2 Drug Metab. Dispos., April 1, 2009; 37(4): 847 - 856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. T. Szabo, V. M. Richardson, D. G. Ross, J. J. Diliberto, P. R. S. Kodavanti, and L. S. Birnbaum Effects of Perinatal PBDE Exposure on Hepatic Phase I, Phase II, Phase III, and Deiodinase 1 Gene Expression Involved in Thyroid Hormone Metabolism in Male Rat Pups Toxicol. Sci., January 1, 2009; 107(1): 27 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang and R. Munday Dithiolethiones for cancer chemoprevention: where do we stand? Mol. Cancer Ther., November 1, 2008; 7(11): 3470 - 3479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Kondraganti, W. Jiang, A. K. Jaiswal, and B. Moorthy Persistent Induction of Hepatic and Pulmonary Phase II Enzymes by 3-Methylcholanthrene in Rats Toxicol. Sci., April 1, 2008; 102(2): 337 - 344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Osabe, J. Sugatani, T. Fukuyama, S.-i. Ikushiro, A. Ikari, and M. Miwa Expression of Hepatic UDP-Glucuronosyltransferase 1A1 and 1A6 Correlated with Increased Expression of the Nuclear Constitutive Androstane Receptor and Peroxisome Proliferator-Activated Receptor {alpha} in Male Rats Fed a High-Fat and High-Sucrose Diet Drug Metab. Dispos., February 1, 2008; 36(2): 294 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. G. van de Kerkhof, I. A. M. de Graaf, M. H. de Jager, and G. M. M. Groothuis Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro Drug Metab. Dispos., June 1, 2007; 35(6): 898 - 907. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-F. Yueh and R. H. Tukey Nrf2-Keap1 Signaling Pathway Regulates Human UGT1A1 Expression in Vitro and in Transgenic UGT1 Mice J. Biol. Chem., March 23, 2007; 282(12): 8749 - 8758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Shelby and C. D. Klaassen Induction of Rat UDP-Glucuronosyltransferases in Liver and Duodenum by Microsomal Enzyme Inducers That Activate Various Transcriptional Pathways Drug Metab. Dispos., October 1, 2006; 34(10): 1772 - 1778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. R. Anderson, A. Hasan, H. Yin, I. Qadri, and L. C. Quattrochi Regulation of the CYP1A1 Gene by 2,3,7,8-Tetrachlorodibenzo-p-dioxin but Not by beta-Naphthoflavone or 3-Methylcholanthrene Is Altered in Hepatitis C Virus Replicon-Expressing Cells Mol. Pharmacol., September 1, 2006; 70(3): 1062 - 1070. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Fisher, J. Campbell, S. Muralidhara, J. V. Bruckner, D. Ferguson, M. Mumtaz, B. Harmon, J. M. Hedge, K. M. Crofton, H. Kim, et al. Effect of PCB 126 on Hepatic Metabolism of Thyroxine and Perturbations in the Hypothalamic-Pituitary-Thyroid Axis in the Rat Toxicol. Sci., March 1, 2006; 90(1): 87 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Cheng, J. Maher, M. Z. Dieter, and C. D. Klaassen REGULATION OF MOUSE ORGANIC ANION-TRANSPORTING POLYPEPTIDES (OATPS) IN LIVER BY PROTOTYPICAL MICROSOMAL ENZYME INDUCERS THAT ACTIVATE DISTINCT TRANSCRIPTION FACTOR PATHWAYS Drug Metab. Dispos., September 1, 2005; 33(9): 1276 - 1282. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Maher, X. Cheng, A. L. Slitt, M. Z. Dieter, and C. D. Klaassen INDUCTION OF THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN FAMILY OF TRANSPORTERS BY CHEMICAL ACTIVATORS OF RECEPTOR-MEDIATED PATHWAYS IN MOUSE LIVER Drug Metab. Dispos., July 1, 2005; 33(7): 956 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Krishnaswamy, Q. Hao, A. Al-Rohaimi, L. M. Hesse, L. L. von Moltke, D. J. Greenblatt, and M. H. Court UDP Glucuronosyltransferase (UGT) 1A6 Pharmacogenetics: I. Identification of Polymorphisms in the 5'-Regulatory and Exon 1 Regions, and Association with Human Liver UGT1A6 Gene Expression and Glucuronidation J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1331 - 1339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Miao, L. Hu, M. Kandouz, and G. Batist Oltipraz Is a Bifunctional Inducer Activating Both Phase I and Phase II Drug-Metabolizing Enzymes via the Xenobiotic Responsive Element Mol. Pharmacol., August 1, 2003; 64(2): 346 - 354. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
