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Carcinogenesis Advance Access first published online on January 6, 2009
This version published online on January 16, 2009
Carcinogenesis, doi:10.1093/carcin/bgn292
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Chemical genomics of cancer chemopreventive dithiolethiones

Quynh T. Tran1,3,6, Lijing Xu1,6, Vinhthuy Phan2,6, Shirlean Goodwin3,6, Mostafizur Rahman3,6, Victor X. Jin3, Carrie H. Sutter3,6, B.D. Roebuck4, Thomas W. Kensler5, E. Olusegun George1,2,6 and Thomas R. Sutter3,6,*

1 Department of Mathematical Sciences
2 Department of Computer Science
3 Department of Biology, University of Memphis, Memphis, TN, USA
4 Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA
5 Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
6 W. Harry Feinstone Center for Genomic Research, University of Memphis, Memphis, TN, USA

* To whom correspondence should be addressed. Tel: +1 901-678-8391; Fax: +1 901-678-4457; Email: tsutter{at}memphis.edu

3H-1,2-Dithiole-3-thione (D3T) and its analogs 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (OLT, oltipraz) and 5-tert-butyl-3H-1,2-dithiole-3-thione (TBD) are chemopreventive agents that block or diminish early stages of carcinogenesis by inducing activities of detoxication enzymes. While OLT has been used in clinical trials, TBD has been shown to be more efficacious and possibly less toxic than OLT in animals. Here we utilize a robust and high-resolution chemical genomics procedure to examine the pharmacological structure-activity relationships of these compounds in livers of male rats by microarray analyses. We identified 226 differentially expressed genes that were common to all treatments. Functional analysis identified the relation of these genes to glutathione metabolism and the Nrf2 pathway that is known to regulate many of the protective actions of dithiolethiones. OLT and TBD were shown to have similar efficacies and both were weaker than D3T. In addition, we identified 40 genes whose responses were common to OLT and TBD, yet distinct from D3T. As inhibition of cytochrome P450 has been associated with the effects of OLT on cytochrome P450 expression, we determined the IC50 values for inhibition of cytochrome P450 1A2. The rank order of inhibitor potency was OLT >> TBD >> D3T, with IC50 values estimated as 0.2, 12.8 and >100 µM, respectively. Functional analysis revealed that OLT and TBD, in addition to their effects on cytochromes P450, modulate liver lipid metabolism, especially fatty acids. Together these findings provide new insight into the actions of clinically relevant and lead dithiolethione analogs.

Received September 25, 2008; revised December 17, 2008; accepted December 20, 2008.


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