Faculty Collaboration Database

Chemical genomics of cancer chemopreventive dithiolethiones. Carcinogenesis 2009 Mar;30(3):480-6

Date

01/08/2009

Pubmed ID

19126641

Pubmed Central ID

PMC2650797

DOI

10.1093/carcin/bgn292

Scopus ID

2-s2.0-62349124312 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

3H-1,2-dithiole-3-thione (D3T) and its analogues 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (OLT) 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 nuclear factor, erythroid derived 2-related factor 2 pathway (Nrf2) 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 (CYP) has been associated with the effects of OLT on CYP expression, we determined the half maximal inhibitory concentration (IC(50)) values for inhibition of CYP1A2. The rank order of inhibitor potency was OLT >> TBD >> D3T, with IC(50) values estimated as 0.2, 12.8 and >100 microM, respectively. Functional analysis revealed that OLT and TBD, in addition to their effects on CYP, modulate liver lipid metabolism, especially fatty acids. Together, these findings provide new insight into the actions of clinically relevant and lead dithiolethione analogues.

Author List

Tran QT, Xu L, Phan V, Goodwin SB, Rahman M, Jin VX, Sutter CH, Roebuck BD, Kensler TW, George EO, Sutter TR

Author

Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Anticarcinogenic Agents
Cytochrome P-450 CYP1A2
Gene Expression Profiling
Genomics
Glutathione
Heterocyclic Compounds, 1-Ring
Liver
Male
Multigene Family
NF-E2-Related Factor 2
Oligonucleotide Array Sequence Analysis
Pyrazines
Rats
Rats, Inbred F344
Structure-Activity Relationship
Thiones
Thiophenes