Tran Quynh T, Xu Lijing, Phan Vinhthuy, Goodwin Shirlean B, Rahman Mostafizur, Jin Victor X, Sutter Carrie H, Roebuck Bill D, Kensler Thomas W, George E Olusegun, Sutter Thomas R
Department of Mathematical Sciences, University of Memphis, Memphis, TN 38152, USA.
Carcinogenesis. 2009 Mar;30(3):480-6. doi: 10.1093/carcin/bgn292. Epub 2009 Jan 6.
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.
3H-1,2-二硫杂环戊烯-3-硫酮（D3T）及其类似物4-甲基-5-吡嗪基-3H-1,2-二硫杂环戊烯-3-硫酮（OLT）和5-叔丁基-3H-1,2-二硫杂环戊烯-3-硫酮（TBD）是化学预防剂，它们通过诱导解毒酶的活性来阻断或减少致癌作用的早期阶段。虽然OLT已用于临床试验，但在动物实验中，TBD已被证明比OLT更有效且毒性可能更低。在此，我们利用一种强大且高分辨率的化学基因组学方法，通过微阵列分析来研究这些化合物在雄性大鼠肝脏中的药理结构-活性关系。我们鉴定出了所有处理共有的226个差异表达基因。功能分析确定了这些基因与谷胱甘肽代谢以及核因子红细胞衍生2相关因子2途径（Nrf2）的关系，已知该途径调节二硫杂环戊烯硫酮的许多保护作用。结果表明OLT和TBD具有相似的功效，且两者都比D3T弱。此外，我们鉴定出40个基因，其反应在OLT和TBD中是共同的，但与D3T不同。由于细胞色素P450（CYP）的抑制与OLT对CYP表达的影响有关，我们测定了抑制CYP1A2的半数最大抑制浓度（IC50）值。抑制剂效力的排序为OLT >> TBD >> D3T，IC50值分别估计为0.2、12.8和>100微摩尔。功能分析表明，OLT和TBD除了对CYP有影响外，还调节肝脏脂质代谢，尤其是脂肪酸。总之，这些发现为临床相关的二硫杂环戊烯硫酮类似物及其先导化合物的作用提供了新的见解。
