Departments of Chemistry (R.S.W., T.R.S.) and Biological Sciences (C.H.S., T.R.S.,) and the W. Harry Feinstone Center for Genomic Research (R.S.W., S.F., T.R.S.), University of Memphis, Memphis, Tennessee; Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee (Q.T.T.); Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (T.W.K.); and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (T.W.K.).
Departments of Chemistry (R.S.W., T.R.S.) and Biological Sciences (C.H.S., T.R.S.,) and the W. Harry Feinstone Center for Genomic Research (R.S.W., S.F., T.R.S.), University of Memphis, Memphis, Tennessee; Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee (Q.T.T.); Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (T.W.K.); and Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (T.W.K.)
Mol Pharmacol. 2018 Apr;93(4):297-308. doi: 10.1124/mol.117.110262. Epub 2018 Jan 24.
The Kelch-like erythroid-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) signaling pathway is the subject of several clinical trials evaluating the effects of Nrf2 activation on the prevention of cancer and diabetes and the treatment of chronic kidney disease and multiple sclerosis. 3-1,2-dithiole-3-thione (D3T) and 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are representative members of two distinct series of Nrf2 chemical activators. Previous reports have described activator-specific effects on Nrf2-dependent gene regulation and physiologic outcomes. Here we used a robust chemical genomics approach to characterize expression profiles between D3T and CDDO-Im in livers from wild-type and Nrf2-null mice. At equally efficacious doses in wild-type mice, 406 genes show common RNA responses to both treatments. These genes enriched the Nrf2-regulated pathways of antioxidant defense and xenobiotic metabolism. In addition, 197 and 745 genes were regulated uniquely in response to either D3T or CDDO-Im, respectively. Functional analysis of the D3T-regulated set showed a significant enrichment of Nrf2-regulated enzymes involved in cholesterol biosynthesis. This result was supported by Nrf2-dependent increases in lanosterol synthase and CYP51 protein expression. CDDO-Im had no effect on cholesterol biosynthesis regardless of the dose tested. However, unlike D3T, CDDO-Im resulted in Nrf2-dependent elevation of peroxisome proliferator and Kruppel-like factor 13, as well as the coactivator peroxisome proliferator coactivator 1, together indicating regulation of -oxidation and lipid metabolic pathways. These findings provide novel insights into the pharmacodynamic action of these two activators of Keap1-Nrf2 signaling. Although both compounds modify Keap1 to affect canonical cytoprotective gene expression, additional unique sets of Nrf2-dependent genes were regulated by each agent with enrichment of selective metabolic pathways.
Kelch 样红细胞相关蛋白 1（Keap1）-NF-E2 相关因子 2（Nrf2）信号通路是多项临床试验的研究主题，这些试验评估了 Nrf2 激活对预防癌症和糖尿病以及治疗慢性肾病和多发性硬化症的影响。3-1,2-二硫杂环戊烷-3-硫酮（D3T）和 1-[2-氰基-3,12-二氧代辛二烯-1,9(11)-二烯-28-酰基]咪唑（CDDO-Im）是两种不同的 Nrf2 化学激活剂系列的代表性成员。先前的报告描述了激活剂对 Nrf2 依赖性基因调控和生理结果的特异性影响。在这里，我们使用强大的化学基因组学方法来描述 D3T 和 CDDO-Im 在野生型和 Nrf2 缺失型小鼠肝脏中的表达谱之间的差异。在野生型小鼠中，以同样有效的剂量处理时，有 406 个基因对两种处理均表现出共同的 RNA 反应。这些基因富集了 Nrf2 调节的抗氧化防御和外来物代谢途径。此外，197 个和 745 个基因分别分别对 D3T 或 CDDO-Im 的反应具有独特的调节作用。对 D3T 调节基因集的功能分析显示，胆固醇生物合成中 Nrf2 调节的酶显著富集。这一结果得到了 Nrf2 依赖性增加的羊毛甾醇合酶和 CYP51 蛋白表达的支持。无论测试的剂量如何，CDDO-Im 对胆固醇生物合成均无影响。然而，与 D3T 不同，CDDO-Im 导致 Nrf2 依赖性过氧化物酶体增殖物和 Kruppel 样因子 13 的升高，以及共激活剂过氧化物酶体增殖物激活物受体 1 的升高，共同表明 -氧化和脂质代谢途径的调节。这些发现为这两种 Keap1-Nrf2 信号通路激活剂的药效学作用提供了新的见解。尽管这两种化合物均通过修饰 Keap1 来影响典型的细胞保护基因表达，但每种化合物还调节了一组独特的 Nrf2 依赖性基因，其中富集了选择性代谢途径。
