Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes
Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes
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DOI：
10.1158/1535-7163.mct-06-0516
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发表时间：
2007-01-01
影响因子：
5.7
通讯作者：
Kensler, Thomas W.
中科院分区：
文献类型：
--
作者：
Yates, Melinda S.;Tauchi, Masafumi;Kensler, Thomas W.
已经开发了合成的三萜类化合物，其是细胞保护酶的有效诱导剂和炎症抑制剂，大大改善了天然存在的三萜类化合物的弱活性。咪唑类三萜衍生物，1-[2-氰基-3，12-二氧代齐墩果烷-1，9（11）-二烯-28-酰基]咪唑（CDDO-Im或TP 235），先前已经显示出有效地防止肝肿瘤发生，部分地通过经由Keap 1-Nrf 2-抗氧化剂反应元件（ARE）信号传导诱导细胞保护基因而起作用。在这些研究中，CDDO-Im的药效学活性在两种不同的ARE报告小鼠系中进行表征，并通过测量作为细胞保护基因诱导标志物的Nqo 1转录物水平的增加来表征。口服施用CDDO-Im在小鼠的许多组织中诱导ARE调节的细胞保护基因，包括肝、肺、肾、肠、脑、心脏、胸腺和唾液腺。CDDO-Im在低至0.3 μ mol/kg体重（口服）的剂量下诱导某些器官中的Nqo 1 RNA转录物。对另外15种三萜类化合物的结构活性评价（a）证实了A和C环上Michael受体基团的重要性，（B）表明A环C-2上需要腈基，（c）表明C-17上的取代基显著影响体内药效学作用。除了CDDO-Im之外，其他三萜类化合物，特别是甲基酯CDDO-Me（TP 155）和二腈TP 225，是小鼠肝脏、肺、小肠粘膜和大脑皮质中细胞保护基因的极其有效的诱导剂。这种药效学特征突出了几种合成三萜类化合物在多个靶器官中的化学预防前景。
Synthetic triterpenoids have been developed, which are potent inducers of cytoprotective enzymes and inhibitors of inflammation, greatly improving on the weak activity of naturally occurring triterpenoids. An imidazolide triterpenoid derivative, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im or TP235), has been previously shown to potently protect against hepatic tumorigenesis, acting in part by inducing cytoprotective genes through Keap1-Nrf2-antioxidant response element (ARE) signaling. In these studies, the pharmacodynamic activity of CDDO-Im is characterized in two distinct lines of ARE reporter mice and by measuring increases in Nqo1 transcript levels as a marker of cytoprotective gene induction. Oral administration of CDDO-Im induces ARE-regulated cytoprotective genes in many tissues in the mouse, including liver, lung, kidney, intestines, brain, heart, thymus, and salivary gland. CDDO-Im induces Nqo1 RNA transcripts in some organs at doses as low as 0.3 mu moI/kg body weight (orally). A structure activity evaluation of 15 additional triterpenoids (a) confirmed the importance of Michael acceptor groups on both the A and C rings, (b) showed the requirement for a nitrile group at C-2 of the A ring, and (c) indicated that substituents at C-17 dramatically affected pharmacodynamic action in vivo. In addition to CDDO-Im, other triterpenoids, particularly the methyl ester CDDO-Me (TP155) and the dinitrile TP225, are extremely potent inducers of cytoprotective genes in mouse liver, lung, small intestine mucosa, and cerebral cortex. This pharmacodynamic characterization highlights the chemopreventive promise of several synthetic triterpenoids in multiple target organs.