Dipartimento di Scienze Farmacologiche, Biologiche e Chimiche Applicate, Università degli Studi di Parma, Parma, Italy.
Br J Pharmacol. 2011 Nov;164(6):1642-51. doi: 10.1111/j.1476-5381.2011.01376.x.
Ro 11-1464 is a thienotriazolodiazepine previously described to selectively stimulate apolipoprotein A-I (apoA-I) production and mRNA level in human liver cells. Here, we studied its effects upon oral administration to human apoA-I transgenic (hapoA-I) mice.
HapoA-I mice were treated for 5 days with increasing doses of Ro 11-1464. Macrophage reverse cholesterol transport (mph-RCT) was assessed by following [(3) H]-cholesterol mobilization from pre-labelled i.p. injected J774 macrophages to plasma, liver and faeces. Effects on plasma lipids, apoproteins, lecithin-cholesterol : acyltransferase (LCAT) and liver enzymes, as well as on faecal excretion of cholesterol and bile salts, and on liver lipids and mRNA contents were determined.
Treatment with Ro 11-1464 300 mg·kg(-1) ·day(-1) resulted in a nearly 2-fold increase in plasma apoA-I, a 2- to 3-fold increase in the level of large sized-pre-β high-density lipoprotein and a 3-fold selective up-regulation of hepatic apoA-I mRNA, but a marked decrease in all plasma lipids and LCAT activity. Mpm-RCT was decreased in blood but markedly increased in faecal sterols (4-fold) and bile acids (1.7-fold). However, liver weight and liver enzymes in plasma were also increased, in parallel with an increase in liver cholesterol ester content (all these effect being significant).
In this model Ro 11-1464 causes increased hepatic expression and plasma levels of apoA-I and a suppression of LCAT, and a marked enhancement of reverse cholesterol transport, but also some symptoms of liver toxicity. The compound may therefore be a prototype for a next generation of anti-atherosclerotic medicines.
Ro 11-1464 是一种噻吩并三氮唑并二氮杂卓，先前被描述为选择性刺激人肝细胞载脂蛋白 A-I（apoA-I）的产生和 mRNA 水平。在这里，我们研究了它在人载脂蛋白 A-I 转基因（hapoA-I）小鼠口服给药后的作用。
用递增剂量的 Ro 11-1464 处理 hapoA-I 小鼠 5 天。通过从预先标记的腹膜内注射的 J774 巨噬细胞中追踪[(3) H]-胆固醇向血浆、肝脏和粪便的动员来评估巨噬细胞胆固醇逆向转运（mph-RCT）。测定血浆脂质、载脂蛋白、卵磷脂-胆固醇酰基转移酶（LCAT）和肝酶的变化，以及粪便中胆固醇和胆汁盐的排泄，以及肝脂质和 mRNA 含量。
用 Ro 11-1464 300mg·kg(-1)·day(-1) 治疗可使血浆 apoA-I 增加近 2 倍，大尺寸前-β 高密度脂蛋白水平增加 2 至 3 倍，肝 apoA-I mRNA 选择性上调 3 倍，但所有血浆脂质和 LCAT 活性明显降低。mph-RCT 在血液中减少，但在粪便甾醇（增加 4 倍）和胆汁酸（增加 1.7 倍）中明显增加。然而，肝重量和血浆中的肝酶也增加了，同时肝胆固醇酯含量增加（所有这些作用均显著）。
在该模型中，Ro 11-1464 导致肝 apoA-I 的表达和血浆水平增加，LCAT 受到抑制，胆固醇逆向转运显著增强，但也存在一些肝毒性症状。该化合物可能是新一代抗动脉粥样硬化药物的原型。
