Heydel Jean-Marie, Garnier Philippe, Faure Philippe, Artur Yves
Université de Bourgogne, UMR Centre des Sciences du Goût et de l'Alimentation, 21000 Dijon, France.
Eur J Drug Metab Pharmacokinet. 2012 Dec;37(4):233-40. doi: 10.1007/s13318-012-0091-z. Epub 2012 Apr 4.
Synthetic fibrates are hypolipidemic drugs known to stimulate hepatic peroxisome proliferation and bilirubin glucuronidation. This study was designed to estimate the effects of ciprofibrate simultaneously on rat hepatic bilirubin glucuronoconjugation and on hepatic expression of UGT1A1, UGT1A2 and UGT1A5, all of which belong to the bilirubin cluster. Hepatic bilirubin glucuronidation activity and UDP-glucuronosyltransferase expression (RT-PCR and Western blotting) were measured after a single-dose ciprofibrate treatment (5 mg/kg by gastric intubation) in 36-h time course experiments. Ciprofibrate regulation of PPARα and UGT1A5 mRNA expression was also investigated in rat hepatocytes. Bilirubin conjugation activity was induced by ciprofibrate, reaching a maximum level (2.4×) 24 h after the treatment. UGT1A1 and UGT1A5 mRNA expression was induced 1.5 times by ciprofibrate, with UGT1A5 reaching the basal level of UGT1A1. Although UGT1A2 mRNA was induced approximately threefold by ciprofibrate, its expression level remained low in comparison with basal or induced levels of UGT1A1 and UGT1A5 mRNA. In the 36-h time course experiment, bilirubin conjugation activity as well as UGT1A5 and PPARα mRNA expression presented a biphasic induction profile. Although a similar level of induction was observed in primary cultured hepatocyte experiments, such biphasic variation was not observed for both UGT1A5 and PPARα, and the induction of UGT1A5 mRNA expression by ciprofibrate required de novo protein synthesis. A single dose of ciprofibrate significantly induces rat liver bilirubin conjugation as well as UGT1A1, UGT1A5 and PPARα expression. The induction mechanism may involve PPARα, at least regarding UGT1A5 regulation.
合成纤维酸类药物是已知的能刺激肝脏过氧化物酶体增殖和胆红素葡萄糖醛酸化的降血脂药物。本研究旨在评估环丙贝特对大鼠肝脏胆红素葡萄糖醛酸结合作用以及对UGT1A1、UGT1A2和UGT1A5（均属于胆红素簇）肝脏表达的同时影响。在36小时的时间进程实验中，通过胃内插管给予单剂量环丙贝特（5毫克/千克）后，测量肝脏胆红素葡萄糖醛酸化活性和UDP - 葡萄糖醛酸基转移酶表达（逆转录 - 聚合酶链反应和蛋白质免疫印迹法）。还在大鼠肝细胞中研究了环丙贝特对PPARα和UGT1A5 mRNA表达的调节作用。环丙贝特诱导了胆红素结合活性，在治疗后24小时达到最高水平（2.4倍）。环丙贝特使UGT1A1和UGT1A5 mRNA表达增加了1.5倍，UGT1A5达到了UGT1A1的基础水平。尽管环丙贝特使UGT1A2 mRNA诱导增加了约三倍，但与UGT1A1和UGT1A5 mRNA的基础或诱导水平相比，其表达水平仍然较低。在36小时的时间进程实验中，胆红素结合活性以及UGT1A5和PPARα mRNA表达呈现双相诱导模式。尽管在原代培养肝细胞实验中观察到了类似的诱导水平，但UGT1A5和PPARα均未观察到这种双相变化，并且环丙贝特对UGT1A5 mRNA表达的诱导需要从头合成蛋白质。单剂量环丙贝特显著诱导大鼠肝脏胆红素结合以及UGT1A1、UGT1A5和PPARα表达。诱导机制可能涉及PPARα，至少在UGT1A5调节方面是这样。
