Kent Rebecca, Jeong Hyunyoung
Department of Pharmacy Practice (H.J.); Department of Biopharmaceutical Sciences (R.K., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
Drug Metab Lett. 2017 Nov 17;11(1):68-72. doi: 10.2174/1872312811666170407164631.
Cytochrome P450 (CYP) 2D6 is a major drug-metabolizing enzyme, responsible for eliminating 25% of marketed drugs. We recently identified SHP as a negative regulator of CYP2D6 expression and showed that factors that alter SHP expression influence CYP2D6 expression. Fenofibrate, an agonist of peroxisome proliferator-activated receptor α(PPARα), has been previously reported to upregulate SHP expression in the mouse liver. The objective of this study was to determine whether fenofibrate decreases CYP2D6 expression via upregulating SHP expression.
CYP2D6-humanized transgenic mice were administered with fenofibrate (100 mg/kg/day intraperitoneally for 5 days) or vehicle control. Hepatic mRNA and protein expression levels of CYP2D6 and SHP were measured.
Results showed that while mRNA levels of SHP did not differ between the groups, protein levels of SHP increased by 2-fold in fenofibrate-treated mice. Despite the increased SHP protein levels, CYP2D6 expression did not decrease at the mRNA or protein levels. Similar results were observed in human hepatocytes treated with fenofibrate. Results from transient transfection and promoter reporter assays indicate that PPARα can transactivate CYP2D6 promoter, suggesting that the lack of CYP2D6 downregulation by fenofibrate may be in part due to the activation of CYP2D6 promoter by PPARα.
These results indicate that fenofibrate has minimal effects on CYP2D6 expression despite increased SHP expression.
细胞色素P450（CYP）2D6是一种主要的药物代谢酶，负责清除25%的上市药物。我们最近鉴定出小异二聚体蛋白（SHP）是CYP2D6表达的负调节因子，并表明改变SHP表达的因素会影响CYP2D6的表达。非诺贝特是过氧化物酶体增殖物激活受体α（PPARα）的激动剂，此前有报道称其可上调小鼠肝脏中SHP的表达。本研究的目的是确定非诺贝特是否通过上调SHP表达来降低CYP2D6的表达。
给CYP2D6人源化转基因小鼠腹腔注射非诺贝特（100mg/kg/天，持续5天）或溶剂对照。检测肝脏中CYP2D6和SHP的mRNA及蛋白表达水平。
结果显示，虽然各组间SHP的mRNA水平无差异，但非诺贝特处理的小鼠中SHP的蛋白水平增加了2倍。尽管SHP蛋白水平升高，但CYP2D6的mRNA和蛋白表达水平并未降低。在用非诺贝特处理的人肝细胞中也观察到了类似结果。瞬时转染和启动子报告基因分析结果表明，PPARα可反式激活CYP2D6启动子，这表明非诺贝特未能下调CYP2D6可能部分归因于PPARα对CYP2D6启动子的激活。
这些结果表明，尽管SHP表达增加，但非诺贝特对CYP2D6表达的影响极小。
