Neumann Elizabeth, Mehboob Huma, Ramírez Jacqueline, Mirkov Snezana, Zhang Min, Liu Wanqing
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University West Lafayette, IN, USA.
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue UniversityWest Lafayette, IN, USA; Department of Biochemistry, University of AgricultureFaisalabad, Pakistan.
Front Pharmacol. 2016 Nov 16;7:437. doi: 10.3389/fphar.2016.00437. eCollection 2016.
UDP-glucuronosyltransferases (UGTs) are important phase II drug metabolism enzymes. The aim of this study was to explore the relationship between age and changes in mRNA expression and activity of major human hepatic UGTs, as well as to understand the potential regulatory mechanism underlying this relationship. Using previously generated data, we investigated age-dependent mRNA expression levels of 11 hepatic UGTs (, and ) and 16 transcription factors (, and ) in liver tissue of donors ( = 38) ranging from 0 to 25 years of age. We also examined the correlation between age and microsomal activities using 14 known UGT drug substrates in the liver samples ( = 19) of children donors. We found a statistically significant increase (nominal < 0.05) in the expression of , , and , as well as glucuronidation activities of serotonin, testosterone, and vorinostat during the first 25 years of life. Expression of estrogen receptor 1 and pregnane X receptor, two strong UGT transcriptional regulators, were significantly correlated with both age and mRNA expression ( ≤ 0.05). These results suggest that both expression and activity increase during childhood and adolescence, possibly driven in part by hormonal signaling. Our findings may help explain inter-patient variability in response to medications among children.
尿苷二磷酸葡萄糖醛酸转移酶（UGTs）是重要的Ⅱ相药物代谢酶。本研究的目的是探讨年龄与主要人类肝脏UGTs的mRNA表达及活性变化之间的关系，并了解这种关系背后的潜在调控机制。利用先前生成的数据，我们研究了年龄在0至25岁之间的38名供体肝脏组织中11种肝脏UGTs（……）和16种转录因子（……）的年龄依赖性mRNA表达水平。我们还使用19名儿童供体肝脏样本中的14种已知UGT药物底物检测了年龄与微粒体活性之间的相关性。我们发现，在生命的前25年中，……、……和……的表达以及血清素、睾酮和伏立诺他的葡萄糖醛酸化活性有统计学意义的增加（名义P<0.05）。两种强大的UGT转录调节因子雌激素受体1和孕烷X受体的表达与年龄和……mRNA表达均显著相关（P≤0.05）。这些结果表明，……的表达和活性在儿童期和青春期增加，可能部分受激素信号驱动。我们的研究结果可能有助于解释儿童患者间药物反应的个体差异。
