Wang Pei, Liu Guangming, Nie Yali, Han Shengna, Li Jiangfeng, Zhong Xiao-Bo, Zhang Lirong
Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 45001, China.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut 06269.
Toxicol Sci. 2019 Nov 1;172(1):98-108. doi: 10.1093/toxsci/kfz177.
Pregnane X receptor (PXR), which can be activated by xenobiotic chemicals (including pediatric drugs), plays a key role in the regulation of drug-processing genes (DPGs). The induction of DPGs due to PXR activation may reduce therapeutic efficacy or cause toxicity. This work aims to demonstrate the impact of pregnenolone 16α-carbonitrile (PCN)-mediated PXR activation during early life on DPGs expression and drug sensitivity in adulthood, as well as the underlying mechanism. In this study, mice were sacrificed at postnatal day 60 to detect the hepatic expression of selected DPGs and histone modifications in the Cyp3a11 promoter. We found that all doses of PCN treatment (50-200 mg/kg/day) at postnatal days 5-8 resulted in persistently increased CYP2B10 expression, whereas only high doses of PCN treatment (150 and 200 mg/kg/day) persistently induced the expression of CYP3A11, 1A2, and UGT1A1. We also demonstrated that PCN treatment before postnatal day 15 had a long-term impact on the expression of CYP3A11, 2B10, ABCC4, and PAPSS2. Additionally, elevated expression of CYP3A11, SULT2A1, UGT1A1, and PAPSS2 was observed in PCN-treated groups at days 25-28. Attenuated inducibility of CYP3A11 by PCN was seen in the primary hepatocytes derived from PCN-pretreated mice. Moreover, enhanced H3K4me3 level and reduced H3K27me3 level in the PXR response elements (PXREs) of the Cyp3a11 promoter may contribute to the persistent upregulation of CYP3A11 by neonatal PCN treatment. Overall, our study suggests that PXR activation during early life could persistently alter the hepatic expression of DPGs and epigenetic memory may be an underlying mechanism in mice.
孕烷X受体（PXR）可被外源性化学物质（包括儿科药物）激活，在药物代谢基因（DPGs）的调控中起关键作用。PXR激活导致的DPGs诱导可能会降低治疗效果或引起毒性。这项工作旨在证明孕烯醇酮16α-腈（PCN）介导的早期生命期PXR激活对成年期DPGs表达和药物敏感性的影响及其潜在机制。在本研究中，于出生后第60天处死小鼠，以检测选定的DPGs的肝脏表达以及Cyp3a11启动子中的组蛋白修饰。我们发现，出生后第5 - 8天给予所有剂量的PCN处理（50 - 200 mg/kg/天）均导致CYP2B10表达持续增加，而只有高剂量的PCN处理（150和200 mg/kg/天）持续诱导CYP3A11、1A2和UGT1A1的表达。我们还证明，出生后第15天之前的PCN处理对CYP3A11、2B10、ABCC4和PAPSS2的表达有长期影响。此外，在第25 - 28天的PCN处理组中观察到CYP3A11、SULT2A1、UGT1A1和PAPSS2的表达升高。在源自PCN预处理小鼠的原代肝细胞中，PCN对CYP3A11的诱导性减弱。此外，Cyp3a11启动子的PXR反应元件（PXREs）中H3K4me3水平升高和H3K27me3水平降低可能有助于新生期PCN处理导致CYP3A11持续上调。总体而言，我们的研究表明，早期生命期的PXR激活可能会持续改变肝脏中DPGs的表达，表观遗传记忆可能是小鼠中的一种潜在机制。
