CAR-HNF1A/HNF4A调控网络对新生鼠苯巴比妥暴露诱导II相酶长期表达的作用及机制

Accumulated evidences have indicated that drug treatment of neonates and infants can result in activation of nuclear receptor and a permanent change of liver drug metabolism. To date, studies concerning this field have focused on the activation of single nuclear receptor, and the regulation of nuclear receptor networks remain elusive. Our preliminary studies have suggested that phenobarbital（PB）exposure in early-life resulted in permanent induction of phase II enzymes UGT1A1 in mice and nuclear receptor regulatory networks and epigenetic modifications involved in the developmental regulation of UGT1A1. Based on these results, we hypothesize that exposure to PB during neonatal period activates CAR-HNF1A/HNF4A nuclear receptor network to trigger epigenetic modifications, which can permanently induce the expression of phase II enzymes in adult and disturb therapeutic efficacy. In the current study, we use phenobarbital as a model drug and hUGT1 mouse as an in vivo model to demonstrate: 1) CAR-HNF1A/HNF4A nuclear receptor network regulating permanent change of phase II enzymes UGTs induced by phenobarbital exposure in neonatal mice; 2) the long-term impacts of PB exposure at early life on therapeutic efficacy; 3) the role of epigenetic memory in the long-term impacts of CAR-HNF1A/HNF4A nuclear receptor network at early life on UGTs expression. This project will focus on mechanism of nuclear receptor network regulating permanent change of phase II enzymes induced by phenobarbital exposure in neonatal mice, which will fill the knowledge gaps on long-term effects of phase II enzymes on drug exposure in early-life and provide a new perspective to explain the inter-individual difference in adults.

发育早期的药物治疗可以激活核受体，对药物代谢产生长期影响。但目前的相关研究多是围绕单一核受体激活，核受体网络的调控作用鲜有报道。我们前期研究发现，新生鼠苯巴比妥（PB）暴露对II相酶UGTs表达产生长期影响，并且核受体网络及表观遗传修饰参与UGT1A1发育表达的转录调控。由此推测：发育早期的药物暴露可激活CAR-HNF1A/HNF4A调控网络，并产生表观遗传记忆，长期诱导II相酶表达，持续影响成年后的药物代谢。本课题采用人源化小鼠hUGT1作为模型动物、PB作为模型药物拟研究：1）新生鼠PB暴露激活核受体网络对UGTs诱导表达的长期影响；2）该长期诱导表达对成年后药物代谢及疗效的影响；3）核受体网络参与诱导表达的表观遗传机制。该研究首次探讨核受体网络参与调控药物暴露对II相酶的长期诱导作用，可填补早期药物暴露对II相酶长期影响的认知不足，并为解释成年人群药物反应个体差异提供新的视角。

药物代谢酶的表达受多种因素调控，且存在显著的个体差异，是引起药物效应差异的主要原因，但影响药物代谢酶个体差异的因素和机制目前尚不明确。本课题从DOHaD理论和表观遗传药理的角度研究了以下内容：①生命早期PB暴露对不同年龄小鼠（新生儿期、青少年期及成年期）肝脏药物代谢酶表达的影响及表观遗传机制；②发育早期PB暴露对小鼠成年后脂肪代谢的影响。研究结果：①发育早期PB不同暴露剂量影响小鼠成年后肝脏中Ugts和Cyps的表达，且可引起小鼠成年后药物敏感性的降低；该长期作用与组蛋白甲基化H3K4me3富集水平的改变相关。②生命早期PB暴露对小鼠脂肪代谢产生长期影响。本研究基于DOHaD理论证实发育早期环境因素（药物暴露）对药物代谢酶表达具有长期影响，并从表观遗传药理的角度阐明了组蛋白甲基化修饰在药物代谢酶表达调控中的作用。该研究将为药物疗效的预测及评价提供新的思路，也为药物反应产生个体差异提供了新的解释。

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