全球每年出生的宫内生长迟缓（IUGR）婴儿约为2400万。IUGR可以导致胎儿期代谢程序化，使肝脏结构和功能发生永久性改变。临床发现部分IUGR病人对药物的反应不同与正常出生体重者，但原因不明。CYP1A、CYP2B、CYP3A和CYP2C是肝脏主要的CYP450酶，参与大部分临床药物的代谢过程，并受PXR/CAR的调控。课题组前期发现：IUGR发育大鼠肝脏PXR/CAR 基因表达持续增高，CYP3A表达和功能发生变化，但对其他CYP450酶的影响及发生机制尚未知。我们推测，IGUR发育肝脏其他CYP450酶也会发生变化，是导致临床药物反应性差异的重要原因。本研究拟在前期工作基础上，利用IUGR大鼠模型，通过研究发育肝脏PXR/CAR调控的CYP450酶的表达和功能，组蛋白修饰、磷酸化修饰对CYP450基因表达和功能的影响，探寻IUGR发育肝脏CYP450表达和功能的变化规律及发生机制。

The annual birth rate of infants with intrauterine growth retardation (IUGR) is approximately 240 million with an increasing tendency. IGUR may result in developmental adaptations that can permanently change the hepatic structure and function in offspring. Adverse drug response has been found in IUGR children clinically, but the underlying mechanism is largely unknown. The nuclear receptors, pregnane x receptor (PXR) and constitutive androstane receptor(CAR) are key regulators of expression of genes involved in drug metabolism such as cytochrome P450 (CYP1A、CYP2B、CYP3A、CYP2C), which involves in the metabolism of a lot of clinically used drugs. Among the CYP450 enzymes, CYP3A enzyme sub-family is the most abundantly expressed in the adult liver and is responsible for the metabolism of almost two-thirds of prescription drugs. We have previously found up-regulation of PXR and CAR mRNA expressions in rats developing IGUR; Alterations in CYP3A mRNA expression and enzymatic activity were also detected in these animals.We speculate that PXR and CAR will regulate other members of the CYP450 superfamily of enzymes, eventually leading to adverse drug response. Therefore, the present study is conducted to investigate the transcriptional and post-transcriptional regulation of PXR/CAR targeting CYP450 members during the development of IUGR in an animal model. In addition, epigenetic modifications of candidate PXR/CAR targeting CYP450 members will also be investigated for better understanding the molecular mechanism for diverse drug response under maternal under-nutrition condition.