Mechanisms of CYP2B6 and CYP2D6 induction during pregnancy

项目总结(见说明)； 孕妇滥用药物是一个问题。约5%的孕妇服用违禁药物，高达20%的孕妇吸烟。药物滥用经常与抑郁症联系在一起，抑郁症在孕妇中也很常见。估计有5%-13%的孕妇服用抗抑郁药物。两种细胞色素P450酶，细胞色素P450酶，细胞色素P450酶和细胞色素P450酶，负责清除大多数常见的抗抑郁药物和滥用药物。最重要的是，CYP2B6是一种主要的酶清除安非他酮，这是一种抗抑郁药物，也用于戒烟，与CYP2D6一起，负责清除许多兴奋剂和阿片类药物，如MDMA和美沙酮。尽管具有这种临床重要性，但人类怀孕期间CYP2B6活性和安非他酮清除量的变化尚不清楚，而人类怀孕期间CYP2D6活性增加是有很好的文献记载的。相比之下，雌激素在体外诱导细胞色素P450_2B6的作用已被证实，但诱导细胞色素P450_2D6的机制尚不清楚。这项建议的长期目标是建立妊娠期间诱导细胞色素P450的机制，并确定是否可以使用细胞色素P450和安非他酮作为模型系统从体外预测妊娠期间P450活性的变化。在我们的具体目标1中，我们将通过1)利用人的肝细胞预测怀孕期间雌激素和ER激活的安非他酮和美沙酮的诱导和安非他酮的释放，以及2)测定安非他酮在人孕期和产后的药代动力学，来检验这一假说，即在人类妊娠期增加雌激素浓度可以诱导细胞色素P450 2B6的活性和表达。在第二个目标中，我们将通过以下方式验证假设：1)确定右美沙芬在妊娠期间的处置并检测CYP2D6在妊娠期间的分布；2)表征HNF4a和RAR激活对人肝细胞中CYP2D6 mRNA和活性的影响。我们还将建立建模和模拟MDMA及其代谢物在怀孕期间的处置所需的体外参数。

PROJECT SUMMARY (See instructions); Drug abuse by pregnant women is a problem. About 5% of pregnant women take illicit drugs and up to 20% smoke. Drug abuse is often associated with depression, which is also common in pregnant women. Estimated 5-13% of pregnant women take antidepressant drugs. Two cytochrome P450 enzymes, CYP2D6 and CYP2B6 are responsible for the clearance of majority of common antidepressants and drugs of abuse. Most importantly, CYP2B6 is a major enzyme clearing bupropion, an antidepressant drug also used for smoking cessation and, together with CYP2D6, is responsible for the clearance of many stimulants and opiates such as MDMA and methadone. Despite this clinical importance, the changes in CYP2B6 activity and in bupropion clearance during human pregnancy are not known, whereas increased activity of CYP2D6 during human pregnancy is well documented. In contrast, induction of CYP2B6 in vitro by estrogens has been demonstrated whereas mechansims responsible for CYP2D6 induction are not known. The long term objective of this proposal is to establish the mechanisms that contribute to CYP2D6 induction during pregnancy and determine whether the changes in P450 activity during pregnancy can be predicted from in vitro using CYP2B6 and bupropion as a model system. In our specific aim 1 we will test the hypothesis that increasing estrogen concentrations during human pregnancy induce CYP2B6 activity and expression via 1) using human hepatocytes to predict CYP2B6 induction and bupropion and methadone disposition during pregnancy by estrogens and via ER activation and 2) determining bupropion pharmacokinetics during human gestation in comparison to postpartum. In the second aim we will test the hypothesis that CYP2D6 activity increases during pregnancy due to increased CYP2D6 mRNA and HNF4a and RAR activation via 1) determining the disposition of dextromethorphan during pregnancy in CYP2D6 humanized mice and measuring CYP2D6 mRNA and activity during gestation 2) characterizing the impact of HNF4a and RAR activation in CYP2D6 mRNA and activity in human hepatocytes. We will also establish the in vitro parameters needed for modeling and simulation of MDMA and its metabolite disposition during pregnancy.