Mechanisms of CYP2B6 and CYP2D6 induction during pregnancy

项目总结（见说明）; 孕妇吸毒是一个问题。大约5%的孕妇服用非法药物，高达20%的孕妇吸烟。药物滥用通常与抑郁症有关，这在孕妇中也很常见。据估计，5-13%的孕妇服用抗抑郁药物。两种细胞色素P450酶，CYP 2D 6和CYP 2B 6负责清除大多数常见的抗抑郁药和滥用药物。最重要的是，CYP 2B 6是清除安非他酮的主要酶，安非他酮是一种抗抑郁药物，也用于戒烟，与CYP 2D 6一起负责清除许多兴奋剂和阿片类药物，如MDMA和美沙酮。尽管有这种临床重要性，但人类妊娠期间CYP 2B 6活性和安非他酮清除率的变化尚不清楚，而人类妊娠期间CYP 2D 6活性增加已有充分记录。相反，已证实雌激素体外诱导CYP 2B 6，而CYP 2D 6诱导的机制尚不清楚。该提案的长期目标是建立有助于妊娠期间CYP 2D 6诱导的机制，并确定是否可以使用CYP 2B 6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，我们将通过以下方式检验人类妊娠期间增加雌激素浓度诱导CYP 2B 6活性和表达的假设：1）使用人类肝细胞预测妊娠期间通过雌激素和通过ER活化的CYP 2B 6诱导以及安非他酮和美沙酮处置; 2）确定人类妊娠期间与产后相比的安非他酮药代动力学。在第二个目的中，我们将通过以下方式检验妊娠期间CYP 2D 6活性由于CYP 2D 6 mRNA和HNF 4a和RAR活化增加而增加的假设：1）测定妊娠期间在CYP 2D 6人源化小鼠中美沙芬的分布，并测量妊娠期间CYP 2D 6 mRNA和活性; 2）表征HNF 4a和RAR活化对人肝细胞中CYP 2D 6 mRNA和活性的影响。我们还将建立体外参数所需的建模和模拟MDMA及其代谢物的处置在怀孕期间。

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.