Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice

Knowing the gene expression profiles of drug-metabolizing enzymes and transporters throughout gestation is important for understanding the mechanisms of pregnancy-induced changes in drug pharmacokinetics. In this study, we compared gene expression of drug-metabolizing enzymes and transporters in the maternal liver, kidney, small intestine, and placenta of pregnant mice throughout gestation by microarray analysis. Specifically, we investigated cytochrome P450 (Cyp), UDP-glucuronosyltranserase (Ugt), and sulfotransferase (Sult), as well as ATP-binding cassette (Abc) and solute carrier (Slc) transporters. We found that relatively few Ugt and Sult genes were impacted by pregnancy in maternal tissues and placenta. Cyp1a2, most Cyp2 isoforms, Cyp3a11, and Cyp3a13 in the liver were down-regulated, with the greatest changes occurring on gestation days (gd) 15 and 19 compared to non-pregnant controls (gd 0). However, Cyp2d40, Cyp3a16, Cyp3a41a, Cyp3a41b, and Cyp3a44 in the liver were induced throughout pregnancy. Cyp expression in mid-gestation placenta (gd 10 and 15) was generally greater than that in term placenta (gd 19). There were also notable changes in Abc and Slc transporters. Abcc3 in the liver was down-regulated by 60%, and Abcb1a, Abcc4, and Slco4c1 in the kidney were down-regulated by 30-60% on gd 15 and 19 versus gd 0. Abcc5 in the placenta was induced 3-fold on gd 10 versus gd 15 and 19, whereas Slc22a3 expression in the placenta on gd 10 was 90% lower than that on gd 15 and 19. Overall, this study demonstrates important gestational age-dependent expression of drug-metabolizing enzymes and transporter genes, which may have mechanistic relevance to human pregnancy. Ninety pregnant mice at gestational days 0, 7.5, 10, 15, and 19 (n = 5-6 per gestational age) were used for the maternal liver, kidney, small intestine and placenta. The placentas were collected on gestational days 10, 15, and 19.阐明妊娠全程中药物代谢酶与转运体的基因表达谱，对于解析妊娠诱导的药物代谢动力学改变机制具有重要意义。 本研究通过微阵列（microarray）分析，比较了妊娠小鼠在妊娠全程中，其母体肝脏、肾脏、小肠及胎盘组织内药物代谢酶与转运体的基因表达水平。 具体而言，本研究检测了细胞色素P450（Cytochrome P450, Cyp）、UDP-葡萄糖醛酸转移酶（UDP-glucuronosyltransferase, Ugt）、磺基转移酶（Sulfotransferase, Sult），以及ATP结合盒（ATP-binding cassette, Abc）转运体与溶质载体（Solute Carrier, Slc）转运体的基因表达情况。 研究发现，在母体组织与胎盘中，受妊娠调控的Ugt与Sult基因数量相对较少。 肝脏中的Cyp1a2、多数Cyp2亚型、Cyp3a11及Cyp3a13均呈现表达下调，与未妊娠对照组（妊娠第0天，gd 0）相比，其表达变化幅度在妊娠第15天与第19天（gd 15、gd 19）最为显著。 但肝脏中的Cyp2d40、Cyp3a16、Cyp3a41a、Cyp3a41b及Cyp3a44在整个妊娠周期中均呈现表达上调。 妊娠中期胎盘（gd 10与gd 15）中的Cyp表达水平普遍高于足月胎盘（gd 19）。 Abc与Slc转运体的基因表达亦存在显著变化。 与gd 0相比，gd 15与gd 19时肝脏中的Abcc3表达下调60%，肾脏中的Abcb1a、Abcc4及Slco4c1表达下调30%~60%。 胎盘组织中的Abcc5在gd 10时的表达量较gd 15与gd 19时升高3倍；而胎盘Slc22a3在gd 10时的表达量较gd 15与gd 19时降低90%。 综上，本研究证实药物代谢酶与转运体基因的表达存在显著的妊娠年龄依赖性，该结果与人类妊娠的相关机制具有潜在关联。 本研究共纳入90只妊娠小鼠，分别于妊娠第0、7.5、10、15及19天（每个妊娠时间点的样本量为5~6只），采集其母体肝脏、肾脏、小肠及胎盘组织。其中胎盘组织仅在gd 10、15及19天采集。