孕期野百合碱暴露对大鼠胎盘的损伤作用及其代谢机制  

Effects of Exposure to Monocrotaline on Placental Damage and Its Mechanism in Rats

作　　者：刘杰 杨晓静[3] 郑江 王艳清[4] 向娥 汪晖[1,2] 郭喻 LIU Jie;YANG Xiaojing;ZHENG Jiang;WANG Yanqing;XIANG E;WANG Hui;GUO Yu(Department of Pharmacology, Basic Medical School of Wuhan University, Hubei Wuhan 430071, China;Hubei Provincial Key Laboratory of Developmentally Originated Disease, Hubei Wuhan 430071, China;School of Pharmacy, Shenyang Pharmaceutical University, Liaoning Shenyang 110016, China;Department of Gynecology, Renming Hospital of Wuhan University, Hubei Wuhan 430060, China)

机构地区：[1]武汉大学基础医学院药理学系,湖北武汉430071 [2]发育源性疾病湖北省重点实验室,湖北武汉430071 [3]沈阳药科大学药学院,辽宁沈阳110000 [4]武汉大学人民医院妇产科,湖北武汉430060

出　　处：《中国药物警戒》2019年第2期65-70,80,共7页Chinese Journal of Pharmacovigilance

基　　金：国家自然科学基金(81473290):吡咯里西啶生物碱致母;胎肝毒性差异及其代谢活化机制;国家自然科学基金青年项目(30901835):胎肾上腺CYP3A介导吡咯双环生物碱类发育毒性的代谢损伤机制;中央高校基本科研业务费专项(2042017Kf1032):吡咯里西啶生物碱致发育毒性的性别差异及其机制研究

摘　　要：目的探讨孕期野百合碱(monocrotaline,MCT)暴露对胎盘的损伤作用及其发生机制。方法 Wistar孕鼠分为给药组和对照组,在妊娠第9天至20天(gestation day,GD)灌胃给予20 mg·kg-1MCT,对照组给予等体积的溶剂处理。在GD 20给药2 h后麻醉处死大鼠,并取母肝及胎盘。观察胎盘重量和形态学改变,分别检测母肝、胎盘中吡咯代谢产物与蛋白结合物(pyrrole-protein adducts,PPAs)的含量,同时检测母肝及胎盘细胞色素P450(cytochrome P450,CYP)3A的基础表达和MCT暴露后表达水平,并确定了胎盘有机阳离子转运体3(organic cation transporter 3,OCT3)和P-糖蛋白(P-glycoprotein,P-gp)的表达变化。结果与对照组相比,孕期MCT处理大鼠胎盘重量显著降低,并伴有胎盘形态结构的损伤。胎盘的CYP3A基础表达远低于母肝,但MCT暴露后,胎盘PPAs含量几乎与母肝一致。与对照组相比,MCT暴露组胎盘的CYP3A1和OCT3表达无显著变化,而P-gp的表达显著增加。结论孕期MCT暴露可造成胎盘损伤,母肝代谢产生的活性吡咯代谢产物可能是造成胎盘损伤的主要原因。Objective To investigate the effects of exposure to monocrotaline (MCT) on placental damage and its mechanism. Methods Pregnant Wistar rats were divided into control and MCT groups. The rats in MCT group were intragastrically given 20 mg·kg^-1 MCT daily from gestation day (GD) 9 to 20, and the control group was given the same volume of solvent. After 2 h of the last administration in GD 20, the rats were anesthetized and executed, and the maternal livers and placentae were collected. The placental weight and morphology was observed. The contents of pyrrole-protein adducts (PPAs) in placenta and mother liver were measured using HPLC-MS. Expression of cytochrome P450 (CYP) 3A and transporters in placenta were also determined. Results Compared with the control group, the placental weight was decreased significantly in the rats treated with MCT during pregnancy, accompanied with an obvious morphological change in placenta structure. The basal expression of CYP3A in placenta was lower than that in maternal liver, while the content of PPAs in placenta was almost equal to that in maternal liver. In addition, there was no significant change in placental expression of CYP3A or organic cation transporter 3. But expression of P-glycoprotein in placenta was increased by MCT exposure. Conclusion Prenatal exposure to MCT caused placenta damage, which may be due to the active pyrrole metabolites generated by maternal liver.

关 键 词：野百合碱 胎盘 细胞色素P4503A 转运体 

分 类 号：R961[医药卫生—药理学]