Maternal-Fetal Disposition and Metabolism of Retrorsine in Pregnant Rats
Maternal-Fetal Disposition and Metabolism of Retrorsine in Pregnant Rats
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妊娠大鼠逆转录碱的母胎处置和代谢
DOI：
10.1124/dmd.117.079186
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发表时间：
2018-04-01
影响因子：
3.9
通讯作者：
Wang, Hui
中科院分区：
文献类型：
--
作者：
Li, Xia;Yang, Xiaojing;Wang, Hui
吡咯里西定生物碱(PAS)是植物合成的一类生物碱，广泛存在于中草药和食品中，具有肝毒性，需要细胞色素P450 3A代谢活化形成亲电性代谢物--吡咯酸酯。PAS也会引起胚胎毒性，但PAS在胎儿和胎盘中的代谢情况还远不清楚。在本研究中，我们在体外测定了逆转录酶(RTS)在大鼠母肝、胎盘和胎肝中的基础代谢活性，并在体内检测了RTS对胎儿的毒性和生物活性。微粒体RTS代谢产物的体外检测表明，胎肝和胎盘对RTS的基础代谢活性明显弱于母肝。此外，正常雄性胎肝中吡咯酸酯的生成率高于雌性仔鼠。在体内暴露于RTS会导致胎儿生长迟缓，以及胎盘和胎儿肝脏损伤。母鼠和胎儿的血清rts差异不大，但胎肝中吡咯蛋白加合物的含量明显低于母肝，这与基础代谢活动相一致。意外的是，与胎肝基础代谢相比，妊娠中晚期暴露于RTS可导致胎肝RTS代谢和细胞色素P3A表达的性别差异。我们的研究首次表明，RTS可以通过胎盘屏障进入胎儿循环，而宫内吡咯酸代谢物主要由胎肝产生，而不是从母体循环转运。RTS诱导胎肝细胞色素P3A的表达具有性别依赖性，这可能是RTS致胎肝损伤的原因之一，尤其是对雌性仔鼠。
Pyrrolizidine alkaloids (PAs) are extensively synthesized by plants, are commonly present in herbs and foodstuffs, and exhibit hepatotoxicity requiring metabolic activation by cytochrome P450 3A to form the electrophilic metabolites-pyrrolic esters. PAs also cause embryo toxicity, but the metabolic profiles of PAs in fetus and placenta have been far from clear. In this study, we determined the basal metabolic activation of retrorsine (RTS) in rat maternal liver, placenta, and fetal liver in vitro and examined the fetal toxicity and bioactivation of RTS in vivo. Detection of microsomal RTS metabolites in vitro showed that the basal metabolic activity of fetal liver and placenta to RTS was much weaker than that of maternal liver. In addition, a higher rate of pyrrolic ester formation was found in normal male fetal liver compared with that of female pups. In vivo exposure to RTS caused fetal growth retardation, as well as placental and fetal liver injury. Little difference in serum RTS was observed in dams and fetuses, but the content of pyrrole-protein adduction in the fetal liver was much lower than that in maternal liver, which was consistent with basal metabolic activity. Unexpectedly, compared with basal metabolism in fetal liver, exposure to RTS during middle and late pregnancy caused an opposite gender difference in RTS metabolism and CYP3A expression in the fetal liver. For the first time, our study showed that RTS can permeate the placenta barrier and entering fetal circulation, whereas the intrauterine pyrrolic metabolite was generated mainly by fetal liver but not transported from the maternal circulation. Induction of CYP3A by RTS was gender-dependent in the fetal liver, which was probably responsible for RTS-induced fetal hepatic injury, especially for female pups.