PT  - JOURNAL ARTICLE
AU  - Xia Li
AU  - Xiaojing Yang
AU  - E Xiang
AU  - Jinyuan Luo
AU  - Shuaikai Qiu
AU  - Yan Fang
AU  - Li Zhang
AU  - Yu Guo
AU  - Jiang Zheng
AU  - Hui Wang
TI  - Maternal-Fetal Disposition and Metabolism of Retrorsine in Pregnant Rats
AID  - 10.1124/dmd.117.079186
DP  - 2018 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 422--428
VI  - 46
IP  - 4
4099  - http://dmd.aspetjournals.org/content/46/4/422.short
4100  - http://dmd.aspetjournals.org/content/46/4/422.full
SO  - Drug Metab Dispos2018 Apr 01; 46
AB  - 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.