Department of Pharmacology, School of Basic Medical Science, Wuhan University, Wuhan 430071, People's Republic of China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, People's Republic of China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, People's Republic of China.
Toxicology. 2019 Apr 15;418:32-40. doi: 10.1016/j.tox.2019.02.014. Epub 2019 Feb 27.
Pyrrolizidine alkaloids (PAs) are a class of hepatic toxins widely existing in plants. Cytochromes P450 (CYP) mediates PA bioactivation and toxicities in mammals. It has been reported that PAs can induce developmental toxicity, but systematic research is lacking. In this study, we investigated developmental toxicity of monocrotaline (MCT) in rats. Pregnant rats were administered with MCT (20 mg/kg) intragastrically from gestation day 9 to 20, followed by determination of changes in fetal growth, hepatic morphology, serum biochemical indices, and indicators of hepatocytes apoptosis. MCT was found to induce developmental toxicity and fetal hepatotoxicity, particularly in female fetuses. Metabolic activation was also studied by examination of bioactivation efficiency of MCT in fetal liver microsomes, serum MCT, pyrrole-protein adduction derived from MCT, and hepatic CYP3 A expression of fetuses in vivo. Male fetuses showed greater basal MCT bioactivation than that of female fetuses, but continuous exposure to MCT caused a selective CYP3 A induction in female fetuses, which may contribute to the sex difference in MCT-induced developmental toxicity.
吡咯里西啶生物碱（PAs）是一类广泛存在于植物中的肝毒素。细胞色素 P450（CYP）介导哺乳动物中 PA 的生物活化和毒性。据报道，PAs 可诱导发育毒性，但系统研究尚缺乏。在这项研究中，我们研究了单端孢霉烯（MCT）在大鼠中的发育毒性。从妊娠第 9 天到第 20 天，妊娠大鼠经胃内给予 MCT（20mg/kg），然后测定胎儿生长、肝形态、血清生化指标和肝细胞凋亡指标的变化。结果发现 MCT 可诱导发育毒性和胎儿肝毒性，尤其是雌性胎儿。通过检测胎肝微粒体中 MCT 的生物活化效率、血清 MCT、MCT 衍生的吡咯蛋白加合物以及体内胎儿肝 CYP3A 的表达，研究了代谢活化。与雌性胎儿相比，雄性胎儿的 MCT 基础生物活化率更高，但持续暴露于 MCT 导致雌性胎儿中 CYP3A 的选择性诱导，这可能是 MCT 诱导的发育毒性存在性别差异的原因。
