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

Chinese Journal of Pharmacovigilance ›› 2019, Vol. 16 ›› Issue (2): 65-70.

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

LIU Jie^1,2, YANG Xiaojing³, ZHENG Jiang³, WANG Yanqing⁴, XIANG E^1,2, WANG Hui^1,2, GUO Yu^1,2,*

1 Department of Pharmacology, Basic Medical School of Wuhan University, Hubei Wuhan 430071, China;
2 Hubei Provincial Key Laboratory of Developmentally Originated Disease, Hubei Wuhan 430071, China;
3 School of Pharmacy, Shenyang Pharmaceutical University, Liaoning Shenyang 110016, China;
4 Department of Gynecology, Renming Hospital of Wuhan University, Hubei Wuhan 430060, China

Received:2019-03-12 Revised:2019-03-12 Online:2019-02-25 Published:2019-03-12
Contact: *郭喻,女,副教授,发育毒理学。E-mail：guoy@whu.edu.cn
Supported by:
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

Abstract

Abstract: 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.

Key words: monocrotaline, placenta, cytochrome P450 3A, transporter

CLC Number:

R961

LIU Jie, YANG Xiaojing, ZHENG Jiang, WANG Yanqing, XIANG E, WANG Hui, GUO Yu. Effects of Exposure to Monocrotaline on Placental Damage and Its Mechanism in Rats[J]. Chinese Journal of Pharmacovigilance, 2019, 16(2): 65-70.

References

[1] Fu P P, Xia Q, Lin G, et al.Pyrrolizidine Alkaloids-Genotoxicity, Metabolism Enzymes, Metabolic Activation, and Mechanisms[J]. Drug Metabolism Reviews, 2004, 36(1):1-55.
[2] Yang Y C, Crowder J, Wardle N J, et al.1H NMR study of monocrotaline and its metabolites in human blood[J]. Food Chem Toxicol., 2011,49(11):2793-2799.
[3] The China Pharmacopoeia Committee. Pharmacopoeia of the People's Republic of China(in Chinese)[S]. 2015ed. Beijing: China Medical Science Press, 2015.
[4] Ruan J, Yang M, Fu P, et al.Metabolic Activation of Pyrrolizidine Alkaloids: Insights into the Structural and Enzymatic Basis[J]. Chem Res Toxicol., 2014,27(16):1030-1039.
[5] Lu Y, Ma J, Song Z, et al.The role of formation of pyrrole-ATP synthase subunit beta adduct in pyrrolizidine alkaloid-induced hepatotoxicity[J]. Archives of Toxicology, 2018,92(11):3403-3414.
[6] Kolrep F, Numata J, Kneuer C, et al.In vitro biotransformation of pyrrolizidine alkaloids in different species. Part I: Microsomal degradation[J]. Archives of Toxicology, 2018,92(3):1089-1097.
[7] Li X, Yang X, Xiang E, et al.Maternal-Fetal Disposition and Metabolism of Retrorsine in Pregnant Rats[J]. Drug Metabolism and Disposition, 2018, 46(4):422-428.
[8] Guo Y, Ma Z, Kou H, et al.Synergistic effects of pyrrolizidine alkaloids and lipopolysaccharide on preterm delivery and intrauterine fetal death in mice[J]. Toxicology Letters, 2013, 221(3):212-218.
[9] Kalisch-Smith J I, Simmons D G, Dickinson H, et al. Review: Sexual dimorphism in the formation, function and adaptation of the placenta[J]. Placenta, 2017,54:10-16.
[10] Mattocks A R, Legg R F, Jukes R.Trapping of short-lived electrophilic metabolites of pyrrolizidine alkaloids escaping from perfused rat liver[J]. Toxicology Letters, 1990, 54(1):93-99.
[11] Cooper R A, Huxtable R J.The relationship between reactivity of metabolites of pyrrolizidine alkaloids and extrahepatic toxicity[J]. Proceedings of the Western Pharmacology Society, 1999, 42:13-16.
[12] Hakkola J, Pasanen M, Hukkanen J, et al.Expression of xenobiotic-metabolizing cytochrome P450 Forms in human full-term placenta[J]. Biochemical Pharmacology, 1996, 51(4):403-411.
[13] Staud F, Cerveny L, Ceckova M.Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure[J]. Journal of Drug Targeting, 20(9):736-763.
[14] Tu M, Li L, Lei H, et al.Involvement of organic cation transporter 1 and CYP3A4 in retrorsine-induced toxicity[J]. Toxicology, 2014, 322:34-42.
[15] Hessel S, Gottschalk C, Schumann D, et al.Structure-activity relationship in the passage of different pyrrolizidine alkaloids through the gastrointestinal barrier: ABCB1 excretes heliotrine and echimidine[J]. Molecular Nutrition & Food Research, 2014, 58(5):995-1004.
[16] Longo L D, Reynolds L P.Some historical aspects of understanding placental development, structure and function[J]. International Journal of Developmental Biology, 2010,54(2-3):237-55.
[17] DuyguIskenderMazman, Zuhal Akçören, Şule Yiğit, et al. Placental findings of IUGR and non-IUGR[J]. Turk J Pediatr, 2014, 56(4):368-373.
[18] Medeiros R M T, Silvana L. Górniak, José Luis Guerra. Fetotoxicity and reproductive effects of monocrotaline in pregnant rats[J]. Journal of Ethnopharmacology, 2000, 69(2):181-188.
[19] Orhan H.Extrahepatic targets and cellular reactivity of drug metabolites[J]. Curr Med Chem, 2015,22(4):408-437.
[20] Lee N, Hebert M F, Prasad B, et al.Effect of Gestational Age on mRNA and Protein Expression of Polyspecific Organic Cation Transporters during Pregnancy[J]. Drug Metabolism and Disposition, 2013, 41(12):2225-2232.