药学学报, 2016, 51(6): 879-885
引用本文:
白梦如, 孙冬黎, 蒋惠娣, 郑彩虹. 胎盘中转运体的功能性表达与调控[J]. 药学学报, 2016, 51(6): 879-885.
BAI Meng-ru, SUN Dong-li, JIANG Hui-di, ZHENG Cai-hong. Expression and regulation of drug transporters in placenta[J]. Acta Pharmaceutica Sinica, 2016, 51(6): 879-885.

胎盘中转运体的功能性表达与调控
白梦如1, 孙冬黎2, 蒋惠娣1, 郑彩虹2
1. 浙江大学药学院, 浙江 杭州 310058;
2. 浙江大学医学院附属妇产科医院, 浙江 杭州 310006
摘要:
胎盘是妊娠期间联系胎儿与母体的重要器官,胎盘屏障在物质交换中起重要作用。胎盘合胞体滋养层细胞中表达有多种转运体,包括ATP结合盒转运体(ABC)和溶质运载转运体(SLC)两大类,其中有一些起到摄取物质的作用,如有机阳离子转运体(OCTs)和有机阴离子转运体(OATs)等,还有些介导多种药物、毒物及内源性物质的外排,如P-糖蛋白(P-gp)、乳腺癌耐药蛋白(BCRP)和多药耐药相关蛋白(MRPs)等。上述转运体在胎盘中的表达并非一成不变,它们可能会随着胎儿的发育而变化,或受某些生理、病理因素及药物的调控。因此,了解胎盘中转运体的种类和功能、调控及机制,将在产科学中发挥积极作用,对妊娠期安全用药具有重要的临床意义,对研究开发妊娠期安全使用的药物也有重要价值。
关键词:    胎盘      ATP 结合盒转运体      溶质运载转运体      调控     
Expression and regulation of drug transporters in placenta
BAI Meng-ru1, SUN Dong-li2, JIANG Hui-di1, ZHENG Cai-hong2
1. College of Pharmaceutical Sciences, Hangzhou 310058, China;
2. Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
Abstract:
Placenta, an important organ, mediates the exchange of nutrients and metabolites between mother and fetus. The transporters, including ATP-binding cassette (ABC) transporters and solute carrier (SLC), expressed in the syncytiotrophoblast play a vital role in substance exchange. Some transporters, such as organic cation transporters (OCTs) and organic anion transporters (OATs), mediate the uptake of endogenous substances and drugs. Some transporters, such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), can excrete their substrates from the syncytiotrophoblast to the maternal circulation. However, the expression and activity of these transporters are not uniform throughout the gestation period, since they can be affected by physiological and pathological changes during pregnancy or drugs. Thus, an understanding of the role of placental transporters and the variation in their expression and activity in response to physiological and pathological changes is essential for efficient and safe therapy during pregnancy, and it also has important value in the development of drug treatment in pregnancy.
Key words:    placenta    ATP-binding cassette transporter    solute carrier    regulation   
收稿日期: 2015-09-28
DOI: 10.16438/j.0513-4870.2015-0861
基金项目: 国家自然科学基金资助项目(81302833).
通讯作者: 郑彩虹,Tel/Fax:86-571-89991730,E-mail:chzheng@zju.edu.cn
Email: chzheng@zju.edu.cn
相关功能
PDF(586KB) Free
打印本文
0
作者相关文章
白梦如  在本刊中的所有文章
孙冬黎  在本刊中的所有文章
蒋惠娣  在本刊中的所有文章
郑彩虹  在本刊中的所有文章

参考文献:
[1] Tomi M, Nishimura T, Nakashima E. Mother-to-fetus transfer of antiviral drugs and the involvement of transporters at the placental barrier[J]. J Pharm Sci, 2011, 100:3708-3718.
[2] Lahjouji K, Elimrani I, Lafond J, et al. L-Carnitine transport in human placental brush-border membranes is mediated by the sodium-dependent organic cation transporter OCTN2[J]. Am J Physiol Cell Physiol, 2004, 287:C263-C269.
[3] Zwart R, Verhaagh S, Buitelaar M, et al. Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice[J]. Mol Cell Biol, 2001, 21:4188-4196.
[4] Bzoskie L, Blount L, Kashiwai K, et al. The contribution of transporter-dependent uptake to fetal catecholamine clearance[J]. Biol Neonate, 1997, 71:102-110.
[5] Staud F, Ceckova M. Regulation of drug transporter expre ssion and function in the placenta[J]. Expert Opin Drug Metab Toxicol, 2015, 11:533-555.
[6] Cordon-Cardo C, O'Brien JP, Boccia J, et al. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues[J]. J Histochem Cytochem, 1990, 38:1277-1287.
[7] Sun M, Kingdom J, Baczyk D, et al. Expression of the multidrug resistance P-glycoprotein, (ABCB1 glycoprotein) in the human placenta decreases with advancing gestation[J]. Placenta, 2006, 27:602-609.
[8] Mathias AA, Hitti J, Unadkat JD. P-glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages[J]. Am J Physiol Regul Integr Comp Physiol, 2005, 289:R963-R969.
[9] Staud F, Ceckova M, Micuda S, et al. Expression and function of P-glycoprotein in normal tissues:effect on pharmacokinetics[J]. Methods Mol Biol, 2010, 596:199-222.
[10] Pavek P, Fendrich Z, Staud F, et al. Influence of P-glycoprotein on the transplacental passage of cyclosporine[J]. J Pharm Sci, 2001, 90:1583-1592.
[11] Molsa M, Heikkinen T, Hakkola J, et al. Functional role of P-glycoprotein in the human blood-placental barrier[J]. Clin Pharmacol Ther, 2005, 78:123-131.
[12] Nanovskaya T, Nekhayeva I, Karunaratne N, et al. Role of P-glycoprotein in transplacental transfer of methadone[J]. Biochem Pharmacol, 2005, 69:1869-1878.
[13] Sudhakaran S, Rayner CR, Li J, et al. Inhibition of placental P-glycoprotein:impact on indinavir transfer to the foetus[J]. Br J Clin Pharmacol, 2008, 65:667-673.
[14] Lankas GR, Wise LD, Cartwright ME, et al. Placental Pglycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice[J]. Reprod Toxicol, 1998, 12:457-463.
[15] Evseenko DA, Paxton JW, Keelan JA. ABC drug transporter expression and functional activity in trophoblast-like cell lines and differentiating primary trophoblast[J]. Am J Physiol Regul Integr Comp Physiol, 2006, 290:R1357-R1365.
[16] Yeboah D, Sun M, Kingdom J, et al. Expression of breast cancer resistance protein (BCRP/ABCG2) in human placenta throughout gestation and at term before and after labor[J]. Can J Physiol Pharmacol, 2006, 84:1251-1258.
[17] Nagashige M, Ushigome F, Koyabu N, et al. Basal membrane localization of MRP1 in human placental trophoblast[J]. Placenta, 2003, 24:951-958.
[18] Nishikawa M, Iwano H, Yanagisawa R, et al. Placental transfer of conjugated bisphenol A and subsequent reactivation in the rat fetus[J]. Environ Health Perspect, 2010, 118:1196-1203.
[19] Lee N, Hebert MF, Prasad B, et al. Effect of gestational age on mRNA and protein expression of polyspecific organic cation transporters during pregnancy[J]. Drug Metab Dispos, 2013, 41:2225-2232.
[20] Ahmadimoghaddam D, Zemankova L, Nachtigal P, et al. Organic cation transporter 3(OCT3/SLC22A3) and multidrug and toxin extrusion 1(MATE1/SLC47A1) transporter in the placenta and fetal tissues:expression profile and fetus protecttive role at different stages of gestation[J]. Biol Reprod, 2013, 88:55.
[21] Sata R, Ohtani H, Tsujimoto M, et al. Functional analysis of organic cation transporter 3 expressed in human placenta[J]. J Pharmacol Exp Ther, 2005, 315:888-895.
[22] Stein H, Oyama K, Martinez A, et al. Plasma epinephrine appearance and clearance rates in fetal and newborn sheep[J]. Am J Physiol, 1993, 265:R756-R760.
[23] Tamai I, Yabuuchi H, Nezu J, et al. Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1[J]. FEBS Lett, 1997, 419:107-111.
[24] Wu X, George RL, Huang W, et al. Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta[J]. Biochim Biophys Acta, 2000, 1466:315-327.
[25] Grube M, Meyer ZSH, Prager D, et al. Uptake of cardiovascular drugs into the human heart:expression, regulation, and function of the carnitine transporter OCTN2(SLC22A5)[J]. Circulation, 2006, 113:1114-1122.
[26] Chang TT, Shyu MK, Huang MC, et al. Hypoxia-mediated down-regulation of OCTN2 and PPARalpha expression in human placentas and in BeWo cells[J]. Mol Pharm, 2011, 8:117-125.
[27] Wu SP, Shyu MK, Liou HH, et al. Interaction between anticonvulsants and human placental carnitine transporter[J]. Epilepsia, 2004, 45:204-210.
[28] Sonne S, Shekhawat PS, Matern D, et al. Carnitine deficiency in OCTN2-/- newborn mice leads to a severe gut and immune phenotype with widespread atrophy, apoptosis and a pro-inflammatory response[J]. PLoS One, 2012, 7:e47729.
[29] Otsuka M, Matsumoto T, Morimoto R, et al. A human transporter protein that mediates the final excretion step for toxic organic cations[J]. Proc Natl Acad Sci USA, 2005, 102:17923-17928.
[30] Terada T, Masuda S, Asaka J, et al. Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1[J]. Pharm Res, 2006, 23:1696-1701.
[31] Ahmadimoghaddam D, Hofman J, Zemankova L, et al. Synchronized activity of organic cation transporter 3(Oct3/Slc22a3) and multidrug and toxin extrusion 1(Mate1/Slc47a1) transporter in transplacental passage of MPP+ in rat[J]. Toxicol Sci, 2012, 128:471-481.
[32] Ahmadimoghaddam D, Staud F. Transfer of metformin across the rat placenta is mediated by organic cation transporter 3(OCT3/SLC22A3) and multidrug and toxin extrusion 1(MATE1/SLC47A1) protein[J]. Reprod Toxicol, 2013, 39:17-22.
[33] Ugele B, St-Pierre MV, Pihusch M, et al. Characterization and identification of steroid sulfate transporters of human placenta[J]. Am J Physiol Endocrinol Metab, 2003, 284:E390-E398.
[34] Ugele B, Bahn A, Rex-Haffner M. Functional differences in steroid sulfate uptake of organic anion transporter 4(OAT4) and organic anion transporting polypeptide 2B1(OATP2B1) in human placenta[J]. J Steroid Biochem Mol Biol, 2008, 111:1-6.
[35] Kimura H, Takeda M, Narikawa S, et al. Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins[J]. J Pharmacol Exp Ther, 2002, 301:293-298.
[36] Schweigmann H, Sánchez-Guijo A, Ugele B, et al. Transport of the placental estriol precursor 16α-hydroxy-dehydroepiandrosterone sulfate (16α-OH-DHEAS) by stably transfected OAT4-, SOAT-, and NTCP-HEK293 cells[J]. J Steroid Biochem Mol Biol, 2014, 143:259-265.
[37] Gil S, Saura R, Forestier F, et al. P-glycoprotein expression of the human placenta during pregnancy[J]. Placenta, 2005, 26:268-270.
[38] Berveiller P, Degrelle SA, Segond N, et al. Drug transporter expression during in vitro differentiation of first-trimester and term human villous trophoblasts[J]. Placenta, 2015, 36:93-96.
[39] Wang JH, Scollard DA, Teng S, et al. Detection of Pglycoprotein activity in endotoxemic rats by 99mTc-sestamibi imaging[J]. J Nucl Med, 2005, 46:1537-1545.
[40] Petrovic V, Wang JH, Piquette-Miller M. Effect of endotoxin on the expression of placental drug transporters and glyburide disposition in pregnant rats[J]. Drug Metab Dispos, 2008, 36:1944-1950.
[41] Javam M, Audette MC, Iqbal M, et al. Effect of oxygen on multidrug resistance in term human placenta[J]. Placenta, 2014, 35:324-330.
[42] Lye P, Bloise E, Dunk C, et al. Effect of oxygen on multidrug resistance in the first trimester human placenta[J]. Placenta, 2013, 34:817-823.
[43] Azzaroli F, Raspanti ME, Simoni P, et al. High doses of ursodeoxycholic acid up-regulate the expression of placental breast cancer resistance protein in patients affected by intrahepatic cholestasis of pregnancy[J]. PLoS One, 2013, 8:e64101.
[44] Camus M, Delomenie C, Didier N, et al. Increased expression of MDR1 mRNAs and P-glycoprotein in placentas from HIV-1 infected women[J]. Placenta, 2006, 27:699-706.
[45] Evseenko DA, Paxton JW, Keelan JA. Independent regulation of apical and basolateral drug transporter expression and function in placental trophoblasts by cytokines, steroids, and growth factors[J]. Drug Metab Dispos, 2007, 35:595-601.
[46] Manceau S, Giraud C, Decleves X, et al. ABC drug transporter and nuclear receptor expression in human cytotrophoblasts:influence of spontaneous syncytialization and induction by glucocorticoids[J]. Placenta, 2012, 33:927-932.