Impact of pregnancy related hormones on drug metabolizing enzyme and transport protein concentrations in human hepatocytes.
Impact of pregnancy related hormones on drug metabolizing enzyme and transport protein concentrations in human hepatocytes.
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DOI：
10.3389/fphar.2022.1004010
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
妊娠改变了治疗妊娠相关并发症的多种药物的处置和暴露。先前的体外研究表明，妊娠相关激素（PRH）改变了人肝细胞中某些细胞色素P450（CYP）的表达和功能。然而，PRH对肝脏非药物代谢酶（DME）和转运蛋白浓度的影响在很大程度上仍然未知。在本研究中，将来自5名女性供体的体外培养人肝细胞（SCHH）暴露于溶剂或PRH（雌酮、雌二醇、雌三醇、孕酮、皮质醇和胎盘生长激素），单独或联合给药，在生理相关PRH浓度范围内持续72 h。使用定量靶向绝对蛋白质组学（QTAP）同位素稀释nanoLC-MS/MS方法定量SCHH膜组分中33种肝脏非β DME和转运蛋白的绝对浓度。数据显示，PRH改变了各种DME和转运蛋白的绝对蛋白浓度的浓度，亚型，肝细胞供体依赖性的方式。总体而言，在肝细胞供体中，33种蛋白质中有8种（24%）表现出相对于溶媒对照（ANOVA p < 0.05）的绝对蛋白浓度的显著PRH诱发净变化：1/11 UGT（9%; UGT 1A 4）、4/6其他DME（67%; CES 1、CES 2、FMO 5、POR）和3/16转运蛋白（19%; OAT 2、OCT 3、P-GP）。另外8种（24%）蛋白质（UGT 1A 1、UGT 2B 4、UGT 2B 10、FMO 3、OCT 1、MRP 2、MRP 3、ENT 1）在至少2个个体肝细胞供体中的绝对蛋白质浓度中显示出显著的PRH变化。相比之下，17种（52%）蛋白质在肝细胞供体内或跨肝细胞供体未表现出PRH的可辨别影响。总的来说，这些结果提供了第一个全面的定量蛋白质组学评估PRH对非-PDMEs和运输蛋白在SCHH的影响，并提供了机制的洞察力，改变处置的药物底物清除这些途径在怀孕期间。
Pregnancy alters the disposition and exposure to multiple drugs indicated for pregnancy-related complications. Previous in vitro studies have shown that pregnancy-related hormones (PRHs) alter the expression and function of certain cytochrome P450s (CYPs) in human hepatocytes. However, the impact of PRHs on hepatic concentrations of non-CYP drug-metabolizing enzymes (DMEs) and transport proteins remain largely unknown. In this study, sandwich-cultured human hepatocytes (SCHH) from five female donors were exposed to vehicle or PRHs (estrone, estradiol, estriol, progesterone, cortisol, and placental growth hormone), administered individually or in combination, across a range of physiologically relevant PRH concentrations for 72 h. Absolute concentrations of 33 hepatic non-CYP DMEs and transport proteins were quantified in SCHH membrane fractions using a quantitative targeted absolute proteomics (QTAP) isotope dilution nanoLC-MS/MS method. The data revealed that PRHs altered the absolute protein concentration of various DMEs and transporters in a concentration-, isoform-, and hepatocyte donor-dependent manner. Overall, eight of 33 (24%) proteins exhibited a significant PRH-evoked net change in absolute protein concentration relative to vehicle control (ANOVA p < 0.05) across hepatocyte donors: 1/11 UGTs (9%; UGT1A4), 4/6 other DMEs (67%; CES1, CES2, FMO5, POR), and 3/16 transport proteins (19%; OAT2, OCT3, P-GP). An additional 8 (24%) proteins (UGT1A1, UGT2B4, UGT2B10, FMO3, OCT1, MRP2, MRP3, ENT1) exhibited significant PRH alterations in absolute protein concentration within at least two individual hepatocyte donors. In contrast, 17 (52%) proteins exhibited no discernable impact by PRHs either within or across hepatocyte donors. Collectively, these results provide the first comprehensive quantitative proteomic evaluation of PRH effects on non-CYP DMEs and transport proteins in SCHH and offer mechanistic insight into the altered disposition of drug substrates cleared by these pathways during pregnancy.
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DOI：
10.1080/15257770.2016.1210805
发表时间：
2017-01-02
期刊：
Nucleosides, nucleotides & nucleic acids
影响因子：
--
作者：
Boswell-Casteel RC;Hays FA
通讯作者：
Hays FA
影响因子：
4.2
作者：
Daud, Aizati N. A.;Bergman, Jorieke E. H.;Bakker, Marian K.;Wang, Hao;Kerstjens-Frederikse, Wilhelmina S.;de Walle, Hermien E. K.;Groen, Henk;Bos, Jens H. J.;Hak, Eelko;Wilffert, Bob
通讯作者：
Wilffert, Bob
影响因子：
9.8
作者：
Beigi RH;Han K;Venkataramanan R;Hankins GD;Clark S;Hebert MF;Easterling T;Zajicek A;Ren Z;Mattison DR;Caritis SN;Obstetric-Fetal Pharmacology Research Units Network
通讯作者：
Obstetric-Fetal Pharmacology Research Units Network
影响因子：
3.4
作者：
Ayad M;Costantine MM
通讯作者：
Costantine MM
影响因子：
3.9
作者：
Eyal, Sara;Easterling, Thomas R.;Hebert, Mary F.
通讯作者：
Hebert, Mary F.