Title : Impact of pregnancy related hormones on drug metabolizing enzyme and transport protein concentrations in human hepatocytes - Fashe_2022_Front.Pharmacol_13_1004010 |
Author(s) : Fashe MM , Fallon JK , Miner TA , Tiley JB , Smith PC , Lee CR |
Ref : Front Pharmacol , 13 :1004010 , 2022 |
Abstract :
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. |
PubMedSearch : Fashe_2022_Front.Pharmacol_13_1004010 |
PubMedID: 36210832 |
Fashe MM, Fallon JK, Miner TA, Tiley JB, Smith PC, Lee CR (2022)
Impact of pregnancy related hormones on drug metabolizing enzyme and transport protein concentrations in human hepatocytes
Front Pharmacol
13 :1004010
Fashe MM, Fallon JK, Miner TA, Tiley JB, Smith PC, Lee CR (2022)
Front Pharmacol
13 :1004010