Khatri Raju, Fallon John K, Sykes Craig, Kulick Natasha, Rementer Rebecca J B, Miner Taryn A, Schauer Amanda P, Kashuba Angela D M, Boggess Kim A, Brouwer Kim L R, Smith Philip C, Lee Craig R
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Front Pharmacol. 2021 Apr 15;12:655320. doi: 10.3389/fphar.2021.655320. eCollection 2021.
Pregnancy-related hormones (PRH) are recognized as important regulators of hepatic cytochrome P450 enzyme expression and function. However, the impact of PRH on the hepatic expression and function of uridine diphosphate glucuronosyltransferases (UGTs) remains unclear. Using primary human hepatocytes, we evaluated the effect of PRH exposure on mRNA levels and protein concentrations of UGT1A1, UGT2B7, and other key UGT enzymes, and on the metabolism of labetalol (a UGT1A1 and UGT2B7 substrate commonly prescribed to treat hypertensive disorders of pregnancy). Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to the PRH estradiol, estriol, estetrol, progesterone, and cortisol individually or in combination. We quantified protein concentrations of UGT1A1, UGT2B7, and four additional UGT1A isoforms in SCHH membrane fractions and evaluated the metabolism of labetalol to its glucuronide metabolites in SCHH. PRH exposure increased mRNA levels and protein concentrations of UGT1A1 and UGT1A4 in SCHH. PRH exposure also significantly increased labetalol metabolism to its UGT1A1-derived glucuronide metabolite in a concentration-dependent manner, which positively correlated with PRH-induced changes in UGT1A1 protein concentrations. In contrast, PRH did not alter UGT2B7 mRNA levels or protein concentrations in SCHH, and formation of the UGT2B7-derived labetalol glucuronide metabolite was decreased following PRH exposure. Our findings demonstrate that PRH alter expression and function of UGT proteins in an isoform-specific manner and increase UGT1A1-mediated labetalol metabolism in human hepatocytes by inducing UGT1A1 protein concentrations. These results provide mechanistic insight into the increases in labetalol clearance observed in pregnant individuals.
妊娠相关激素（PRH）被认为是肝细胞色素P450酶表达和功能的重要调节因子。然而，PRH对尿苷二磷酸葡萄糖醛酸转移酶（UGT）肝脏表达和功能的影响仍不清楚。我们使用原代人肝细胞，评估了PRH暴露对UGT1A1、UGT2B7和其他关键UGT酶的mRNA水平和蛋白质浓度的影响，以及对拉贝洛尔（一种常用于治疗妊娠高血压疾病的UGT1A1和UGT2B7底物）代谢的影响。来自女性供体的三明治培养人肝细胞（SCHH）分别或联合暴露于PRH雌二醇、雌三醇、雌四醇、孕酮和皮质醇。我们定量了SCHH膜组分中UGT1A1、UGT2B7和另外四种UGT1A同工型的蛋白质浓度，并评估了SCHH中拉贝洛尔向其葡萄糖醛酸代谢物的代谢情况。PRH暴露增加了SCHH中UGT1A1和UGT1A4的mRNA水平和蛋白质浓度。PRH暴露还以浓度依赖的方式显著增加了拉贝洛尔向其UGT1A1衍生的葡萄糖醛酸代谢物的代谢，这与PRH诱导的UGT1A1蛋白质浓度变化呈正相关。相比之下，PRH没有改变SCHH中UGT2B7的mRNA水平或蛋白质浓度，并且PRH暴露后UGT2B7衍生的拉贝洛尔葡萄糖醛酸代谢物的形成减少。我们的研究结果表明，PRH以同工型特异性方式改变UGT蛋白的表达和功能，并通过诱导UGT1A1蛋白质浓度增加人肝细胞中UGT1A1介导的拉贝洛尔代谢。这些结果为在孕妇中观察到的拉贝洛尔清除率增加提供了机制性见解。
