Abstract
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.
Highlights
80% of pregnant individuals take at least one medication for the treatment of either a preexisting chronic or acute condition during pregnancy (Ayad and Costantine, 2015)
Evaluation of additional UGT1A isoforms revealed that UGT1A3 mRNA levels were modestly induced by the pregnancy related hormones (PRH) CKTL, and UGT1A6 and UGT1A9 mRNA levels were not altered by PRH (Supplementary Figure S1)
Our in vitro experiments in sandwich-cultured human hepatocytes (SCHH) lay a foundation for these future studies. This is the first study in primary human hepatocytes to evaluate the impact of PRH on Uridine 5′-diphospho-glucuronosyltransferase (UGT) mRNA levels and protein concentrations, and the glucuronidation of labetalol, a UGT1A1 and UGT2B7 substrate commonly prescribed to treat hypertensive disorders of pregnancy
Summary
80% of pregnant individuals take at least one medication for the treatment of either a preexisting chronic or acute condition during pregnancy (Ayad and Costantine, 2015). Accumulating evidence has demonstrated that PRH significantly alter hepatic mRNA levels and metabolic activity of certain cytochrome P450 enzymes, most notably CYP2B6 and CYP3A4 (Choi et al, 2013; Papageorgiou et al, 2013; Zhang et al, 2015; Khatri et al, 2021), which has been hypothesized as a central mechanism underlying altered hepatic clearance of cytochrome P450 substrates during pregnancy in vivo (Jeong, 2010; Isoherranen and Thummel, 2013; Dallmann et al, 2018b). Significant gaps in knowledge remain surrounding the mechanisms underlying pregnancy-associated changes in the expression and function of uridine diphosphate glucuronosyltransferases (UGTs), a key family of phase II DMEs involved in the conjugation and clearance of numerous drug substrates (Williams et al, 2004; Anderson, 2005; Fujiwara et al, 2016)
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