Pregnancy-Related Hormones Increase UGT1A1-Mediated Labetalol Metabolism in Human Hepatocytes

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.

Impact of pregnancy related hormones on drug metabolizing enzyme and transport protein concentrations in human hepatocytes

“…Our observations that PRHs increased UGT1A1 protein concentration in SCHH in a concentration-dependent and hepatocyte donor-specific manner were also consistent with our prior study, which demonstrated that PRHs increase UGT1A1 expression and UGT1A1-mediated labetalol glucuronidation in SCHH, and that the magnitude of these effects vary across hepatocyte donors ( Khatri et al, 2021a ). These results provide further mechanistic insight into clinically observed gestational age dependent increases in labetalol oral clearance, which vary in magnitude and exhibit and inter-individual differences, in hypertensive pregnant patients ( Fischer et al, 2014 ; Khatri et al, 2021a ; Mulrenin et al, 2021 ). Although the functional implications remain unclear, we also report for the first time hepatocyte donor-specific increases in UGT2B4 and UGT2B10 protein concentrations in SCHH.…”

“…Moreover, in the absence of DME and transporter protein concentrations in liver tissue collected from pregnant and non-pregnant individuals, data from this study also could be used to inform pharmacokinetic models of drug disposition changes in pregnancy. Khatri et al previously reported that PRHs increased mRNA levels and absolute protein concentrations of UGT1A1 and UGT1A4, but did not significantly alter UGT1A3, UGT1A6, UGT1A9 and UGT2B7 expression, in SCHH from three donors (Khatri et al, 2021a). The current experiments extend these observations by evaluating a larger panel of UGT1A and UGT2B proteins across a larger number of hepatocyte donors.…”

“…Khatri et al previously reported that PRHs increased mRNA levels and absolute protein concentrations of UGT1A1 and UGT1A4, but did not significantly alter UGT1A3, UGT1A6, UGT1A9 and UGT2B7 expression, in SCHH from three donors ( Khatri et al, 2021a ). The current experiments extend these observations by evaluating a larger panel of UGT1A and UGT2B proteins across a larger number of hepatocyte donors.…”

“…Cocktail and individual PRH experiments were carried out as previously described ( Khatri et al, 2021a ; Khatri et al, 2021b ). Briefly, SCHH were cultured for 72 h (day-3 to day-5) in QualGro ™ Induction medium supplemented with vehicle control, PRH (using the treatment concentrations summarized in Table 2 ), or nuclear receptor activators (RIF 10 μM, CITCO 1 μM, or CDCA 100 µM).…”

Disease burden and management of Crigler‐Najjar syndrome: Report of a world registry

“…For CNS patients, we describe this sex difference for the first time. In Gilbert syndrome this difference is explained by the influence of sex steroids on UGT1A1 activity 18,21,22 . In CNS, the difference cannot fully be explained by this mechanism since in most patients, it is impossible to increase UGT1A1 activity, which is shown by failed treatment with PB.…”