Pregnancy-Related Hormones Increase Nifedipine Metabolism in Human Hepatocytes by Inducing CYP3A4 Expression

Pregnancy-related hormones (PRH) have emerged as key regulators of hepatic cytochrome P450 (CYP) enzyme expression and function. The impact of PRH on protein levels of CYP3A4 and other key CYP enzymes, and the metabolism of nifedipine (a CYP3A4 substrate commonly prescribed during pregnancy), was ev...

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Published in:Journal of pharmaceutical sciences 2021-01, Vol.110 (1), p.412-421
Main Authors: Khatri, Raju, Kulick, Natasha, Rementer, Rebecca J.B., Fallon, John K., Sykes, Craig, Schauer, Amanda P., Malinen, Melina M., Mosedale, Merrie, Watkins, Paul B., Kashuba, Angela D.M., Boggess, Kim A., Smith, Philip C., Brouwer, Kim L.R., Lee, Craig R.
Format: Article
Language:English
Subjects:
Cytochrome P-450 CYP3A - genetics
Cytochrome P450
Estradiol
Exosomes
Female
Hepatic metabolism
Hepatocytes
Humans
Hypertension
Nifedipine
Pregnancy
Progesterone
Tandem Mass Spectrometry
Targeted proteomics
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Summary:Pregnancy-related hormones (PRH) have emerged as key regulators of hepatic cytochrome P450 (CYP) enzyme expression and function. The impact of PRH on protein levels of CYP3A4 and other key CYP enzymes, and the metabolism of nifedipine (a CYP3A4 substrate commonly prescribed during pregnancy), was evaluated in primary human hepatocytes. Sandwich-cultured human hepatocytes (SCHH) from female donors were exposed to PRH (estradiol, estriol, estetrol, progesterone, and cortisol), individually or in combination as a cocktail. Absolute protein concentrations of twelve CYP isoforms in SCHH membrane fractions were quantified by nanoLC-MS/MS, and metabolism of nifedipine to dehydronifedipine in SCHH was evaluated. PRH significantly increased CYP3A4 protein concentrations and nifedipine metabolism to dehydronifedipine in a concentration-dependent manner. CYP3A4 mRNA levels in hepatocyte-derived exosomes positively correlated with CYP3A4 protein levels and dehydronifedipine formation in SCHH. PRH also increased CYP2B6, CYP2C8 and CYP2A6 levels. Our findings demonstrate that PRH increase nifedipine metabolism in SCHH by inducing CYP3A4 expression and alter expression of other key CYP proteins in an isoform-specific manner, and suggest that hepatocyte-derived exosomes warrant further investigation as biomarkers of hepatic CYP3A4 metabolism. Together, these results offer mechanistic insight into the increases in nifedipine metabolism and clearance observed in pregnant women.
ISSN:0022-3549
1520-6017
1520-6017
DOI:10.1016/j.xphs.2020.09.013