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Licensed Unlicensed Requires Authentication Published by De Gruyter April 7, 2021

Co-expression of drug metabolizing cytochrome P450 enzymes and estrogen receptor alpha (ESR1) in human liver: racial differences and the regulatory role of ESR1

  • Joseph M. Collins and Danxin Wang ORCID logo EMAIL logo

Abstract

Objectives

The function and expression of cytochrome P450 (CYP) drug metabolizing enzymes is highly variable, greatly affecting drug exposure, and therapeutic outcomes. The expression of these enzymes is known to be controlled by many transcription factors (TFs), including ligand-free estrogen receptor alpha (ESR1, in the absence of estrogen). However, the relationship between the expression of ESR1, other TFs, and CYP enzymes in human liver is still unclear.

Methods

Using real-time PCR, we quantified the mRNA levels of 12 CYP enzymes and nine TFs in 246 human liver samples from European American (EA, n = 133) and African American (AA, n = 113) donors.

Results

Our results showed higher expression levels of ESR1 and six CYP enzymes in EA than in AA. Partial least square regression analysis showed that ESR1 is the top-ranking TF associating with the expression of eight CYP enzymes, six of which showed racial difference in expression. Conversely, four CYP enzymes without racial difference in expression did not have ESR1 as a top-ranking TF. These results indicate that ESR1 may contribute to variation in CYP enzyme expression between these two ancestral backgrounds.

Conclusions

These results are consistent with our previous study showing ESR1 as a master regulator for the expression of several CYP enzymes. Therefore, factors affecting ESR1 expression may have broad influence on drug metabolism through altered expression of CYP enzymes.


Corresponding author: Danxin Wang, MD, PhD, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, PO Box 100486, 1345 Center Drive MSB PG-05B, Gainesville, FL 32610, USA, Phone: +1 352 273 7673; Fax: +1 352 273 6121, E-mail:

Funding source: National Institute of Health, Institute of General Medical Sciences

Award Identifier / Grant number: R01 GM120396

  1. Research funding: This work was supported by National Institute of Health, Institute of General Medical Sciences (R01 GM120396 to DW). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Liver samples were provided by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The University of Florida Institutional Review Board approved the human tissue study.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/dmpt-2020-0160).


Received: 2020-10-07
Accepted: 2021-01-03
Published Online: 2021-04-07

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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