Megestrol acetate is a synthetic progestogen used to treat some cancers and cancer-associated cachexia, but its potential interactions with other drugs are not well known. This study aims to determine the regulation of drug metabolizing enzymes by megestrol acetate.
Primary human hepatocytes were treated and analyzed by PCR array to identify genes involved in drug metabolism that are impacted by megestrol acetate. P450 3A4 (CYP3A4) reporter gene assay and HPLC analyses of nifedipine metabolites were used to determine CYP3A4 gene expression and activities. Competitive ligand binding assay was used to determine the affinity of megestrol acetate toward human pregnane x receptor (hPXR). Electrophoretic mobility shift assay and mammalian two hybrid assay were used to determine the mechanism of megestrol to activate hPXR.
The levels and activities of CYP3A4 were significantly induced (> 4-folds) by megestrol acetate in human hepatocytes and HepG2 cells. Megestrol treatment induced CYP3A4 through the activation of hPXR, a ligand-activated transcription factor that plays a role in drug metabolism and transport. Other tested nuclear receptors showed no response. The mechanism studies showed that megestrol activated hPXR by binding to the ligand binding domain (LBD) of hPXR and increasing the recruitment of the cofactors such as steroid receptor cofactor (SRC-1).
The results suggest that megestrol acetate is a specific inducer of CYP3A4 mediated by hPXR and therefore has the potential to cause drug interactions, especially in the co-administration with drugs that are substrates of CYP3A4.
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We acknowledge and thank the following people for providing plasmids: Gal4DB-SRC-1-RID and TK-MH100×4-LUC from Dr. Sridhar Mani at Albert Einstein College of Medicine. pTracer-CMV2-CAR3 and pTracer-CMV2 from Dr. Curtis J. Omiecinski at Center for Molecular Toxicology and Carcinogenesis, the Pennsylvania State University. pSG5-mPXR and pVP-hPXR from Dr. Jeff L. Staudinger at Department of Pharmacology and Toxicology, University of Kansas. pCMX-RXRa from Dr. David John Mangelsdorf at Howard Hughes Medical Institute, UT Southwestern Medical Center. We also acknowledge and thank Lydia Howes at Southern Illinois University School of Medicine Library for professional editing of the manuscript.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Megestrol acetate specifically induces the expression of cytochrome P450 3A4 (CYP3A4) in human hepatocytes through binding to human PXR and recruitment of cofactors. But it has minimal effects on the expression of other drug metabolizing enzymes and efflux transporters. The study suggests a potential interaction of megestrol acetate with other drugs that are substrates of CYP3A4, as well as the utility of this compound to induce CYP3A4 specifically for pharmacological studies.
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Chen, Y., Tang, Y., Nie, J.Z. et al. Megestrol acetate is a specific inducer of CYP3A4 mediated by human pregnane X receptor. Cancer Chemother Pharmacol (2021). https://doi.org/10.1007/s00280-021-04352-9
- Megestrol acetate
- Drug metabolizing enzymes