Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone.
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Choi SY, Koh KH, Jeong H
Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone.
Drug Metab Dispos. 2013 Feb;41(2):263-9. doi: 10.1124/dmd.112.046276. Epub 2012 Jul 26.
- PubMed ID
- 22837389 [ View in PubMed]
- Abstract
Results from clinical studies suggest that pregnancy alters hepatic drug metabolism in a cytochrome P450 (P450) isoform-specific manner, and rising concentrations of female hormones are potentially responsible for the changes. The objective of this study was to comprehensively characterize the effects of estrogen and progesterone on the expression and activity of major drug-metabolizing P450s. To this end, primary human hepatocytes were treated with estradiol and progesterone, and mRNA expression and activity levels of 10 different P450 isoforms were determined. The results showed that estradiol enhances CYP2A6, CYP2B6, and CYP3A4 expression, whereas progesterone induces CYP2A6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 expression. The induction was mainly observed when the average hormone concentrations were at the levels reached during pregnancy, suggesting that these effects are likely pregnancy-specific. Estradiol also increased enzyme activities of CYP2C9 and CYP2E1 without affecting the mRNA expression levels by unknown mechanisms. Taken together, our results show differential effects of estrogen and progesterone on P450 expression, suggesting involvement of different regulatory mechanisms in female hormone-mediated P450 regulation. Our findings potentially provide a basis in mechanistic understanding for altered drug metabolism during pregnancy.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Estradiol Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Estradiol acetate Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Estradiol benzoate Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Estradiol dienanthate Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails Progesterone Cytochrome P450 2A6 Protein Humans UnknownInducerDetails Progesterone Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Estradiol Approved Investigational Vet Approved CYP2A6 1548 upregulated Estradiol results in increased expression of CYP2A6 mRNA 19q13.2 Estradiol Approved Investigational Vet Approved CYP2B6 1555 upregulated Estradiol results in increased expression of CYP2B6 mRNA 19q13.2 Estradiol Approved Investigational Vet Approved CYP3A4 1576 upregulated Estradiol results in increased expression of CYP3A4 mRNA 7q22.1 Progesterone Approved Vet Approved CYP2A6 1548 upregulated Progesterone results in increased expression of CYP2A6 mRNA 19q13.2 Progesterone Approved Vet Approved CYP2B6 1555 upregulated Progesterone results in increased expression of CYP2B6 mRNA 19q13.2 Progesterone Approved Vet Approved CYP2C8 1558 upregulated Progesterone results in increased expression of CYP2C8 mRNA 10q23.33 Progesterone Approved Vet Approved CYP3A4 1576 upregulated Progesterone results in increased expression of CYP3A4 mRNA 7q22.1 Progesterone Approved Vet Approved CYP3A5 1577 upregulated Progesterone results in increased expression of CYP3A5 mRNA 7q22.1