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Published on: March 28, 2017
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CYP2D6 Is Inducible by Endogenous and Exogenous Corticosteroids
Muhammad Farooq1, Edward J Kelly1, Jashvant D Unadkat2
1Department of Pharmaceutics, University of Washington, Seattle, Washington.
Summary
Cytochrome P450 (CYP) 2D6 is inducible in vitro, contrary to previous belief. Standard lab conditions using dexamethasone mask this induction, but cortisol shows significant effects, aligning with pregnancy observations.
Area of Science:
- Pharmacology
- Biochemistry
- Hepatology
Background:
- Cytochrome P450 (CYP) 2D6 is crucial for drug metabolism.
- Previous human hepatocyte studies suggested CYP2D6 is noninducible.
- In vivo data indicates CYP2D6 can be induced by endogenous and exogenous substances.
Purpose of the Study:
- To investigate if standard experimental conditions in human hepatocyte studies mask CYP2D6 induction.
- To determine the inducibility of CYP2D6 in vitro using various corticosteroids.
- To explore the role of cortisol in CYP2D6 induction.
Main Methods:
- Sandwich cultured human hepatocytes (SCHH) were used.
- Hepatocytes were preincubated with or without dexamethasone.
- CYP2D6 mRNA, protein, and activity were quantified after corticosteroid exposure.
Main Results:
- All four tested corticosteroids (cortisol, corticosterone, dexamethasone, prednisolone) robustly induced CYP2D6 (>10-fold) in the absence of supplemental dexamethasone.
- Preincubation with dexamethasone abolished the observed CYP2D6 induction.
- Cortisol-induced CYP2D6 levels mirrored in vivo observations during late pregnancy.
Conclusions:
- CYP2D6 is inducible in vitro, but commonly used dexamethasone concentrations mask this effect.
- Cortisol may be a key factor in the in vivo induction of CYP2D6 during pregnancy.
- Findings necessitate re-evaluation of regulatory guidelines for assessing CYP2D6 induction and predicting drug-drug interactions.
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