Regulation of drug-metabolizing cytochrome P450 enzymes by glucocorticoids

Abstract

The regulation of drug-metabolizing cytochrome P450 enzymes (CYP) is a complex process involving multiple mechanisms. Among them, transcriptional regulation through ligand-activated nuclear receptors is the crucial mechanism involved in hormone-controlled and xenobiotic-induced expression of drug-metabolizing CYPs. In this article, we focus, in detail, on the role of the glucocorticoid receptor (GR) in the transcriptional regulation of human drug-metabolizing CYP enzymes and the mechanisms of the regulation. There are at least three distinct transcriptional mechanisms by which GR controls the expression of CYPs: 1) direct binding of GR to a specific gene-promoter sequence called the glucocorticoid responsive element (GRE); 2) indirect binding of GR in the form of a multiprotein complex to gene promoters without a direct contact between GR and promoter DNA; and 3) up- or downregulation of other CYP transcriptional regulators or nuclear receptors (i.e., transcriptional regulatory cross-talk). However, due to the general effect of glucocorticoids on numerous cellular pathways and functions, the net transcriptional effect of glucocorticoids on drug-metabolizing enzymes is usually a combination of several mechanisms. Since synthetic glucocorticoids are widely prescribed in human pharmacotherapy for the treatment of many diseases, comprehensive understanding of the transcriptional regulation of drug-metabolizing CYPs via GR with respect to glucocorticoid therapy or glucocorticoid hormonal status will aid in the development of efficient individualized pharmacotherapy without drug-drug interactions.

Keywords::

• Cytochrome P450
• glucocorticoid receptor
• nuclear receptors
• drug metabolism
• glucocorticoids

Acknowledgments

Our laboratories are supported by grants from the Czech Scientific Agency (GACR 303/07/0128, GACR 503/10/0579, and GACR 304/10/0149) and a research project (MZ0FNHK2005) from the Czech Ministry of Education.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.