Regulation of drug-metabolizing cytochrome P450 enzymes by glucocorticoids.
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.
Dvorak
Zdenek
Z
Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Olomouc, Czech Republic. moulin@email.cz
Pavek
Peotr
P
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism* / Q000502:physiology; D005938:Glucocorticoids / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000502:physiology*
D005938:Glucocorticoids; D004364:Pharmaceutical Preparations; D011965:Receptors, Glucocorticoid; D003577:Cytochrome P-450 Enzyme System