The transcriptional regulation of the human CYP2C genes

Abstract

In humans, four members of the CYP2C subfamily (CYP2C8, CYP2C9, CYP2C18, and CYP2C19) metabolize more than 20% of all therapeutic drugs as well as a number of endogenous compounds. The CYP2C enzymes are found predominantly in the liver, where they comprise approximately 20% of the total cytochrome P450. A variety of xenobiotics such as phenobarbital, rifampicin, and hyperforin have been shown to induce the transcriptional expression of CYP2C genes in primary human hepatocytes and to increase the metabolism of CYP2C substrates in vivo in man. This induction can result in drug-drug interactions, drug tolerance, and therapeutic failure. Several drug-activated nuclear receptors including CAR, PXR, VDR, and GR recognize drug responsive elements within the 5' flanking promoter region of CYP2C genes to mediate the transcriptional upregulation of these genes in response to xenobiotics and steroids. Other nuclear receptors and transcriptional factors including HNF4alpha, HNF3gamma, C/EBPalpha and more recently RORs, have been reported to regulate the constitutive expression of CYP2C genes in liver. The maximum transcriptional induction of CYP2C genes appears to be achieved through a coordinative cross-talk between drug responsive nuclear receptors, hepatic factors, and coactivators. The transcriptional regulatory mechanisms of the expression of CYP2C genes in extrahepatic tissues has received less study, but these may be altered by perturbations from pathological conditions such as ischemia as well as some of the receptors mentioned above.

Figure 1

Summary of the known response elements for nuclear receptors regulating the CYP2C8, 2C9, and 2C19 genes. This figure summarizes our current view of the regulatory elements within the three human CYP2C gene promoters. The hexamer sequences are shown in capital letters for each element along with their exact locations within each promoter. The arrows indicate the direct repeat of each element. The elements which bind nuclear receptors in vitro but are identified as nonfunctional by mutagenesis in luciferase promoter studies are shown with grey lines. Newly identified HNF4α sites in CYP2C9 and CYP2C8 are indicated with dark parallel lines (Chen unpublished).

Figure 2

Interactions between nuclear receptors and coactivators precisely modulate the transcription of CYP2C9. The coactivator NcoA6 bridges the HNF4α binding site(s) within the basal promoter and the proximal CAR/PXR-RE site by interacting with HNF4α and CAR, producing a synergistic transactivation of the CYP2C9 promoter. The coactivators PGC-1α and SRC-1 also interact with HNF4α, and probably also with GR, to regulate the activity of the CYP2C9 promoter.