Gene regulation of cytochrome P450--an overview.

ABSTRACT

Xenobiotics have played a role in elucidating the regulation of gene expression of hepatic cytochrome P450 in the eukaryotes. The major regulation of P450 genes in the eukaryotes is at the transcriptional and post transcriptional level. Polycyclic aromatic hydrocarbons regulate the gene expression by binding the cytosolic aryl hydrocarbon receptor and its translocation to the nucleus where it forms a ternary complex with aryl hydrocarbon nuclear translocator. The ternary complex PAH-AHR-ARNT acts as a transcription factor and binds aromatic hydrocarbon responsive element to increase the expression of CYP1A1 gene. Phenobarbitone and ethanol regulate the expression of respective P450s within CYP2 gene family by different mechanisms but without the involvement of a cytosolic receptor. PB uses phosphorylation as a switch to increase the affinity of the transcription factor(s) for the positive rather than negative PB regulatory element within CYP2B1/2. This is one of the novel ways that nature has designed for a protein to act as a negative as well as a positive acting transcription factor. Ethanol regulates the expression of CYP2E1 by posttranslational stabilization making it resistant to the proteolytic digestion. Steroids regulate expression of CYP3A genes through a receptor mediated mechanism. The binary complex of the steroid and its receptor increases the transcription of CYP3 genes by binding glucocorticoid responsive element which is already occupied by another protein. Peroxisome proliferators also follow a receptor mediated mechanism in which a binary complex of PP activated receptor and retinoid X receptor acts a transcription factor and increases the expression of CYP4A genes by binding peroxisome proliferator responsive element. These studies demonstrate that PAH, glucocorticoids and PP follow a receptor mediated whereas PB and ethanol follow a nonreceptor mediated mechanism for the regulation of respective P450 genes in the eukaryotes.