Transcriptional and posttranscriptional regulation of CYP2E1, an N-nitrosodimethylamine demethylase.

CYP2E1 is a cytochrome P-450 that is well conserved in many species and carries out oxidation of both endogenous and numerous foreign chemicals. This enzyme is the primary component of the methylglyoxal and propandiol pathways of gluconeogenesis. It is also the principal P-450 involved in metabolism of many small molecular weight chemicals that are found in solvents and in the environment. Among important drugs metabolized by CYP2E1 are anesthetic agents such as halothane, the analgesic acetaminophen, and the muscle relaxant chlorzoxazone. Most importantly CYP2E1 is capable of converting certain procarcinogenic nitrosamines to their active DNA-binding metabolites. The CYP2E1 gene becomes transcriptionally active in the liver soon after birth. Although the physiological stimulus for this increase is still unknown, the molecular basis of CYP2E1 gene activation is becoming clear. Transcription of the CYP2E1 gene is primarily due to the binding of the hepatocyte-specific transcription factor HNF-1 to a segment of DNA just upstream of the start site for RNA synthesis. In adult animals, CYP2E1 is posttranscriptionally regulated through mRNA and protein stabilization. Stabilization of CYP2E1 protein is due to interaction of the enzyme with its own substrate.