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.
Gonzalez
F J
FJ
Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Gelboin
H V
HV
D000096:Acetone / Q000494:pharmacology; D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008099:Liver / Q000378:metabolism; D009687:Nuclear Proteins; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*; D051381:Rats; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496489:Hnf1a protein, rat; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D000096:Acetone; D051539:Hepatocyte Nuclear Factor 1-beta; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating