Disease relevance of Cyp2e1

• Cytochrome P450 2E1 (CYP2E1) plays an important role in alcohol-induced toxicity and oxidative stress [1].
• Increased expression of cytochrome P450 2E1 (CYP2E1) occurs in alcoholic liver disease, and leads to the hepatocellular generation of toxic reactive oxygen intermediates (ROI) [2].
• Enhanced hepatic levels of cytochrome P450 2E1 (CYP2E1) may play a key role in the pathogenesis of some liver diseases because CYP2E1 represents a significant source of reactive oxygen species [3].
• Liver nitrites, number of granulocytes, liver weight/body weight ratio, cytochrome P450 2E1 protein, and chymotrypsin-like activity changed in the same direction compared with control values [4].
• Role of ethanol-inducible cytochrome P-450 2E1 in the development of hepatocellular carcinoma by the chemical carcinogen, N-nitrosodimethylamine [5].

Psychiatry related information on Cyp2e1

• Chronic alcohol consumption may potentiate acetaminophen (APAP) hepatotoxicity through enhanced formation of N-acetyl-p-benzoquinone imine (NAPQI) via induction of cytochrome P450 2E1 (CYP2E1) [6].
• Cytochrome P450 2E1 (CYP 2E1), the principal component of MEOS, is ethanol inducible and has been implicated in hepatotoxicity associated with alcohol abuse and exposure to organic solvents [7].
• The following results were obtained recently from our laboratories; in rats with 72-h water deprivation (rats with dehydration), the hepatic cytochrome P450 2E1 (CYP2E1) was three-fold induced with an increase in the mRNA [8].

High impact information on Cyp2e1

• Cytochrome P450 2E1 was down-regulated in fa/fa compared with Fa/? rats; however, the ethanol binge increased cytochrome P450 2E1 in both genotypes [9].
• Liver samples were analyzed for histopathology, lipid peroxidation, fatty acid composition, cytochrome P450 2E1 activity, and tocopherol levels [10].
• No increase in either of the endpoints was observed in ethanol-treated Cyp2e1-null mice, whereas the magnitude of response in p47(phox)-null mice and transgenic hCyp2e1 was identical to that in wild types [11].
• Partial inhibition of NAPQI formation by CYP2E1 inhibitor diethyldithiocarbamate to that of pair-fed controls abolished APAP toxicity in the 10-day ethanol group only [6].
• We studied the effects of acarbose on the hepatotoxicity of carbon tetrachloride (CCl4) and acetaminophen (AP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 2E1 (CYP2E1) [12].

Chemical compound and disease context of Cyp2e1

• Fao hepatoma cells, where CYP2E1 showed a half-life of 4 h upon serum withdrawal, were treated for 1 h with 0.3 microM diphenylene iodonium (DPI), a suicide inhibitor of flavoenzymes, which resulted in approximately 90% inhibition of the microsomal NADPH-cytochrome P450 reductase and CYP2E1-dependent chlorzoxazone hydroxylase activities [13].
• Isoniazid, an inhibitor of cytochrome P450 2E1, protected cells against APAP toxicity and prevented glutathione depletion [14].
• The present study was designed to establish the role of plasma urea nitrogen and L-arginine on hepatic CYP2E1 expression in rats or rats with acute renal failure [15].
• In the Fao hepatoma cell line, CYP2E1 was found to be fairly stable (half-life of 26 h), but serum withdrawal resulted in its rapid disappearance from the microsomal fraction (half-life of about 7 h) as evaluated using cycloheximide chase [16].
• Intestinal toxicity of acrylonitrile: in vitro metabolism by intestinal cytochrome P450 2E1 [17].

Biological context of Cyp2e1

• These results indicate, for the first time, a marked increase in mitochondrial oxidative stress in target tissues of STZ-treated rats and implicate a direct role for mitochondrial CYP2E1 in the generation of intramitochondrial ROS [18].
• It is thus suggested that LPS induces MKK3 activation in astrocytes, which in turn stimulates a C/EBPbeta and -delta binding element to mediate transcriptional activation of CYP2E1 [19].
• Bimodal targeting of microsomal CYP2E1 to mitochondria through activation of an N-terminal chimeric signal by cAMP-mediated phosphorylation [1].
• Transient transfection of COS cells with CYP2E1 cDNA caused a similar accumulation of CYP2E1 and GST A4-4 in mitochondria and increased production of mitochondrial ROS [18].
• Sensitization to TNF-alpha-induced cell death by CYP2E1 overexpression was inhibited by antioxidants or adenoviral expression of a dominant-negative c-Jun [20].

Anatomical context of Cyp2e1

• Lipopolysaccharide induces CYP2E1 in astrocytes through MAP kinase kinase-3 and C/EBPbeta and -delta [19].
• Cytochrome P450 2E1 (CYP2E1) exhibits a pronounced oxidase activity that may mediate apoptotic injury in glial cells as well as hepatocytes [21].
• Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-alpha [20].
• Thus, ethanol intoxication increases CYP2E1 not only in the endoplasmic reticulum but also in mitochondria, thus favouring oxidative stress in these compartments [3].
• Protease protection experiments performed on microsomes isolated from cDNA transfected cells revealed that a small fraction of CYP2E1 and all variant proteins was found to be located in the lumen of the endoplasmic reticulum (type II orientation), whereas the majority of the proteins were in the expected cytosolic or type I orientation [22].

Associations of Cyp2e1 with chemical compounds

• N-acetyl-cysteine served as an antioxidant, and diethyldithiocarbamate served as an inhibitor of cytochrome P450 2E1 [23].
• Elevated mitochondrial cytochrome P450 2E1 and glutathione S-transferase A4-4 in streptozotocin-induced diabetic rats: tissue-specific variations and roles in oxidative stress [18].
• 5. Modulation of RLM6 mRNA level in the diabetic rat by insulin and testosterone, and the nucleotide sequence similarity with that of P4502E1 confirms that diabetes-inducible P450RLM6 and ethanol-inducible P4502E1 are coded for by the same gene [24].
• S-CYP15 cells had increased levels of CYP2E1 as demonstrated by Northern blot analysis, immunoblotting, catalytic activity, and increased cell sensitivity to death from acetaminophen [2].
• The aim of this study was to examine the effect of oral administration of diallyl sulfide--a cytochrome P450 2E1 inhibitor and cimetidine--a cytochrome P450 2C6 and 2C11 inhibitor on rat serum concentration of phenacetin and its metabolite acetaminophen [25].

Physical interactions of Cyp2e1

• A novel lipopolysaccharide-modulated Jun binding repressor in intron 2 of CYP2E1 [21].

Other interactions of Cyp2e1

• Increased Sp1-dependent transactivation of the LAMgamma 1 promoter in hepatic stellate cells co-cultured with HepG2 cells overexpressing cytochrome P450 2E1 [26].
• MAP kinase kinase-3 (MKK3) was phosphorylated in response to LPS, and expression of constitutively active MKK3, but not the MAP kinase kinases MEKK1 or MKK1, activated CYP2E1 [19].
• The element very potently repressed CYP2E1 and SV40 promoters and consisted of the non-palindromic core sequence 5'-TTCCACTCA-3'. Jun proteins were found to interact with the site [21].
• It is suggested that CYP2E1, together with interleukin-6 and ciliary neurotrophic factor, is part of a response of astrocytes to cellular stress elicited by, e.g. cerebral injury, cytokines or phorbol ester, and mediated in part through protein kinase C [27].
• Western immunoblotting indicated that ethylbenzene treatment induced cytochrome P450 2B1/2B2 to a greater extent in male rats and cytochrome P450 2E1 only in females [28].

Analytical, diagnostic and therapeutic context of Cyp2e1

• Molecular cloning of a cDNA for rat diabetes-inducible cytochrome P450RLM6: hormonal regulation and similarity to the cytochrome P4502E1 gene [24].
• The Cyp2e1 gene was isolated and its organization was established by PCR using oligonucleotides to its predicted intron/exon boundaries [29].
• Southern blot analysis of genomic DNA prepared from C57BL/6 and DBA/2N mice suggests the presence of only a single Cyp2e1 gene [29].
• In this study we have used highly purified peroxisomes (> 95%) to provide evidence by analytical cell fractionation, enzyme activity, Western blot, and immunocytochemical analysis that cytochrome P-450 2E1 (Cyp 2E1) is present in peroxisomes [30].
• Ischemia alone had no effect; however, reperfusion following ischemia resulted in decrease in Cyp 2E1 both in microsomes and peroxisomes [30].

References