High impact information on CYP2E1

• Livers from ethanol-fed animals showed increased centrilobular CYP2E1 and protein adducts with acetaldehyde and MDA [1].
• The most significant increases occurred in CYP2E1 and CYP3A in the noncastrated animals and in CYP2E1 and CYP2A in the castrated animals [2].
• The effects of ethanol feeding or folate-deficient diets, singly or in combination, on cytochrome P-450 2E1 (CYP2E1) and signal pathways for apoptosis and steatosis were analyzed using microarray, real-time PCR, and immunoblotting techniques [3].
• Liver CYP2E1 and the endoplasmic reticulum stress signals glucose-regulated protein 78 (GRP78), caspase 12, and sterol regulatory element binding protein-1c (SREBP-1c) were each activated in pigs fed folate-deficient or ethanol diets singly or in combination [3].
• These in vitro results suggest that propofol could have a protective effect on toxic metabolite activation of compounds catalyzed by CYP2E1 [4].

Biological context of CYP2E1

• In addition, a microsatellite marker tightly linked to the CYP2E1 gene was subcloned from the BAC [5].
• This sequence information was used to identify six single nucleotide polymorphisms (SNPs) within the CYP2E1 gene and its promoter [5].
• One of these markers was used to map the CYP2E1 gene distal of SWC27 on SSC14, well outside reported quantitative trait loci on SSC14 for skatole, indole and taste test measures of boar taint [5].
• The induction of abnormal hepatic methionine metabolism through the combination of ethanol feeding with folate deficiency is associated with the activation of CYP2E1 and enhances endoplasmic reticulum stress signals that promote steatosis and apoptosis [3].
• The aim of this study was to measure the expression pattern of CYP2E1 mRNA in various tissues of the pig, to identify genetic polymorphisms, and to evaluate the functional relevance of polymorphic sites with respect to the skatole level in fat [6].

Anatomical context of CYP2E1

• The results offer an explanation for the inhibition of CYP2E1 protein expression by androstenone in isolated pig hepatocytes and may be relevant to the low expression of hepatic CYP2E1 in those pigs which accumulate high levels of androstenone in vivo [7].
• RESULTS: CYP2E1 was identified in the LLC-PK1 cells [8].
• Excessive accumulation of skatole together with androstenone, a metabolite of testosterone, in adipose tissue in some pigs is a major cause of 'boar taint' and is associated with defective expression of CYP2E1 [9].
• Diethyldithiocarbamate (DDC), a CYP2E1 inhibitor in humans, was a potent mechanism-based inhibitor of 6OH-CLZ formation in microsomes from all species examined [10].
• A competitive inhibition of CYP2E1 by propofol was observed with low inhibition constants in the therapeutic range in both porcine (19 microM) and human (48 microM) liver microsomes [4].

Associations of CYP2E1 with chemical compounds

• Minipig CYP2E1 was shown to be able to convert two prototypical substrates of human CYP2E1, chlorzoxazone and p-nitrophenol, to the respective metabolites [11].
• However, in a population of commercial pigs scored for backfat skatole levels, there was evidence of association between a SNP in the CYP2E1 promoter and skatole deposition, although there was no significant association between this SNP and skatole levels in the experimental cross [5].
• Exposure of LLC-PK1 cells to CP resulted in marked generation of hydrogen peroxide (H2O2), reduction of CYP2E1 content, increase in catalytic iron and hydroxyl radical formation accompanied by significant cytotoxicity [8].
• Skatole, a derivative of tryptophan, is produced in the hind-gut of pigs and is metabolised via hepatic cytochrome P4502E1 (CYP2E1) [9].
• This study investigates the role of CYP2E1 in the proximal tubular cell injury induced by hydrogen peroxide (H2O2) [12].

References