The impact of CYP2E1 on the development of alcoholic liver disease as studied in a transgenic mouse model.
OBJECTIVE
CYP2E1 metabolizes ethanol, generates reactive oxygen species, and is suggested to be important for development of alcoholic liver disease. The present study aims to evaluate the role of CYP2E1 in combination with ethanol for development of alcoholic liver disease using mice transgenic for the human CYP2E1 gene.


METHODS
Changes in hepatic gene expression were monitored in controls and mice transgenic for human CYP2E1, treated with ethanol or isocaloric dextrose intragastrically for 4 weeks, and related to pathology using Affymetrix microarrays and TaqMan RealTime PCR.


RESULTS
Presence of the CYP2E1 transgene increased liver injury and increased expression of stress related genes. Microarray analyses revealed the expression of structural genes, particularly cytokeratin 8 and 18, to be highly related to pathology.


CONCLUSIONS
This in vivo study confirms several findings regarding CYP2E1 and alcohol previously found only in vitro. These results provide in vivo evidence that CYP2E1 overexpression aggravates hepatic injury, and suggest that expression of cytokeratins 8 and 18 can be considered as biomakers for the progression of alcoholic liver disease.
Butura
Angelica
A
Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. angelica.butura@ki.se
Nilsson
Kerstin
K
Morgan
Kengathevy
K
Morgan
Timothy R
TR
French
Samuel W
SW
Johansson
Inger
I
Schuppe-Koistinen
Ina
I
Ingelman-Sundberg
Magnus
M
D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D005235:Fatty Liver, Alcoholic / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053538:Keratin-18 / Q000235:genetics; D053533:Keratin-8 / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics
D053538:Keratin-18; D053533:Keratin-8; D012313:RNA; D019392:Cytochrome P-450 CYP2E1