Related Experiment Video
Updated: Jan 12, 2026
The Murine Choline-Deficient, Ethionine-Supplemented CDE Diet Model of Chronic Liver Injury
Published on: October 21, 2017
Cytochrome P450 as possible link between Mallory-Denk body formation in DDC-intoxicated mouse liver and human
Cornelia Stumptner1, Karoline Fechter1, Kurt Zatloukal1
1Diagnostic and Research Institute of Pathology, Center of Molecular Biomedicine, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010, Graz, Austria.
Abstract:
Mallory-Denk bodies (MDBs) are hepatocytic inclusions in alcohol-related (ASH) and metabolic dysfunction-associated (MASH) steatohepatitis as well as in some other apparently etiologically different chronic human liver disorders. They are experimentally induced in mouse liver by chronic intoxication with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Like in human diseases, mouse liver MDBs consist of stress proteins as major components indicating their relationship to chronic cellular stress. Mouse livers at different stages of DDC intoxication, recovery, and re-intoxication were analyzed with regard to cytochrome P450 (CYP) expression, enzyme activity, oxidative stress, and anti-oxidative response. mRNAs of cytochrome P450 2A5 (CYP2A5), heme oxygenase-1 (Hmox-1), and the ubiquitin-binding adapter protein p62/sequestosome1 (p62) were significantly elevated by DDC treatment. CYP2A5 protein correlated at the cellular level with the presence of MDBs, and CYP2A5-related coumarin 7-hydroxylase (COH) activity was increased in relation to MDB expression. A functional relationship between CYP2A5 and Hmox-1 activity was established by the identification of bilirubin as a potent inhibitor of the production of reactive oxygen species (ROS) by CYP2A5. Moreover, CYP2E1 as well as CYP2A6, which are induced in human steatohepatitis, showed similar H2O2 production and inhibition by bilirubin in vitro. These findings suggest similar pathogenic mechanisms involved in MDB formation related to the overexpression of ROS-producing CYP2A5 in mice and CYP2E1 and CYP2A6 in human steatohepatitis.
Insights
Mallory-Denk bodies (MDBs) in liver disease are linked to cellular stress. Researchers found that cytochrome P450 (CYP) enzymes, specifically CYP2A5 in mice and CYP2E1/CYP2A6 in humans, contribute to MDB formation through reactive oxygen species (ROS) production.
Area of Science:
- Hepatology
- Biochemistry
- Cellular Biology
Background:
- Mallory-Denk bodies (MDBs) are protein inclusions found in various chronic liver diseases, including alcohol-related (ASH) and metabolic dysfunction-associated steatohepatitis (MASH).
- MDBs are associated with chronic cellular stress and can be experimentally induced in mice using 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC).
Purpose of the Study:
- To investigate the role of cytochrome P450 (CYP) enzymes and oxidative stress in the formation of MDBs.
- To explore the relationship between CYP expression, enzyme activity, and cellular stress responses during MDB development.
Main Methods:
- Mice were subjected to chronic DDC intoxication, followed by recovery and re-intoxication.
- Analysis included gene expression (mRNA) of CYP2A5, heme oxygenase-1 (Hmox-1), and p62, as well as CYP protein levels and coumarin 7-hydroxylase (COH) activity.
- In vitro experiments assessed reactive oxygen species (ROS) production by CYPs and inhibition by bilirubin.
Main Results:
- DDC treatment significantly elevated mRNA levels of CYP2A5, Hmox-1, and p62.
- CYP2A5 protein expression correlated with MDB presence, and CYP2A5 activity (COH) increased with MDB formation.
- Bilirubin was identified as an inhibitor of CYP2A5-induced ROS production. Human steatohepatitis-associated CYPs (CYP2E1, CYP2A6) showed similar ROS production and bilirubin inhibition.
Conclusions:
- Overexpression of ROS-producing CYP2A5 in mice and CYP2E1/CYP2A6 in humans may represent a common pathogenic mechanism in MDB formation.
- These findings highlight the role of specific CYP enzymes and oxidative stress in the pathogenesis of MDB-associated liver disorders.
