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Role of cytochrome P4502E1 in alcoholic liver disease pathogenesis |
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| Authors: | M Morimoto A-L Hagbjrk AA Nanji M Ingelman-Sundberg KO Lindros PC Fu E Albano SW French |
| Institution: | * Department of Pathology, Harbor-UCLA Medical Center, Torrance, CA 90509, USA † Department of Physiological Chemistry, Karolinska Institute, Stockholm, Sweden ‡ Department of Pathology, New England Deaconess Hospital and Harvard Medical School, Boston, MA, USA § Research Laboratories of the State Alcohol Monopoly (Alko), Helsinki, Finland ¶ Department of Experimental Medicine and Oncology, University of Torino, Torino, Italy |
| Abstract: | The intragastric tube feeding model is ideal for the study of the role of dietary factors and the effect of drugs on experimental alcoholic liver disease (ALD), since the model allows us to study the effect of a single variable in the diet on the pathology of liver where the blood alcohol level (BAL) is maintained over 150 mg%. By varying the dietary fatty acid composition we showed that the pathology was worsened by increasing linoleic acid or polyunsaturated fatty acids (PUFAs) in the diet where cytochrome P4502E1 (CYP2E1) was increased posttranslationally by high BAL. Concomitant with the increase in CYP2E1 there was evidence for an increase in lipid peroxidation (LP) by microsomes. Protein adducts of the products of LP were increased in the blood. Isoniazid (INH) enhanced this process and the pathology of ALD when INH was fed at therapeutic levels with ethanol. Preliminary studies show that diallyl sulfide, which inhibits and destroys liver CYP2E1 selectively, also modified the pathologic effects of ethanol. Thus we postulate that CYP2E1 induction plays a central role in the pathogenesis of ALD. |
| Keywords: | ALD model Lipid peroxidation PUFA Fatty acid Linoleic acid Protein adducts Diallyl sulfide Cytochrome P4502E1 |
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