alpha-chymotrypsin and Liver-Diseases--Alcoholic

The variety of animal models used in the study of alcoholic liver disease reflects the formidable task of developing a model that replicates the human disease. We show that oral feeding of fatty acids derived from fish oil and ethanol induces fatty liver, necrosis, inflammation, and fibrosis. Together with the study of oxidative and nitrosative stress markers, cytokines, proteasome function, and protein studies, this model has provided an inexpensive and technically simple method of establishing pathological alcoholic liver injury.

Topics: Administration, Oral; Alanine Transaminase; Alcohol Drinking; Animals; Blotting, Western; Central Nervous System Depressants; Chymotrypsin; Cytochrome P-450 CYP2E1; Dinoprost; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Endotoxins; Ethanol; Fatty Acids; Fatty Liver, Alcoholic; Female; Immunohistochemistry; Liver; Liver Diseases, Alcoholic; Oxidative Stress; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Self Administration; Specimen Handling; Staining and Labeling; Thiobarbituric Acid Reactive Substances

The purpose of this investigation was to assess the effect of chlormethiazole treatment on liver damage in the experimental rat intragastric ethanol-feeding model of alcoholic liver disease. Chlormethiazole has been used in the treatment of alcoholic withdrawal and has been shown to inhibit cytochrome P4502E1. Since treatment of experimental alcoholic liver disease with CYP2E1 inhibitors had an ameliorating effect on liver injury in the rat, chlormethiazole was used to see if it had a similar effect. Rats fed ethanol for 2 months had significantly less liver injury when chlormethiazole was added to the diet, fed intragastrically. The CYP2E1 apoprotein levels, which were increased by ethanol feeding, were also increased when chlormethiazole was fed with ethanol. Chlormethiazole inhibited the increase in the ethanol-induced CYP2E1 activity in vivo, as measured by chlorzoxazone 6-hydroxylation, but did not affect the level of CYP2E1 apoprotein. Likewise, the reduction in proteasome proteolytic enzyme activity produced by ethanol feeding was blunted in chlormethiazole-fed rats. These results support the conclusion that chlormethiazole treatment partially protects the liver from injury by inhibiting CYP2E1 activity in vivo.

Topics: Animals; Apoenzymes; Body Weight; Chlormethiazole; Chlorzoxazone; Chymotrypsin; Cysteine Endopeptidases; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; Disease Models, Animal; Ethanol; Hydroxylation; Immunohistochemistry; Liver; Liver Diseases, Alcoholic; Male; Multienzyme Complexes; Organ Size; Proteasome Endopeptidase Complex; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Trypsin

We studied 229 patients with biopsy verified liver disease and compared the plasma levels of alpha 1-antichymotrypsin and alpha 1-antitrypsin. We found a significant overall correlation between alpha 1-antichymotrypsin and alpha 1-antitrypsin levels (r = 0.50, p less than 0.001). The strongest correlations were found in patients with chronic active hepatitis (r = 0.76, p less than 0.0001) and alcohol hepatitis (r = 0.60, p less than 0.001). Several clinical subgroups lacked correlation. Unexpectedly high alpha 1-antichymotrypsin values were found in patients with venous congestion. We also used the alpha 1-antichymotrypsin/alpha 1-antitrypsin ratio as a tool to identify PiZ carriers (intermediate alpha 1-antitrypsin-deficiency, PiZ). The sensitivity and predictive values were low and did not exceed that obtained by the simple use of an isolated alpha 1-antitrypsin determination. A small subgroup with low alpha 1-antichymotrypsin/alpha 1-antitrypsin ratio included patients with chronic active hepatitis of unknown etiology. Hypo-alpha 1-antichymotrypsinemia may be secondary to the liver disease per se or be an expression of an abnormal genetic trait.

Topics: Adolescent; Adult; Aged; alpha 1-Antichymotrypsin; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Chymotrypsin; Female; Genetic Carrier Screening; Hepatitis, Alcoholic; Hepatitis, Chronic; Humans; Liver Diseases; Liver Diseases, Alcoholic; Male; Middle Aged; Phenotype