Cellular and subcellular localization of acetaldehyde-protein adducts in liver biopsies from alcoholic patients.

Abstract

Acetaldehyde, the first product of ethanol in hepatocytes, can react with protein to form acetaldehyde-protein adducts (APAs). Because it has been suggested that these adducts could be involved in the pathogenesis of ethanol-induced hepatic lesions and in fibrogenesis, we performed an ultrastructural immunohistochemical study to precisely define the cellular and subcellular localization of APAs. A preembedding technique of indirect immunoperoxidase was performed in liver biopsy specimens from eight patients with alcoholic liver disease, using a specific antiserum against APAs. In all specimens, APAs were detected in the rough endoplasmic reticulum, in some peroxisomes, and in the cytosol of hepatocytes. In four patients with steatofibrosis or cirrhosis, labeling of Ito cells was also observed. In these cases, the same staining pattern was observed in the cytoplasmic processes of myofibroblasts in areas of fibrogenesis. When isolated rat Ito cells were incubated in the presence of acetaldehyde, APAs were also detected in the cytoplasm. These results show that APA formation occurs in hepatocytes at the sites of acetaldehyde production. Detection of APAs in human and rat Ito cells strongly suggests that acetaldehyde can diffuse into Ito cells and bind to cytoplasmic proteins to form local APAs. Because Ito cells are the main effector cells of liver fibrosis, detection of APAs in these cells points to their possible involvement in liver fibrogenesis.

Acetaldehyde Adducts in Alcoholic Liver Disease

“…Acetaldehyde protein adducts are detectable in alcohol-related disease-associated inflammation and fibrosis 11,64. Ultrastructural and immunohistochemical staining methods revealed that acetaldehyde adducts are detectable in hepatic stellate cells (HSC) in the context of steatofibrosis or cirrhosis, and in myofibroblasts in zones with bridging fibrosis 65. Liver injury is likely mediated by binding of acetaldehyde to lysine residues and secondary interference with lysine-dependent enzymes such as calmodulin, and also tubulin 11.…”

Induction of cytochrome P450 enzymes and generation of protein-aldehyde adducts are associated with sex-dependent sensitivity to alcohol-induced liver disease in micropigs

“…1,[4][5][6] The appearance of aldehyde-protein adducts in zone 3 hepatocytes has been shown to be a typical feature of alcohol-induced liver disease. 5,7,8 Our previous follow-up studies in ethanol-fed micropigs have shown that the formation of aldehyde adducts in the liver coincide with elevation of serum transaminases and progressive histopathology. 7 High levels of reactive aldehydic products in the liver also appear to be associated with activation of fibrogenesis.…”

Autoimmune Responses Against Oxidant Stress and Acetaldehyde‐Derived Epitopes in Human Alcohol Consumers

“…It may be speculated that ethanol-induced oxidative stress could also aggravate injurious effects of ethanol in several target tissues through adverse immune responses. To date, the existence of acetaldehyde-and malondialdehyde-derived protein epitopes in tissues have, however, only been demonstrated from the liver ( Halsted et al, 1993;Holstege et al, 1994;Niemela et al, 1991Niemela et al, , 1994Niemela et al, , 1995Paradis et al, 1996). Nevertheless, the fact that the antibodies against oxidant stress derived epitopes consist primarily of IgGs is noteworthy since IgG antibodies are known to be the primary mediators of several harmful immunologic consequences, including activation of the complement system, induction of cytotoxic reactions, and release of tissue-damaging mediators, such as proteases and oxygen radicals (Johnson et al, 1994).…”