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tion.1 Ach has been shown to be capable of conjugating covaChronic ethanol ingestion has been suggested to triglently with exposed proteins, particularly under reducing ger the formation of antibodies that recognize acetaldeconditions, and these modified proteins, in turn, may trigger hyde-protein condensates. In this study, assays for imIg formation that is directed against Ach-derived protein admunoglobulin (Ig) A, IgG, and IgM antibodies to ducts. [2][3][4][5][6][7] Previous studies have indicated that antibodies recacetaldehyde-derived adducts were performed on sera ognizing Ach adducts of proteins are found from sera of paof 140 alcohol consumers, 19 patients with nonalcoholic tients with ALD [3][4][5][6][7] ; however, such antibodies have also been liver disease (NALD), 35 healthy nondrinking controls, found to occur in patients with nonalcoholic liver disease and 10 nondrinking patients with IgA or IgG myeloma.(NALD). 3,4 Although Igs are known to exhibit remarkable Anti-acetaldehyde (Ach)-adduct antibodies of each Ig diversity, with respect to their physical characteristics and isotype were found from the alcohol abusers. In alcoeffector functions, only a limited number of studies have adholic liver disease (ALD, n Å 86) IgA titers were elevated dressed the expression of the different isotypic variants of in 69% of the patients. These titers were significantly the antibodies against Ach-derived adducts in consumers of higher than those from patients with NALD (P õ .001), alcohol. The question whether the formation of antibodies is nondrinking controls (P õ .001), or heavy drinkers (n Å directly related to the amount of alcohol consumed or with 54) without any clinical and biochemical signs of liver presence of liver disease has also remained unclear. disease (P õ .001). In contrast, anti-adduct IgG titersWorrall et al. 6 have previously reported that the antibody were significantly elevated both in ALD and in heavy responses against Ach-modified proteins in alcoholics consist drinkers as compared with patients with NALD (P õ exclusively of IgA; IgG and IgM were not found to differ be-.001) or nondrinking controls (P õ .01 and P õ .05, retween alcoholics and nonalcoholics because IgG response was spectively). The anti-adduct immunoglobulin (Ig)A, IgG, negligible in all subjects and because IgM activities were high and IgM titers in patients with alcoholic liver disease in both alcoholic patients and social drinkers. Because the (ALD) correlated with the combined clinical and laboraIgA titers were also found to correlate with the amount of tory index of liver disease severity (r s Å .497, P õ .001; r s alcohol consumed, not with the degree of liver disease sever-Å .361, P õ .01; and r s Å .322, P õ .01). Anti-adduct IgA ity as assessed by biochemical data, 6 it was further suggested titers also correlated with serum bilirubin (r Å .768, P õ that such titers could serve as markers of alcohol consump-.001) and interleukin 6 (r Å .504, P õ .001). Anti-adduct tion. IgG titers were, in turn, found to correlate ...

To assess possible links between ethanol-induced oxidant stress, expression of hepatic cytochrome P450 (CYP) enzymes, and sex steroid status, we used immunohistochemical methods to compare the generation of protein adducts of acetaldehyde (AA), malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE) with the amounts of CYP2E1, CYP2A, and CYP3A in the livers of castrated and noncastrated male micropigs fed ethanol for 12 months. In castrated micropigs, ethanol feeding resulted in accumulation of fat, hepatocellular necrosis, inflammation, and centrilobular fibrosis, whereas only minimal histopathology was observed in their noncastrated counterparts. CYP2A and CYP3A were more prominent in the castrated animals than in the noncastrated micropigs. Ethanol feeding increased the hepatic content of all CYP forms. The most significant increases occurred in CYP2E1 and CYP3A in the noncastrated animals and in CYP2E1 and CYP2A in the castrated animals. Ethanol-fed castrated animals also showed the greatest abundance of perivenular adducts of AA, MDA, and HNE. In the noncastrated ethanol-fed micropigs a low expression of each CYP form was associated with scant evidence of aldehyde-protein adducts. Significant correlations emerged between the levels of different CYP forms, protein adducts, and plasma levels of sex steroids. The present findings indicate that the generation of proteinaldehyde adducts is associated with the induction of several cytochrome enzymes in a sex steroid-dependent manner. It appears that the premature, juvenile, metabolic phenotype, as induced by castration, favors liver damage. The present findings should be implicated in studies on the gender differences on the adverse effects of ethanol in the liver.

The present results indicated that autoantibodies against several distinct types of protein modifications are generated in ALD patients showing an association with the severity of liver disease.

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