Early Alcoholic Liver Injury: Formation of Protein Adducts with Acetaldehyde and Lipid Peroxidation Products, and Expression of CYP2E1 AND CYP3A

Abstract

The formation of protein adducts with reactive aldehydes resulting from ethanol metabolism and lipid peroxidation has been suggested to play a role in the pathogenesis of alcoholic liver injury. To gain further insight on the contribution of such aldehydes in alcoholic liver disease, we have compared the appearance of acetaldehyde, malondialdehyde, and 4-hydroxynonenal adducts with the expression of cytochrome P-450IIE1, and cytochrome P-4503A enzymes in the liver of rats fed alcohol with a high-fat diet for 2 to 4 weeks according to the Tsukamoto-French procedure and in control rats (high-fat liquid diet or no treatment). Urine alcohol and serum aminotransferase levels were recorded, and the liver pathology was scored from 0 to 10 according to the presence of steatosis, inflammation, necrosis, and fibrosis. The ethanol treatment resulted in the accumulation of fat, mild necrosis and inflammation, and a mean liver pathology score of 3 (range: 1 to 5). Liver specimens from the ethanol-fed animals with early alcohol-induced liver injury were found to contain perivenular, hepatocellular acetaldehyde adducts. Malondialdehyde and 4-hydroxynonenal adducts were also present showing a more diffuse staining pattern with occasional sinusoidal reactions. In the control animals, a faint positive reaction for the hydroxynonenal adduct occurred in some of the animals fed the high fat diet, whereas no specific staining was observed in the livers from the animals receiving no treatment. Expression of both CYP2E1 and CYP3A correlated with the amount of protein adducts in the liver of alcohol-treated rats. Distinct CYP2E1-positive immunohistochemistry was seen in 3 of 7 of the ethanol-fed animals. In 5 of 7 of the ethanol-fed animals, the staining intensities for CYP3A markedly exceeded those obtained from the controls. The present findings indicate that acetaldehyde and lipid peroxidation-derived adducts are generated in the early phase of alcohol-induced liver disease. The formation of protein adducts appears to be accompanied by induction of both CYP2E1 and CYP3A.

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

“…Autoantibodies against MMA were significantly elevated in sera of chronic alcoholexposed animals [46] and in patients with ALD, and the titers are correlated with the severity of liver damage [11,47,48] and progression of liver fibrosis. Interestingly, adducts accumulate in perivenous regions both in alcohol-fed rats [49,50] and in the liver of alcoholics [51,52] , overlapping with the distribution of fatty accumulation.…”

Preventive Effects of Puerarin on Alcohol-induced Osteonecrosis

“…Furthermore, the direct cytotoxicity of lipid peroxidation, caused by alcohol and its metabolites, might further insult ischemic osteocytes, resulting in an irreversible state of injury leading to cell death and finally ON. In addition, alcohol consumption produces a fatty liver and alcoholic liver injury [17,31,37]. Serum triglyceride and cholesterol levels increase, fat degeneration is induced, and liver cells are injured.…”

Hydrogen peroxide: A link between acetaldehyde-elicited α1(i) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells

“…[1][2][3][4][5][6] It has been already established that in rats receiving a continuous infusion of ethanol to produce liver fibrosis and cirrhosis, there is a significant increase in aldehydes resulting from increased lipoperoxidation. 2,[33][34][35] Moreover, some of these aldehydes, including malondialdehyde and 4-hydroxy-2,3-nonenal, are also fibrogenic and enhance the production of type I collagen. [7][8][9] Recently, it has been shown that when rat liver epithelial cells are treated with 4-hydroxy-2,3-nonenal, there is induction of an oxidative stress state manifested by a significant increase in intracellular peroxides.…”