Comparison of thermally oxidized lipids and acetaminophen with concurrent consumption of ethanol as inducers of liver cirrhosis

Abstract

The mechanism(s) of liver damage initiated by ingestion of toxic components of thermally oxidized lipids was compared in a rat model with the documented mechanisms of hepatic failure and necrosis initiated by acetaminophen. Acetaminophen (50 mg/kg body weight) or oxidized lipids (0.15 ml oxidized trilinolein or 1.05 ml oxidized butter oil per rat) were intubated at 12-h intervals to rats. Treated rats were allowed free access to food and water containing 3% ethanol. Changes in relative concentration of acute-phase plasma proteins, determined by two-dimensional (2D) immunoelectrophoresis, were taken as a marker of liver damage. In contrast to simple inflammation, acute-phase plasma proteins in this study disproportionately increased or decreased as histological damage of the liver due to intubation oxidized lipids or acetaminophen. Histological examination of liver of rats intoxicated with oxidized lipids revealed severe liver cirrhosis at the end of the trial, where the remaining viable hepatocytes were separated in a matrix of collagen. [3H1]Thymidine incorporation in hepatic DNA of acetaminophen or oxidized lipid intoxication increased in the early stages of intoxication, indicative of regenerative activity of the liver. Further progression of the cirrhosis inhibited continued liver regeneration and [3H1]thymidine incorporation into hepatic DNA. The cirrhotic liver at this stage failed to regenerate to the original mass upon 75% partial hepatectomy. Therefore, it may be concluded that hepatic necrosis produced by oxidized lipids or by acetaminophen may have similar mechanisms.

Acute-Phase Response in Rat to Carbon Tetrachloride-Azathioprine Induced Cirrhosis and Partial Hepatectomy of Cirrhotic Liver

“…This may be accounted for by assuming that the reduction in the number of rough endoplasmic reticulumbound polyribosomes per volume of cytoplasm due to early intoxication with CCl 4 and azathioprine is counteracted at later stages of the developing liver cirrhosis by increased translation of mRNA by rough endoplasmic reticulum-bound polyribosomes. This proposition is similar to those of earlier reports on livers made cirrhotic by intubation of oxidized lipids or acetaminophen (Fouad et al, 1995) or by supplementing drinking water of rats with thioacetam ide and suggests a general trend of APR to cirrhotic insults that may provide guidance for further research on underlying mechanisms of selective hepatic protein synthesis in the milieu of chronic active liver cirrhosis. At later stages of cirrhosis, hepatocytes failed to regenera te and to biosynthesize some intracellular and nuclear proteins while maintaining efficient biosynthesis of some APR proteins.…”

“…While the mechanism of the cellular response manifested as immune suppression to the administration of azathioprine is not understood (Reuber, 1970), the drug appears to act chiefly on cell nucleoprotein, and most likely on nucleic acid synthesis (Dameshek & Schwartz, 1960). In a closely related study on toxin-induced liver cirrhosis, the precise function of ethanol as a cofactor in accelerating liver cirrhosis in rats intubated with acetaminophen or oxidized lipids remains unknow n, as partially hepatectomized control rats allowed free access to 3% ethanol in drinking water showed pathology similar to partially hepatectomized rats without access to ethanol (Fouad et al, 1995).…”

“…Histologic examination of rat liver made cirrhotic by supplementing drinking water with thioacetamide , or by intubating rats with 4-acetamidophenol or oxidized triacylglycerols and concomitantly supplementing drinking water with ethanol (Fouad et al, 1995), revealed a significant reduction in the number of viable hepatic parenchymal cells. The remaining viable hepatocytes, scattered in a matrix of collagen although metabolically fatigued, disproportionally biosynthesized and released higher concentrations of some APR proteins in atypical patterns.…”

“…The remaining viable hepatocytes, scattered in a matrix of collagen although metabolically fatigued, disproportionally biosynthesized and released higher concentrations of some APR proteins in atypical patterns. For example, haptoglobin, -lipoprotein, -1-antitrypsin, and transferrin were greatly increased wherea s C3c + C3, albumin, -1-acid glycoprotein, and -1-lipoprotein were low and never recovered to values of healthy animals and these cirrhotic livers failed to regenerate upon partial hepatectomy (PH) (Fouad et al, , 1995.…”

“…The term acute-phase reaction (APR) is generally considered to refer to significant changes in concentrations of certain plasma proteins that increase or decrease during the course of inflammation (Koj, 1974) and regress to healthy levels upon cessation of the inflammatory insult (Scherer et al, 1977). In order to establish the significance of APR in various cirrhotic liver rat models and inquire into the efficiency of cirrhotic liver to biosynthesize secretable and intracellular proteins, changes in APR to azathioprine-and CCl 4 -induced liver cirrhosis were measured and compared to APR changes in response to alterations reported for liver cirrhosis produced by ingestion of acetaminophen or oxidized oil (Fouad et al, 1995) or thioacetamide . In addition, CCl 4 -azathioprine cirrhotic livers were partially hepatectomized to determine whether the remaining 25% liver may proliferate and improve its pathology.…”