Experimental alcohol-induced hepatic necrosis: suppression by propylthiouracil.

Abstract

We have previously reported that a hypermetabolic state, resembling that produced by thyroid hormones, exists in the livers of animals treated chronically with ethanol. We propose that this alteration produces a relative hypoxia in the centrilobular zone of the liver which, if severe enough, leads to cellular death and to the production of hepatitis.Rats consuming ethanol for 30 days, given with a nutritionally adequate diet, and exposed to reduced oxygen tensions for only 6 hr, developed histological and biochemical evidence of hepatocellular necrosis and inflammatory lesions confined to the centrilobular zone. The severity was proportional to the degree of hypoxia. Pair-fed (nonalcohol) controls showed no such lesions. Treatment of the animals with propylthiouracil for 3-10 days abolished the hypermetabolic state of the liver in ethanolconsuming animals, and drastically reduced the histological and biochemical effects of hypoxia in them. These findings may have implications for pathogenesis and treatment of alcoholic hepatitis in man.Livers of rats chronically treated with ethanol utilize oxygen at higher rates than control livers (1-5). The hypermetabolic state results from increased utilization of ATP by the cell membrane (Na+K)-ATPase (ATP phosphohydrolase, EC 3.6.1.3), associated with an increase in the active transport of monovalent cations across the membrane (2, 6). We have also reported that the hypermetabolic state can be completely abolished by ouabain, an inhibitor of the (Na+K)-ATPase (2, 3).Similar changes in (Na+K)-ATPase activity, cation transport, and oxygen consumption occur in livers of animals treated with thyroid hormones, and can also be completely abolished by ouabain (3, 4, 7-10). We have also pointed out other similarities between the livers of animals chronically treated with ethanol and those treated with thyroid hormones (3, 4, 7). These similarities suggested that a functional hyperthyroid state exists in the livers of alcohol-treated animals (3, 7).In human alcoholic hepatitis (11,12), hepatocellular necrosis is most commonly seen in the central region of the hepatic lobule (zone 3 of Rappaport). Since the livers of ethanoltreated animals consume oxygen at higher rates (1-5), the possibility exists that the gradient of decreasing oxygen tension from the portal to the central venous end of the sinusoid is accentuated. We propose that, when the availability of oxygen is reduced, it is this accentuation of centrilobular hypoxia which leads to necrosis.Abbreviations: PTU, 6-propyl-2-thiouracil; SGOT, serum glutamic-oxalacetic transaminase [aspartate transferase]; SOCT, serum ornithine carbamyltransferase.To test this hypothesis we have exposed rats briefly to atmospheres with reduced oxygen tensions (5-11%). In animals treated chronically with ethanol, but not in controls, this period of hypoxia resulted in various degrees of centrilobular damage ranging from focal necrosis to massive confluent necrosis with accompanying inflammatory reaction. We have also found that a short pr...

In vivo Effect of L-Cysteine on Ethanol-Induced Alterations in Membrane-Bound ATPases of Liver and Kidney of Experimental Rats.

“…ATPase is a lipid-dependent, membrane-bound enzyme involved in active transport processes and has been implicated in the pathogenesis of ethanol-induced liver cell injury [14]. In our study we observed that the activities of Nat, K+-ATPase in liver and kidney were decreased significantly.…”

Stimulation of hepatic sodium and potassium-activated adenosine triphosphatase activity by phenobarbital. Its possible role in regulation of bile flow.

“…Consistent with previous studies (53,71) (21) have demonstrated that thyroid hormone increases (Na+-K+)-ATPase and Layden and Boyer (55) recently have shown that this altered enzyme activity is associated with changes in bile salt independent flow. Since thyroid hormone has also been implicated in the increased hepatic (Na+-K+)-ATPase activity of chronic alcohol ingestion in rats (77,78), we investigated whether thyroxine may also mediate the hepatic response to phenobarbital. Hypothyroidism was confirmed by unmeasurable serum thyroxine binding capacity in untreated and phenobarbital-treated rats.…”

Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice

“…The mitochondrial pellet was dissolved in isolation buffer containing 18% Percoll and centrifuged at 10,000 ϫ g for 10 min. The mitochondrial pellet was gently removed from the Percoll solution and layered on top of three discontinuous Percoll gradient tubes (18,30, and 60%). The Percoll gradient was spun at 30,700 ϫ g for 5 min at 4°C.…”

“…The liver adapts to alcohol and develops an enhanced capacity to metabolize alcohol following feeding (13,16,17). This enhanced capacity to metabolize alcohol is associated with increased oxygen uptake by the liver (13,18,19), suggesting that there is greater mitochondrial respiration in these hepatocytes. ADH and ALDH2 levels do not change with alcohol feeding, suggesting that adaptation to alcohol occurs through mitochondrial alterations or other pathways (15)(16)(17).…”