Metabolic alterations produced in the liver by chronic ethanol administration. Increased oxidative capacity

Abstract

1. Administration of ethanol (14g/day per kg) for 21-26 days to rats increases the ability of the animals to metabolize ethanol, without concomitant changes in the activities of liver alcohol dehydrogenase or catalase. 2. Liver slices from rats chronically treated with ethanol showed a significant increase (40-60%/) in the rate of 02 consumption over that of slices from control animals. The effect of uncoupling agents such as dinitrophenol and arsenate was completely lost after chronic treatment with ethanol. 3. Isolated mitochondria prepared from animals chronically treated with ethanol showed no changes in state 3 or state 4 respiration, ADP/O ratio, respiratory control ratio or in the dinitrophenol effect when succinate was used as substrate. With f-hydroxybutyrate as substrate a small but statistically significant decrease was found in the ADP/O ratio but not in the other parameters or in the dinitrophenol effect. Further, no changes in mitochondrial Mg2+-activated adenosine triphosphatase, dinitrophenol-activated adenosine triphosphatase or in the dinitrophenol-activated adenosine triphosphatase/Mg2+-activated adenosine triphosphatase ratio were found as a result of the chronic ethanol treatment. 4. Liver microsomal NADPH oxidase activity, a H202-producing system, was increased by 80-100 % by chronic ethanol treatment. Oxidation offormate to CO2 in vivo was also increased in these animals. The increase in formate metabolism could theoretically be accounted for by an increased production of H202 by the NADPH oxidase system plus formate peroxidation by catalase. However, an increased production of H202 and oxidation of ethanol by the catalase system could not account for more than 10-20% of the increased ethanol metabolism in the animals chronically treated with ethanol. 5. Results presented indicate that chronic ethanol ingestion results in a faster mitochondrial 02 consumption in situ suggesting a faster NADH reoxidation. Although only a minor change in mitochondrial coupling was observed with isolated mitochondria, the possibility of an uncoupling in the intact cell cannot be completely discarded. Regardless of the mechanism, these changes could lead to an increased metabolism of ethanol and of other endogenous substrates.Previous studies by our group (Videla & Israel, 1970) indicate that the rate of ethanol metabolism by the liver depends on the rate of mitochondrial reoxidation of the cytoplasmic NADH produced in the oxidation of ethanol. Uncoupling agents such as 2,4-dinitrophenol or arsenate were shown to increase markedly the rate of ethanol metabolism by normal rat liver slices. Dinitrophenol was also shown to be effective in increasing the rate of ethanol metabolism in vivo . However, although dinitrophenol increased the ethanol metabolism in liver slices from control animals, it was not effective in those from animals chronically treated with ethanol, in which the rate of ethanol metabolism had already been increased. This suggested that the rate ofethanol metabolism in these animals was no longer ...

Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice

“…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). Could mitochondria in the liver undergo plasticity changes to help enhance alcohol metabolism?…”

“…Both ADH and ALDH2 are kinetically limited by NAD ϩ , with the levels of NAD ϩ being dependent on mitochondrial respiration, which oxidizes NADH to NAD ϩ (13)(14)(15). 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.…”

Experimental alcohol-induced hepatic necrosis: suppression by propylthiouracil.

“…Since the livers of ethanoltreated animals consume oxygen at higher rates (1)(2)(3)(4)(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.…”

“…Livers of rats chronically treated with ethanol utilize oxygen at higher rates than control livers (1)(2)(3)(4)(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).…”

“…Rats were fed liquid diets containing 35% of the total calories as ethanol or as isocaloric sucrose for 28-49 days, as described by Videla et al (1). PTU (5 mg/100 g daily) was given by stomach tube for 3-21 days, starting after 28 days on the ethanol or sucrose diets.…”