Minoru Yasuhara

Changes in blood acetaldehyde levels after ethanol administration in alcoholics

Serial changes in blood ethanol (Et-OH) and acetaldehyde (Ac-CHO) levels following a single oral administration of 0.8 g/kg of Et-OH were determined in order to clarify the metabolism of Ac-CHO in alcoholic liver disease (ALD). The Et-OH metabolic rate (EMR) in alcoholics either with or without liver disease was significantly higher than the rate in nonalcoholics. Peak values of blood Ac-CHO levels and the Ac-CHO/EMR ratios in ALD were significantly higher than those in subjects with nonALD or alcoholics and nonalcoholics without liver disease. In the type I aldehyde dehydrogenase isozyme deficient cases (unusual type), blood Ac-CHO levels and Ac-CHO/EMR ratios were very high and the levels remain at a plateau until 90 minutes after Et-OH administration and then decreased relatively quickly. Changes in blood Ac-CHO levels and Ac-CHO/EMR ratios in ALD were similar to those in cases of the unusual type. These results indicate that Ac-CHO metabolism in ALD is decreased relative to its production and that this decrease might be due to increased production of Ac-CHO in the nonalcohol dehydrogenase pathway located in the microsomes, in which degradation of Ac-CHO was slow.

Effects of ethanol on the secretion of hepatic secretory protein in rat alcoholic liver injury.

It has been pointed out that one of the pathogenetic causes of alcoholic liver injury is the hepatocytic accumulation of exportable proteins due to a decrease in hepatic microtubules caused by acetaldehyde. To confirm and extend this secretory protein accumulation in the hepatocytes, the effects of alcohol treatment on the intracellular transport of secretory protein in the hepatocyte was studied using radioisotope-labeled leucine and fucose. Acute ethanol administration to rats did not show any effects on intrahepatocytic transport and secretion of transferrin. In alcohol pyrazole hepatitis rats, the secretion of transferrin labeled with both radioactive leucine and fucose into the serum was significantly delayed. Delaying in the secretion of fucose-labeled transferrin was more prominent than in leucine-labeled transferrin. This secretory inhibition was accompanied by a corresponding increase in the hepatic retention of both leucine- and fucose-labeled transferrin. At the time of the maximum inhibition of secretion, radioisotope labeled transferrin mainly retained in the Golgi apparatus. These results indicated that movement of secretory proteins along the secretory pathway impaired in alcoholic liver injury and that accumulation of the secretory proteins might play an important role in the development of alcoholic liver injury.

Effects of malotilate treatment on the serum markers of hepatic fibrogenesis in liver cirrhosis

SummaryMalotilate, a hepatotropic agent, was given to 39 cirrhotic patients for more than 32 weeks. The serial changes in the serum levels of hepatic fibrogenesis markers, such as procollagen type III N-terminal peptides (P-III-N-P) and immunoreactive prolyl hydroxylase beta-subunit (IR-BPH) were analyzed. Serum albumin levels, transaminase and choline esterase activities and the Normotest values were found to be significantly improved by malotilate treatment. The levels of both serum markers of hepatic fibrogenesis were also significantly reduced by malotilate. The prognoses of the decompensated liver cirrhosis patients treated with malotilate were significantly better than those who did not receive malotilate. These results indicate that the effects of malotilate on chronic liver diseases are not simply biocosmetic, but rather are related to an improvement in the basal changes of the liver, including a decrease in the fibrogenetic stimulus. These effects of malotilate improved the prognosis of liver cirrhosis.

Comparison of ballooned hepatocytes in alcoholic and non-alcoholic liver injury in rats.

Ballooned hepatocytes are commonly observed in alcoholic and sometimes in non-alcoholic liver diseases. To clarify whether pathogenesis of this change is different in alcoholic and non-alcoholic liver diseases, changes of the livers in rats fed alcohol with pyrazole for 12 weeks were compared with those of CCl4 treated rats. Both groups of rats showed marked ballooning of the hepatocytes in the centrolobular area. Immunohistochemically, the ballooned hepatocytes in alcohol-pyrazole treated rats reacted strongly with transferrin and albumin staining. However, staining reaction of the ballooned hepatocytes in the CCl4 treated rats was slight. In alcohol-pyrazole treated rats, hepatic microtubules were significantly decreased. Retention of transferrin and albumin were found only in the ballooned hepatocytes of alcohol-pyrazole treated rats. However, in the CCl4 treated rats, neither microtubular alteration nor retention of the exportable proteins was observed. These findings indicate that the pathogenesis of ballooning of hepatocytes is different in alcoholic and non-alcoholic liver injuries. In alcoholic liver injury, microtubular alteration may lead to retention of protein and ballooning of hepatocytes by interfering with the hepatic secretion of proteins.

Effects of malotilate treatment on alcoholic liver disease

Malotilate, a new hepatotrophic drug, improves serum transaminase levels and the markers of protein metabolism in the liver in chronic liver diseases. However, the effects of malotilate on alcoholic liver disease are not well known. In the present study, the effects of this drug on the recovery process of alcoholic liver disease after abstinence were analyzed. Many hepatic test values were significantly improved after abstinence from alcohol in both the malotilate-treated and nontreated control groups. However, the Normotest values improved significantly only in the malotilate group, and not in the control group. The improvement rates for choline esterase activity were significantly greater in the malotilate group than in the control group. Serum albumin levels significantly increased in the malotilate group but not in the control group. Changes in the serum markers of hepatic fibrogenesis were not different between the 2 groups. These results indicate that malotilate accelerates the recovery of impaired protein metabolism in alcoholic liver disease and that this drug may be useful for the treatment of alcoholic liver diseases.