Yasuhiro Ueshima

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.

Histochemical Study of Hyaluronate in Alcoholic Liver Disease

Recently, it has been reported that serum hyaluronate (hyaluronic acid; HA) concentrations increase in various liver diseases, especially in alcoholic liver disease (ALD), and serum HA concentration has been used as a marker for hepatic fibrosis. However, it is unknown whether hepatic HA contents in ALD increase by alcohol or not. In this study, we histochemically stained HA in liver biopsy specimens obtained from ALD patients while actively drinking and after abstinence to clarify the effects of alcohol on hepatic HA contents. Liver biopsy specimens were obtained from 13 patients with ALD and 10 patients with non-ALD. In ALD patients, liver biopsy was performed twice within 3 days, and 4 to 8 weeks after abstinence when serum levels of AST and ALT normalized. HA in biopsy specimens was stained histochemically with biotinylated HA binding protein. Staining intensity of HA in liver tissue was also determined by computer-assisted imaging analyzer. HA staining was clearly observed in sinusoidal wall and fibrous regions around the portal tract and central vein in liver diseases. HA staining intensities in patients actively drinking with ALD increased markedly, compared with those in patients with non-ALD, and these intensities decreased with abstinence. These results clearly suggest that hepatic HA contents in ALD may be increased by alcohol in addition to hepatic fibrosis, and, therefore, increased HA deposition in the liver may be reversible by abstinence of alcohol.

Clinicopathological study of chronic hepatitis induced by alcohol with or without hepatitis G virus

The concept of chronic hepatitis induced by alcohol (AL-CH) has not been widely accepted, because AL-CH may be due to non-A-E hepatitis virus in heavy drinkers. Recently, hepatitis G virus (HGV) was identified as a positive-strand RNA virus related to members of the Flaviviridae family. In this study, we determined serum HGV in patients with AL-CH and analyzed the clinicopathological changes after abstinence to evaluate whether AL-CH is caused by alcohol or not. Serum samples were obtained from 16 patients with AL-CH who had neither hepatitis B nor C virus. The diagnosis was confirmed histologically. In eight patients, liver biopsy was performed twice, within 3 days and 4 to 8 weeks after abstinence. The NS3 region of the HGV genome was detected using an reverse transcriptase-polymerase chain reaction method. Serum levels of AST, ALT and -γ-glutamyltranspeptidase were measured once a week sequentially after admission. Serum HGV-RNA was detected in only one patient with AL-CH (6.3%). In all patients, including one patient with HGV, serum levels of AST, ALT and γ-glutamyltranspeptidase clearly decreased to normal levels after abstinence. Inflammatory activity in the periportal area of patients with actively drinking decreased or disappeared after abstinence for 4 to 8 weeks. These results suggest that HGV may not play an important role for development of AL-CH, and that AL-CH may be caused by alcohol itself, although a more larger number of patients with AL-CH are needed to obtain definitive conclusions.

Effects of a new orally active dopamine prodrug, docarpamine, on refractory ascites: a pilot study

OBJECTIVE:Refractory ascites is a debilitating condition in patients with cirrhosis. Recently, docarpamine, an orally active dopamine prodrug, was reported to increase renal blood flow, glomerular filtration, and sodium excretion. This suggests docarpamine may be useful for the treatment of refractory ascites.METHODS:In this study, we investigated docarpamine metabolism in cirrhotic patients and its effect on refractory ascites.RESULTS:Blood samples were obtained from seven cirrhotic patients and six healthy subjects after administration of 750 mg docarpamine, and plasma levels of free dopamine were measured. In healthy subjects, maximum plasma concentration (Cmax), time taken to reach Cmax (Tmax), elimination half-life (T1/2), and area under the plasma concentration-time curve (AUC) of plasma free dopamine were 76.8 ± 24.1 ng/ml, 1.3 ± 0.2 h, 0.8 ± 0.1 h, and 97.5 ± 21.1 ng · h /ml, respectively. In patients with cirrhosis, Cmax (53.1 ± 24.9 ng/ml), T1/2 (0.8 ± 0.1 h), and AUC (100.6 ± 45.6 ng · h /ml) were no different from healthy subjects when comparing each parameter, whereas Tmax (2.7 ± 0.2) was significantly longer than that of healthy subjects. We treated 10 cirrhotic patients with refractory ascites with docarpamine or placebo and the same dose of diuretics used before hospitalization. After 8 wk of docarpamine treatment, ascites disappeared completely in three of the five patients and decreased in the remainder. However, in five patients treated with placebo, ascites was not changed or increased. Side effects were not observed in any case.CONCLUSIONS:Docarpamine was found to metabolize in cirrhotic patients as well as in normal subjects and may be an effective treatment for refractory ascites.

Ethanol and acetaldehyde metabolism in cultured hepatocytes from chronic alcoholic rats.

SummaryIn this study the authors analyzed ethanol (Et-OH) and acetaldehyde (Ac-CHO) metabolism in cultured hepatocytes isolated from chronic alcoholic rats. Hepatocytes were isolated and cultured from two groups of rats, one was fed with a liquid diet containing Et-OH and another was pair-fed with a control diet for 4 weeks. After 48 hours of the primary culture, Et-OH was added to the culture medium at a final concentration of 5 mM with or without 2 mM 4-methyl pyrazole (Py). Serial changes of Et-OH and Ac-CHO levels in the medium for 48 hours were determined in 4 groups of the alcohol alone, alcohol-Py, control and controlPy groups. In the alcohol alone and control groups, Et-OH disappearance rates (EDR), which are roughly equivalent to Et-OH oxidation rates in the hepatocytes, were significantly higher than those in the corresponding Py treated groups. In the two alcoholic groups, the EDR was significantly higher than those in the corresponding control groups. In cultured hepatocytes, 75–80% of Ac-CHO produced from Et-OH was oxidized. The increasing rates of Ac-CHO (AcICR), a function of Ac-CHO production and oxidation rates in the hepatocytes, increased in parallel with the increase in the EDR. However, the AcICR/EDR rate, which is a parameter of the Ac-CHO oxidation rate in the hepatocytes, was not different among the 4 groups. These results indicate that the cultured cells maintain the characteristics of Et-OH metabolism in chronic alcoholic rats and may also be used for the study of Et-OH and Ac-CHO metabolism as anin vitro model.

Pharmacokinetics of roxatidine acetate in patients with chronic liver disease

Background and Aim: Patients with liver disease are prone to develop peptic ulceration and often receive H2‐receptor antagonists. Therefore, it is important to clarify whether the pharmacokinetics of H2‐receptor antagonists is affected by hepatic function. However, pharmacokinetics of a new H2‐receptor antagonist, roxatidine acetate, in chronic liver disease has not been well known. In this study, we analyzed the pharmacokinetics of roxatidine in patients with liver disease.