C. Di Padova

Effect of the variations of S-adenosyl-l-methionine liver content on fat accumulation and ethanol metabolism in ethanol-intoxicated rats

The protective effect of S-adenosyl-L-methionine against rat liver steatosis induced by chronic ethanol ingestion was investigated. S-Adenosyl-L-methionine given during ethanol treatment prevented steatosis and accelerated recovery from steatosis when given after ethanol withdrawal. It also caused a slight inhibition of blood ethanol consumption in both acutely and chronically intoxicated rats. About 30% inhibition of alcohol dehydrogenase, but not of the microsomal ethanol oxidation system, occurred in rats subjected to acute ethanol toxicity as well as in normal rats as a consequence of S-adenosyl-L-methionine treatment. A comparison between S-adenosyl-L-methionine and pyrazole, as concerns inhibition of ethanol oxidation and fat accumulation, revealed that a greater inhibition of ethanol metabolism by pyrazole was associated with incomplete prevention of steatosis, while a lower inhibition by S-adenosyl-L-methionine was coupled to a complete prevention. Ethanol induced a drastic decrease of reduced glutathione liver content as well as 630 and 133% increases of blood and liver acetaldehyde contents, respectively. S-Adenosyl-L-methionine treatment almost completely reconstituted the liver reduced glutathione pool and caused a large decrease of the liver and blood acetaldehyde contents. 1-Chloro-2,4-dinitrobenzene, which depletes the cellular reduced glutathione, and diethylethanolamine, an inhibitor of the phosphatidylethanolamine methylation, abolished the S-adenosyl-L-methionine-induced modifications of the reduced glutathione, acetaldehyde, and triacylglycerol contents in the liver of ethanol-treated rats. Neither S-adenosyl-L-methionine nor reduced glutathione inhibitors affected the liver acetaldehyde dehydrogenase activity. It is suggested that, although S-adenosyl-L-methionine induced a small inhibition of ethanol metabolism in the liver, its antisteatosic effect could largely depend on its role as a modulator of the reduced glutathione liver content.

Impaired antipneumococcal antibody production in patients without spleens.

Fifteen splenectomised and 15 normal subjects were studied, in absence of any intentional immunisation, for pokeweed mitogen induced synthesis of antipneumococcal capsular polysaccharide antibodies in vitro by peripheral blood mononuclear cells. Results showed that removal of the spleen had caused a persistent immune deficiency of circulating B cells capable of synthesising IgM antipneumococcal capsular polysaccharide. In vitro synthesis of polyclonal IgM and IgG by peripheral blood mononuclear cells of subjects without spleens was also depressed. These defects were due to an abnormality of the B cell compartment. These data are evidence of the major role of the spleen in the control and production of a consistent part of pokeweed mitogen responsive circulating B cells and add another facet to the complex immune dysfunction of splenectomised subjects. The findings, moreover, may help in understanding the susceptibility of splenectomised people to pneumococcal sepsis and the delayed and impaired antibody response to pneumococcal vaccine.

Effects of Phlebotomy on Urinary Porphyrin Pattern and Liver Histology in Patients with Porphyria Cutanea Tarda

Urinary porphyrin profiles and liver histology have been investigated in a group of adult alcoholics with porphyria cutanea tarda (PCT) before and after one year phlebotomy. Both parameters were evaluated during the same period in a group of patients who did not undergo specific therapy for PCT. All patients were advised to abstain from alcohol. At the end of the one year observation period there was a significant fall of urinary total porphyrins and in the uro/coproporphyrin ratio in treated patients compared to basal values whereas no changes were found in controls. Liver biopsy findings revealed a significant reduction of hepatic fatty degeneration and siderosis with no changes in inflammatory infiltrates and fibrosis in treated patients, so the progression of liver disease was similar to controls. These results show that clinical and biochemical remission of PCT can occur independently of the evolution of the concomitant liver disease.

Effect of S-adenosyl-L-methionine on ethynylestradiol-induced impairment of bile flow in female rats

Prevention by S-adenosyl-L-methionine (SAMe) of the bile flow reduction induced by ethynylestradiol (EE) is demonstrated by comparing the flow rate and the bile salt concentration of bile in EE-treated animals with that in animals given both EE and SAMe.

Decreased Blood Levels of Ethanol and Acetaldehyde by S-Adenosyl-L-Methionine in Humans

In view of the protective effects of SAM on alcohol-induced fatty liver degeneration, an investigation has been carried out to see if this compound accelerates the clearance of ethanol and acetaldehyde in humans. Both parameters were significantly lower after SAM, indicating the capability of exogenous SAM to favour the inactivation of ethanol without increasing blood levels of acetaldehyde.

HPLC method for the evaluation of blood acetaldehyde without ethanol interference

Abstract The evaluation of acetaldehyde blood levels is important in view of possible toxic effects in the acute and chronic alcohol intoxication. Artefactual formation of acetaldehyde and its binding to erythrocyte components are the main problems that scientists have faced with in the measurement of acetaldehyde blood levels. The results reported herein show that addition of butyraldehyde as internal standard to the blood immediately after withdrawal allows to obviate these inconveniences. Aldehydes converted into their 2,4-dinitrophenylhydra-zones are then analyzed by HPLC. The mean value of acetaldehyde blood concentration measured by this method in 15 healthy subjects was 12.2 ± 1.3 μM. The increase of acetaldehyde concentration in rabbits after ethanol infusion is also shown.

Inhibition of lymphocyte function by a naturally occurring nucleoside: 5′-Methylthioadenosine (MTA)

The link between immunodeficiencies and nucleoside metabolism is exemplified by the inherited deficiencies of adenosine deaminase and purine nucleoside phosphorylase which are associated with an abnormal development of the immune system. In this report we show that high doses of methylthioadenosine (MTA), a natural purine nucleoside, inhibit both the mitogen-induced blastogenesis of human peripheral blood lymphocytes (PBL) and the pokeweed mitogen (PWM)-driven in vitro immunoglobulin synthesis by PBL in a non-toxic and reversible fashion. Our data support the view that both T and B cells are sensitive to MTA inhibition and that PWM-driven Ig production is more affected by MTA than the mitogen-induced PBL proliferation. The observation that MTA causes an evident inhibition of in vitro PWM-driven Ig secretion when added four days after the start of the cultures suggests that MTA can exert its activity not only on proliferation but also on differentiation of B cells.

Effects of compactin (ML-236 B) on biliary lipid composition and cholesterol catabolism in the hamster

Summary The effects of compactin (ML-236 B) administration on bile saturation and on the activity of hepatic HMG-CoA reductase, acylCoA cholesterol acyl transferase and cholesterol 7α-hydroxylase were studied in hamsters fed either a standard or a lithogenic diet. In control animals, treatment with this compound resulted in a stimulation of HMG-CoA reductase associated with supersaturation of the bile. Hypercholesterolemic hamsters in which compactin reduced plasma cholesterol levels responded to the treatment with a decrease of both HMG-CoA reductase and cholesterol 7α-hydroxylase activities. Supersaturation of the bile induced by the lithogenic diet was not modified by compactin.

Spontaneous reversal of ethinyl estradiol-induced cholestasis in the rat

The spontaneous reversal of ethinyl estradiol-induced cholestasis has been documented 7 days after the last estrogen administration in the rat. This finding supports the hypothesis that estrogens produce only a transient functional failure of the hepatocytic structures responsible for bile secretion.

Estrogens and Bile Secretion

The purpose of this report is to present an overview of the influence of natural and synthetic estrogen on the bile-secreting apparatus. Estrogen-induced alterations of hepatobiliary function range from modifications of bile lipid composition, so that bile becomes supersaturated with cholesterol, to bile flow impairment, i. e., intrahepatic cholestasis (Kern et al. 1978). Most of the knowledge regarding estrogen-induced liver dysfunction has been obtained from experiments focusing on estrogen treatment of animals as well as from clinical experience of estrogen hepatotoxicity in pregnant women and in subjects receiving drugs containing these hormones (Strieker and Spoelstra 1985). The mechanism(s) whereby estrogens interfere with bile secretion is still unknown.