An antioxidant drug, silibinin, modulates steroid secretion in human pathological adrenocortical cells.

Because human adrenocortical cells from different adrenal disorders exhibit pathologically altered corticosteroid synthesis, and free radical mechanisms may induce pathological changes in the activities of corticosteroid biosynthetic enzymes (cytochrome P-450), we examined the effect of an antioxidant, silibinin, on basal and ACTH-stimulated secretion of several corticosteroids in isolated adrenal cells from an aldosterone-producing adenoma, atrophied adrenal tissues surrounding the adenoma, and hyperplastic adrenals from Cushing's syndrome. In the presence of a high concentration (100 mumol/l) of silibinin, variably diminished secretion of basal aldosterone, corticosterone, cortisol, 18-OH-corticosterone and 11-deoxycorticosterone was found. In contrast, the addition of 0.01 mumol silibinin/l, which failed to produce a clear effect on basal corticosteroid secretion, resulted in a potentiation of ACTH-stimulated secretion of several corticosteroids in the adenomatous and hyperplastic adrenocortical cells. These results suggest that the dose-dependent dual effect of silibinin on corticosteroid secretion may be attributed to corresponding changes in the activities of cytochrome P-450 enzymes, and that stimulation of ACTH-induced corticosteroidogenesis by silibinin is presumably due to the antioxidant property of the drug.

[Pharmacotherapy of Amanita phalloides poisoning using silybin]. / Pharmakotherapie der Knollenblätterpilzvergiftung mit Silibinin.

A total of 18 cases of Amanita phalloides poisoning was treated by combined chemotherapy during 1980 and 1981. After attempted primary elimination of the toxin all patients received silybin as basic therapy mainly by infusion and, in two instances, silymarin orally. In order to investigate the effect of silybin therapy a retrospective study of the followed-up case records was made. The cases were arbitrarily classified into three groups of severity (light, medium and severe) according to clinical and laboratory findings. A close relationship was found between the severity of the intoxication and the time elapsed before commencement of silybin therapy. The time interval between mushroom intake and the commencement of the silybin administration averaged 71.5 hours in the "severe" group compared with 46 and 33.8 hours, respectively, in the "medium" and "light" groups. The mean silybin dosage was 33 mg/kg body weight/day; the mean duration of silybin therapy was 81.6 hours. With the exception of one fatality in a particularly high dosage suicidal intoxication, all patients survived. Administration of silybin within about 48 hours after mushroom intake seems to be an effective measure to prevent severe liver damage in Amanita phalloides poisoning.

[Hepatic encephalopathy syndrome]. / A hepatikus encephalopathia szindróma.

The syndrome of hepatic encephalopathy includes all the neuropsychiatric changes which appear in acute and chronic liver diseases. To understand the pathophysiology of hepatic encephalopathy, it would be essential to accurately study cerebral activity in human, but it is impossible at present. Animal models of acute hepatic encephalopathy available at present, reproduce just a narrow aspect of the human disease. Moreover, there is no useful animal model for chronic hepatic encephalopathy. Therefore, the exact pathophysiology of hepatic encephalopathy in human, is yet unknown. Theoretically, the disturbance of cerebral activity can be explained by the altered permeability of the blood-brain-barrier, the accumulation of neurotoxins, disturbance of neurotransmission by the altered substrate-supply, or by the disturbance of energy-balance. This review summarize those possible pathomechanisms, which are playing--in our present knowledge--important role in the development of hepatic encephalopathy.

[Alcohol and the liver: ethanol metabolism and the pathomechanism of alcoholic liver damage]. / Az alkohol és a máj: az ethanol metabolizmusa és az alkoholos májkárosodás pathomechanizmusa.

Ethanol is oxidized in the liver by three different enzyme systems, namely by alcohol dehidrogenase (ADH), the microsomal ethanol oxidizing system and catalase. Alcohol also undergoes a first pass metabolism in the gastric mucosa due to alcohol dehydrogenase. This first pass metabolism of ethanol is decreased in the alcoholic, in the fasted state, in the elderly and during cimetidine therapy leading to elevated alcohol blood-concentrations. Ethanol toxicity is closely related to its metabolism in the liver. Ethanol oxidation by ADH generates reducing equivalents (NADH) and acetaldehyde (AA). The elevated NADH/NAD ratio results in alterations of the intermediary metabolism of lipids, carbohydrates, proteins, purines, hormones and porphyrins. Furthermore, NADH flavours free radical production. The ethanol-associated redox changes are pronounced in the perivenular zone, since this is the area of low oxygen tension and of high ADH activity. In addition to NADH, AA exerts striking toxic effects on the hepatocyte. AA binds to cellular proteins and membranes including the mitochondria, microtubules, glutathion and various enzymes. In addition, AA and lactate stimulate collagen production in fibroblasts. AA-adducts stimulate the production of antibodies against AA-epitopes and could thus aggravate the liver injury. Chronic ethanol consumption results also in the microsomal induction of a specific ethanol-inducible form of cytochrome P--450, the cytochrome P--450IIE1 with high affinity not only to ethanol but also to some drugs (acetaminophen), procarcinogens (nitrosamines) and industrial agents (carbon tetrachloride). The interaction between ethanol metabolism and the metabolism of these compounds including vitamin A may also contribute to hepatic toxicity, since the susceptibility of the alcoholic toward those compounds is enhanced.

[Liver transplantation--preparing patients, early postoperative care and occupational rehabilitation]. / Májtranszplantáció--a betegek elökészítése, korai posztoperatív gondozása és foglalkozási rehabilitációja.

Authors summarize the results of liver transplantation first of all in the view of rehabilitation. Role of rehabilitation experts is discussed in the period before and after transplantation. The necessity of information for the patients is specially underlined already from the first raise of the possibility of liver transplantation. They express that after successful operation it is needed for the patients to return gradually to the used activities of everyday life. All the questions of immunosuppressive treatment, hygienic rules, physical activities, patient care at home and work place rehabilitation are discussed.

Chemotherapy of Amanita phalloides poisoning with intravenous silibinin.

1 A total of 18 cases of Amanita phalloides intoxication was treated by combined chemotherapy during 1980 and 1981. After attempted primary elimination of the toxin all patients received silibinin as basic therapy mainly by infusion and in two instances orally. 2 In order to evaluate the effect of silibinin therapy a retrospective study of the followed-up case records was made. The cases were arbitrarily classified into three groups according to the severity of liver damage (light, medium and severe). 3 There was found a close relationship between the severity of liver injury and the delay between mushroom ingestion and the onset of silibinin therapy. With the exception of one fatality in a particularly high dosage suicidal intoxication, all patients survived. 4 Administration of silibrinin even up to 48 h after mushroom ingestion appears to be an effective measure to prevent severe liver damage in Amanita phalloides poisoning. Contrarily, the onset of general supportive treatment together with penicillin therapy which was throughout several hours before silibinin administration did not correlate with the severity of liver damage.

Liver cell protection in toxic liver lesion.

Most of the hepatoprotective drugs belong to the group of free radical scavangers. The mechanism of their action involves membrane stabilisation, neutralisation of free radicals and immunomodulation. The authors demonstrate the effect of different-drugs used in therapy of liver diseases (silymarin, silibinin, Aica-P) in human clinico-pharmacological study and in animal experiments. A wide number of methods was used. Both the silymarin preparates and the Aica-P corrected the altered immunreaction and the decreased superoxid-dismutase (SOD) activity of erythrocytes and lymphocytes in patients with alcoholic liver cirrhoses. The scavanger effect of these drugs was demonstrated in the subcellular fractions of liver cells in animal experiments. The data support the therapeutic effect of these drugs in liver diseases.

Effect of silibinin on the activity and expression of superoxide dismutase in lymphocytes from patients with chronic alcoholic liver disease.

The in vitro and in vivo effects of the naturally occuring flavolignan hepatoprotective agent silibinin on the expression and activity of superoxide dismutase (SOD) enzyme were studied in lymphocytes from patients with chronic alcoholic liver disease. In vitro incubation with silibinin in a concentration corresponding to the usual therapeutic dosage markedly increased the SOD--expression of lymphocytes as measured by flow-cytofluorimetry following staining with monoclonal anti-Cu, Zn-SOD--antibody and FITC-conjugated anti-mouse Ig. In vivo treatment with the drug restored the originally low SOD activity of the patients' lymphocytes. These data indirectly suggest that antioxidant activity might be one of the important factors in the hepatoprotective action of silibinin.

Silibinin (Legalon-70) enhances the motility of human neutrophils immobilized by formyl-tripeptide, calcium ionophore, lymphokine and by normal human serum.

Experiments reported here were designed to investigate the effect of silibinin (extracted from Silybum marianum) on human polymorphonuclear leukocyte (PMN) motility and on leukocyte immobilizing activity of lymphokine (leukocyte inhibitory factor, LIF), formyl-Met-Leu-Phe (fMLP), calcium ionophore A-23187 and human sera inactivated by heat (HI-S). In the in vitro experiments, silibinin (1-10 micrograms/ml) failed to influence the random motility of unstimulated PMNS in agarose droplet assay, but enhanced the motility of the PMNs immobilized by fMLP, calcium ionophore, LIF or by autologous human sera. In the in vivo study, silibinin (Legalon-70) two hours after the administration was effective in enhancing spontaneous motility of leukocytes obtained from health volunteers which action could be regarded as a consequence of the decrease of leukocyte immobilizing activity being present in normal human plasma.

Immunomodulatory and hepatoprotective effects of in vivo treatment with free radical scavengers.

The hepatoprotective and immunomodulatory effects of silymarin and amino-imidazol-carboxamid-phosphate were studied in 60 patients with compensated alcoholic cirrhosis of the liver in a one month double blind clinical trial. Treatment with both drugs normalized the elevated levels of aspartate aminotransferase, alanine aminotransferase and serum bilirubin, markedly reduced the high level of gamma-glutamyl transferase, increased lectin-induced lymphoblasttransformation, decreased the percentage of CD8+ cells and suppressed lymphocytotoxicity. None of these changes occurred in the placebo-treated group. Thus the hepato-protective effects of silymarin and amino-imidazol-carboxamid-phosphate are accompanied by changes in parameters of cellular immunoreactivity of the treated patients.

Effect of Silybin on biliary lipid composition in rats.

The authors studied the influence of Silybin in rats, administered i.p. for 7 days (daily dose of 100 mg/kg/b.w.) on the biliary lipid composition and on the maximal excretory rate of bile salts. Following this treatment, biliary cholesterol excretion was reduced, while the other lipids and bile flow were not significantly modified. After sodium cholate infusion (1.6 mumol/min/100 g b.w. i.v. for 80 minutes), the Tm of bile salts and bile flow remained unchanged in Silybin pretreated rats. The mechanism by which Silybin treatment reduces cholesterol excretion, is discussed.