Sanguinarine: its potential as a liver toxic alkaloid present in the seeds of Argemone mexicana

The alkaloid sanguinarine reported to be responsible for several outbreaks of epidemic dropsy in the tropics was examined for its hepatotoxic potential in rats. The studies showed that a single i.p. dose (10 mg/kg) of sanguinarine not only increased the activity of SGPT and SGOT substantially but also caused a significant loss of microsomal cytochrome P-450 and benzphetamine N-demethylase activity. Furthermore, the treated rats exhibited considerable loss of body and liver weight, peritoneal edema and slightly enlarged livers with fibrinous material. Microscopic examination of the liver tissue showed progressive cellular degeneration and necrosis further substantiating that sanguinarine is a potential hepatotoxic alkaloid.     

Evaluation of the hepatotoxicological effects of a drug in an in vivo/in vitro model

Both in vivo and in vitro models have certain disadvantages for the study of the chronic hepatotoxicity of drugs. The aim of this work was to evaluate a new approach based on an in vivo/in vitro model. After chronic in vivo treatment of rats with Vincamine and Vindeburnol (an eburnamenine derivative which exhibits hepatotoxic properties in man) liver cells were isolated, and functional and metabolic disorders (metabolic utilization of fructose and protein biosynthesis) were studied to determine injury. The results showed no modification of blood parameters, but a direct relationship between the dose of Vindeburnol administered in vivo and the metabolic disorders observed in vitro, evidencing the high sensitivity and reliability of this model.     

Evaluation of the hepatotoxicological effects of a drug in an in vivo/in vitro model.

Both in vivo and in vitro models have certain disadvantages for the study of the chronic hepatotoxicity of drugs. The aim of this work was to evaluate a new approach based on an in vivo/in vitro model. After chronic in vivo treatment of rats with Vincamine and Vindeburnol (an eburnamenine derivative which exhibits hepatotoxic properties in man) liver cells were isolated, and functional and metabolic disorders (metabolic utilization of fructose and protein biosynthesis) were studied to determine injury. The results showed no modification of blood parameters, but a direct relationship between the dose of Vindeburnol administered in vivo and the metabolic disorders observed in vitro, evidencing the high sensitivity and reliability of this model.     

Increased activity of dipeptidyl peptidase IV in serum of hepatoma-bearing rats coincides with the loss of the enzyme from the hepatoma plasma membrane

Summary The specific activity of dipeptidyl peptidase IV (DPPIV E.C. 3.4.14.-) in the plasma membrane of Morris hepatoma 9121 or hepatoma 7777 was 3.5% and 2.9%, respectively, of that in the plasma membrane of rat liver. The enzyme activity in the serum of hepatoma-bearing rats was 141% (hepatoma 91219) and 162% (hepatoma 7777) of the normal value. cytochemical investigation showed that the DPP IV activity was almost completely absent from the hepatoma cell plasma membrane and was not sequestered within these cells. Indirect immunofluorescence staining with a polyclonal antibody directed against DPP IV indicated that the loss of activity was due to the absence of DPP IV molecules in the plasma membrane. The possibility that the enzyme is transferred from the membrane into the serum as a result of structural alterations is discussed.     

Increased activity of dipeptidyl peptidase IV in serum of hepatoma-bearing rats coincides with the loss of the enzyme from the hepatoma plasma membrane

The specific activity of dipeptidyl peptidase IV (DPP IV E.C. 3.4.14.-) in the plasma membrane of Morris hepatoma 9121 or hepatoma 7777 was 3.5% and 2.9%, respectively, of that in the plasma membrane of rat liver. The enzyme activity in the serum of hepatoma-bearing rats was 141% (hepatoma 91219) and 162% (hepatoma 7777) of the normal value. Cytochemical investigation showed that the DPP IV activity was almost completely absent from the hepatoma cell plasma membrane and was not sequestered within these cells. Indirect immunofluorescence staining with a polyclonal antibody directed against DPP IV indicated that the loss of activity was due to the absence of DPP IV molecules in the plasma membrane. The possibility that the enzyme is transferred from the membrane into the serum as a result of structural alterations is discussed.     

Hepatic effects of <Emphasis Type="Italic">Cimicifuga racemosa</Emphasis> extract <Emphasis Type="Italic">in vivo</Emphasis> and <Emphasis Type="Italic">in vitro</Emphasis>

Extracts of Cimicifuga racemosa are used frequently for menopausal complaints. Cimicifuga is well tolerated but can occasionally cause liver injury. To assess hepatotoxicity of cimicifuga in more detail, ethanolic C. racemosa extract was administered orally to rats, and liver sections were analyzed by electron microscopy. Tests for cytotoxicity, mitochondrial toxicity and apoptosis/necrosis were performed using HepG2 cells. Mitochondrial toxicity was studied using isolated rat liver mitochondria. Microvesicular steatosis was found in rats treated with > 1,000 mg/kg [DOSAGE ERROR CORRECTED] body weight cimicifuga extract. In vitro, cytotoxicity was apparent at concentrations > or =75 microg/mL, and mitochondrial beta-oxidation was impaired at concentrations > or =10 microg/mL. The mitochondrial membrane potential was decreased at concentrations > or =100 microg/mL, and oxidative phosphorylation was impaired at concenq trations > or =300 microg/mL. The mechanism of cell death was predominantly apoptosis. C. racemosa exerts toxicity in vivo and in vitro, eventually resulting in apoptotic cell death. The results are compatible with idiosyncratic hepatotoxicity as observed in patients treated with cimicifuga extracts.     

Histologische Veränderungen der Magenschleimhaut des Hundes bei wiederholter Tetrachlormethanzufuhr

Summary Long-term administration of tetrachloromethane led to cirrhosis of the liver in dogs. Neither a repeated administration of the hepatotoxic substance nor cirrhotic changes of the liver led to changes of the gastric mucosa. The histological picture of the gastric mucosa was the same in dogs with liver cirrhosis as in healthy animals.     

Oyster mushroom (Pleurotus ostreatus) reduces the activity of 3-hydroxy-3-methylglutaryl CoA reductase in rat liver microsomes

The effect of dried oyster mushroom (Pleurotus ostreatus) on cholesterol (C) content in serum, in lipoproteins and in liver, and on the activity of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase in liver microsomes, was studied in male rats (strain Wistar, initial body weight 75 g) fed on low-cholesterol (9 mg/100 g) and high-cholesterol (0.3%) diets. Addition of 5% oyster mushroom to both diets reduced significantly the C-content in serum (by 30%), in very-low- and low-density lipoproteins (in a 11 ratio to the decrease of total serum C) and in liver (by 50%), as well as the activity of HMG-CoA reductase (by more than 30%).     

Effects of chronic caffeine feeding on the activities of oxygen free radical defense enzymes in the growing rat heart and liver

The purpose of the present study was to determine the relationship between concentration of Zn, Cu and Fe, and the catalase, glutathione peroxidase and superoxide dismutase activities in the heart and liver of newborn rats whose dams were fed a diet supplemented with caffeine. Heart Zn levels of the 22- and 30-day-old rats of the caffeine group showed a decrease, whereas liver Zn levels showed an increase compared to the control. Cu levels in the liver at day 22 in the caffeine group were less than in the control. Cu- and Zn-containing superoxide dismutase activities showed an increase in the hearts of the caffeine group compared to the control. The activity of catalase and glutathion peroxidase showed no difference in the heart and liver between the groups. The present study suggests the possible involvement of superoxide dismutase enzyme in the impairment of heart formation as a result of chronic caffeine intake in the early growing period.     

Purealidin A,a new cytotoxic bromotyrosine-derived alkaloid from the Okinawan marine spongePsammaplysilla purea

Summary A new bromotyrosine-derived alkaloid with antileukemic activity, purealidin A (5), has been isolated from the Okinawan marine spongePsammaplysilla purea and its chemical structure elucidated on the basis of the spectroscopic data.     

Age-related response of citrate synthase to hydrocortisone in the liver and brain of male rats

The activity of citrate synthase of the liver and brain of rats shows a gradual increase as a function of age. Adrenalectomy causes no significant change in the activity of citrate synthase in either of these tissues in young, adult or old rats. Administration of hydrocortisone to adrenalectomized rats depresses the activity of this enzyme maximally in the liver and brain of young rats. Administration of actinomycin D tends to normalize the depressed level of this enzyme.     

Effect of liver damage by thioacetamide on microsomal aromatization of testosterone in rats (author's transl)]

Rat liver microsomes, NADPH-regenerating system, and 1beta, 2beta-3H-testosterone have been incubated in vitro. The loss of tritium from the steroid, associated with aromatization of testosterone, was linear with time for 20 min and required NADPH. Pre-treatment of the rats with thioacetamide raised the liberation of tritium from 1beta, 2beta-3H-testosterone. The results suggest that liver damage by thioacetamide in rats may give rise to increased aromatization of testosterone.     

Structure and toxicity of the alkaloids of Russian comfrey (Symphytum x uplandicum Nyman), a medicinal herb and item of human diet

Summary Eight pyrrolizidine alkaloids of hepatotoxic type have been indentified in leaves ofSymphytum × uplandicum The combined alkaloids exhibit chronic hepatotoxicity in rats.The authors thank N. Anderton and P. Stewart for skilled assistance and V. Lord for statistical analyses.     

A sigmoidal relationship between liver stearoyl CoA desaturase activity and serum hormone concentrations caused by streptozocin and its antagonists

Stearoyl CoA desaturase activity in liver microsomes, and insulin, thyroxine, and triiodothyronine levels in serum were measured after administration of streptozocin (STZ) and its antagonists to rats. The effect of STZ, which caused hyperglycemia and inhibited the desaturase activity, was antagonized by 2-desoxyglucose and 3-O-methyl-glucose; 1-O-methyl-3-desoxyglucose and 1-O-methyl-3-O-methylglucose were without any effect. The enzyme activity plotted against insulin levels showed a broad sigmoidal curve, whereas the activities versus thyroid hormone levels showed steeper sigmoidal curves.     

Age-related response of citrate synthase to hydrocortisone in the liver and brain of male rats

Summary The activity of citrate synthase of the liver and brain of rats shows a gradual increase as a function of age. Adrenalectomy causes no significant change in the activity of citrate synthase in either of these tissues in young, adult or old rats. Administration of hydrocortisone to adrenalectomized rats depresses the activity of this enzyme maximally in the liver and brain of young rats. Administration of actinomycin D tends to normalize, the depressed level of this enzyme.Acknowledgments. The authors are indebted to Professor M.S. Kanungo of the Department of Zoology of Banaras Hindu University for helpful advice and facilities. A part of this project was presented at the 12th International Congress of Biochemistry, Australia, 1982.     

A signoidal relationship between liver stearoyl CoA desaturase activity and serum hormone concentrations caused by streptozocin and its antagonists

Summary Stearoyl CoA desaturase activity in liver microsomes, and insulin, thyroxine, and triiodothyronine levels in serum were measured after administration of streptozocin (STZ) and its antagonists to rats. The effect of STZ, which caused hyperglycemia and inhibited the desaturase activity, was antagonized by 2-desoxyglucose and 3-O-methyl-glucose; 1-O-methyl-3-desoxyglucose and 1-O-methyl-3-O-methylglucose were without any effect. The enzyme activity plotted against insulin levels showed a broad sigmoidal curve, whereas the activities versus thyroid hormone levels showed steeper sigmoidal curves.     

Elevation of serum xanthine oxidase following halothane anesthesia in the rat

Summary Halothane anesthesia was found to be hepatotoxic in the rat, as demonstrated by a significant elevation of serum xanthine oxidase (SXO) level. SXO appeared to be a more sensitive marker of liver damage than serum, glutamic oxalacetic transaminsa. SXO was found to be elevated also following exposure to relative hypoxia.     

Alteration of mitochondrial bioenergetics due to intravenous injection of a perfluorocarbon emulsion

Wistar albino rats were intravenously injected with 1 ml of an oxyphoretic emulsion of perfluorobutylfurane and killed 3, 7 or 30 days later. Mitochondria isolated from the liver and kidneys of treated rats showed a small decrease in the transmembrane electrical potential and a substantial depression of the rates of both ATP synthesis and ADP-stimulated respiration. These alterations in mitochondrial oxidative phosphorylation appear to be induced by perfluorocarbon and/or tensioactive molecules interacting with hydrophobic cell structures.     

Acetyl-L-carnitine treatment stimulates oxygen consumption and biosynthetic function in perfused liver of young and old rats

The effect of treatment with acetyl-L-carnitine on hepatic mitochondrial respiration and biosynthetic function in perfused liver from young (90 days) and old (22-24 months) rats was studied. Rats were given a 1.5% (w/v) solution of acetyl-L-carnitine in their drinking water for 1 month and oxygen consumption together with the rate of gluconeogenesis, urea synthesis, and ketogenesis with and without added substrates were measured in perfused liver. Mitochondrial oxygen consumption was also assessed in liver homogenate and isolated mitochondria to determine the maximal capacity for oxidative phosphorylation. Acetyl-L-carnitine treatment almost completely restored the age-dependent decline in oxygen consumption, gluconeogenesis, urea synthesis, and ketogenesis found in perfused liver of old rats to the levels found in young rats. In addition, acetyl-L-carnitine treatment increased oxygen consumption and biosynthetic function in perfused liver from young rats. After acetyl-L-carnitine treatment, we found detectable 3-oxoacyl-CoA-transferase activity associated with a consumption of ketone bodies in young and old rats. Finally, oxygen consumption measured in homogenate and isolated mitochondria did not change with age and acetyl-L-carnitine treatment. Our results show that in perfused liver, acetyl-L-carnitine treatment slows the age-associated decline in mitochondrial respiration and biosynthetic function. In addition, treatment of young rats with acetyl-L-carnitine has a stimulating effect on liver metabolism, probably through an increase in ATP production. Received 25 October 2000; received after revision 14 December 2000; accepted 11 January 2001