Hepatoprotective effect of an active constituent isolated from the leaves of Ricinus communis Linn

Dose (1.5–12 mg/kg p.o. × 7) dependent choleretic, anticholestatic, and hepatoprotective activity in rat was observed with N-demethyl ricinine isolated from the leaves of Ricinus communis Linn. The anticholestatic and hepatoprotective activity was seen against paracetamol-induced hepatic damage. The choleretic and anticholestatic activity was evidenced by an increase in the volume of bile and its contents. The hepatoprotective effect was evaluated by an increase in the percent viability of hepatocytes (ex vivo) and by the reversal of altered enzymatic levels (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT], and alkaline phosphatase) towards normal. The compound showed more potent activity than silymarin, a known hepatoprotective agent.     

Hepatoprotective effect of picroliv against rifampicin-induced toxicity

Picroliv, the active constituent of the plant Picrorhiza Kurroa, showed significant hepatoprotective as well as anticholestatic activity against rifampicin-induced hepatic damage. Rifampicin (50 mg/kg ip × 6 days) resulted in the reduction of bile flow as well as its contents (bile salts and bile acids) in the conscious rat and anesthetized guinea pig. Further, it also caused a decrease in the viability and rate of oxygen consumption in isolated rat hepatocytes. Picroliv treatment significantly reversed the altered parameters of bile and hepatocytes. The hepatoprotective drug silymarin on comparison was found to be less active than picroliv. Drug Dev. Res. 40:299–303, 1997. © 1997 Wiley-Liss, Inc.     

Choleretic effect of andrographolide in rats and guinea pigs.

Andrographolide from the herb Andrographis paniculata (whole plant) per se produces a significant dose (1.5-12 mg/kg) dependent choleretic effect (4.8-73%) as evidenced by increase in bile flow, bile salt, and bile acids in conscious rats and anaesthetized guinea pigs. The paracetamol induced decrease in volume and contents of bile was prevented significantly by andrographolide pretreatment. It was found to be more potent than silymarin, a clinically used hepatoprotective agent.     

Silymarin as a new hepatoprotective agent in experimental cholestasis: new possibilities for an ancient medication

Silymarin is a purified extract from milk thistle (Silybum marianun (L.) Gaertn), composed of a mixture of four isomeric flavonolignans: silibinin (its main, active component), isosilibinin, silydianin and silychristin. This extract has been empirically used as a remedy for almost 2000 years, and remains being used as a medicine for many types of acute and chronic liver diseases. Despite its routinely clinical use as hepatoprotectant, the mechanisms underlying its beneficial effects remain largely unknown. This review addresses in detail a number of recent studies showing a novel feature of silymarin as a hepatoprotective drug, namely: its anticholestatic properties in experimental models of hepatocellular cholestasis with clinical correlate. For this purpose, this review will cover the following aspects: 1. The chemistry of silymarin, including chemical composition and properties. 2. The current clinical applications of silymarin as a hepatoprotective agent, including the mechanisms by which silymarin is thought to exert its hepatoprotective properties, when known. 3. The physiological events involved in bile formation, and the mechanisms of hepatocellular cholestasis, focusing on cellular targets and mechanisms of action of drugs used to reproduce experimentally cholestatic diseases of clinical interest, in particular estrogens and monohydroxylated bile salts, where anticholestatic properties of silymarin have been tested so far. 4. The recent findings describing the impact of silymarin on normal bile secretion and its novel, anticholestatic properties in experimental models of cholestasis, with particular emphasis on the cellular/molecular mechanisms involved, including modulation of bile salt synthesis, biotransformation/depuration of cholestatic compounds, changes in transporter expression/activity, and evocation of signaling pathways.     

Hepatoprotective activity of picroliv,the active principle of Picrorhiza kurrooa,on rat hepatocytes against paracetamol toxicity

Picroliv, the active principle an iridoid glycoside mixture isolated from the plant Picrorhiza kurrooa, showed dose-dependent (0.75–12 mg/kg × 7 days) protective activity on isolated hepatocytes (ex vivo) against paracetamol-induced hepatic damage in rats. It increased the percent viability of the hepatocytes. Picroliv also restored the normal values of enzyme (glutamic oxaloacetic transaminase [GOT], glutamic-pyruvic transaminase [GPT], and alkaline phosphatase) both in the isolated hepatocyte suspension as well as in the serum. Picroliv was found to be more potent than silymarin, a known hepatoprotective agent.     

Effect of Picroliv on cadmium-induced hepatic and renal damage in the rat

The therapeutic efficacy of Picroliv--a standardized extract of Picrorhiza kurroa--was investigated in male rats exposed to CdCl2 (0.5 mg/kg, sc), 5 days/week for 18 weeks. Picroliv at two doses (6 and 12 mg/kg, po) was given to the cadmium (Cd)-administered group for the last 4 weeks (i.e., weeks 15-18). The Cd altered oxidative stress indices, such as increased lipid peroxidation and membrane fluidity, reduced levels of non-protein sulphydryls (NPSHs), and Na+K+ATPase activity in the liver and kidney were found close to the control values by Picroliv treatment, suggesting its antioxidant potential. The hepatoprotective action of Picroliv was evident by its ability to lower the Cd-induced liver function parameters--the serum enzymes, such as alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and lactate dehydrogenase (LDH). Bile flow and biliary Cd also increased as a result of Picroliv's choleretic property. The Cd-induced serum urea and urinary excretion of proteins, calcium (Ca), Cd and enzymes, such as N-acetyl-beta-D-glucosaminidase (NAG) and LDH, were less marked on Picroliv treatment, indicating recovery from nephrotoxicity. Organ uptake of Cd and essential metals by Cd exposure was reduced on Picroliv treatment. Cd-induced hepatic metallothionein (MT) was lowered by Picroliv, whereas renal MT was unaltered. Cd-induced hepatic damage was also minimized. However, the renal morphological changes were marginally protected by Picroliv. The 12-mg Picroliv dose was more effective than the 6-mg dose in causing amelioration of the above parameters. This study has provided clear evidence for the hepato- and renal protective efficacy of Picroliv against experimental Cd toxicity.     

Hepatoprotective activity of Achyrocline satureioides(Lam) D. C.

Aerial parts of Achyrocline satureioides(Lam) D. C. (Asteraceae) are used in folk medicine as infusions or decoctions for the management of several diseases including gastrointestinal and hepatic disorders. These data and the presence of flavonoids and caffeoyl derivatives have led us to study its hepatoprotective and choleretic activities. The hepatoprotective activity was evaluated in the bromobenzene- (BB-) induced hepatotoxicity model in mice through the measurement of the serum levels of alanine-aminotransferase (ALT) and aspartate transaminase (AST), thiobarbituric acid reacting substances (TBARS) and glutathione levels. The aqueous extract of the aerial parts of A. satureioides administered before BB, at the dose of 300 mg kg(-1)p.o., demonstrated significant inhibition (P< 0.01) in the BB increase of liver ALT and AST and in the BB-induced increase of liver TBARS content. Also it was able to significantly increase (P< 0.05) the depleted levels of liver glutathione. In addition, at the same dose, a significant increase (P< 0.01) in the bile flow of rats was found. The results obtained with the aqueous extract of A. satureioides support its use in popular medicine as a hepatoprotective and digestive agent, and the effects might be mediated through the antioxidant and choleretic activities.     

Prevention of taurolithocholate-induced hepatic bile canalicular distortions by HPLC-characterized extracts of artichoke (Cynara scolymus) leaves

The effects of water-soluble extracts of artichoke (Cynara scolymus L.) leaves on taurolithocholate-induced cholestatic bile canalicular membrane distortions were studied in primary cultured rat hepatocytes using electron microscopy. Artichoke extracts at concentrations between 0.08 and 0.5 mg/ml were able to prevent the formation of bizarre canalicular membrane transformations in a dose-dependent manner when added simultaneously with the bile acid. However, prevention also occurred when the hepatocytes were preincubated with the extracts, indicating that absorption of the bile acid to components of the extracts was not involved. These results demonstrate that artichoke leaf extracts exert a potent anticholestatic action at least in the case of taurolithocholate. This effect may contribute to the overall hepatoprotective influence of this herbal formulation.     

Picroliv affords protection against thioacetamide-induced hepatic damage in rats

Thioacetamide (100 mg/kg), when administered to normal rats, caused a significant increase in the activities of 5'-nucleotidase and gamma-glutamyl transpeptidase and a decrease in the activities of glucose 6-phosphatase and succinate dehydrogenase enzymes in the liver. DNA, RNA, and proteins were increased while the cytochrome P450 in the microsomal fraction and the glycogen content in the liver were decreased significantly. Elevations in the activities of GOT, GPT, and alkaline phosphatase and bilirubin content in serum were also observed. Picroliv, a standardised glycoside fraction of Picrorhiza kurroa, in doses of 12.5 and 25 mg/kg prevented most of the biochemical changes induced by thioacetamide in liver and serum. The hepatoprotective activity of Picroliv was comparable with that of silymarin, a known hepatoprotective agent obtained from seeds of Silybum marianum.     

Choleretic and hepatoprotective properties of Eupatorium cannabinum in the rat

According to our results, the traditional therapeutic indications of Eupatorium cannabinum L., choleretic and hepatoprotective effects, have been widely demonstrated. An aqueous extract induces hypercholeresis in the rat, the site of bile formation is canalicular in origin and both bile acid-dependent and bile acid-independent flows could be stimulated; the extract possesses anti-necrotic properties against carbon tetrachloride-induced hepatotoxicity, reducing widely the plasma GPT level in pretreated rats.     

Comparison of the choleretic properties of bile acids

The choleretic properties of cholic, chenodeoxycholic, and deoxycholic acid and their taurine and glycine conjugates were compared to their ability to form micelles. It has previously been concluded that deoxycholate has the lowest critical micellar concentration; chenodeoxycholate is slightly higher and cholic is much higher. Conjugation with glycine and taurine has little or no effect on the critical micelle concentration. Since the choleretic properties of bile salts are thought to be directly proportional to their osmotic activities, one might suspect that deoxycholic acid would be the least choleretic, chenodeoxycholic slightly more choleretic and cholic much more choleretic, with little difference between the conjugated and unconjugated forms. However, in the present study, cholic, chenodeoxycholic and taurocholic acid produced similar increases in bile flow (450–700 μl/kg) after an equimolar dose (55 μM/kg). Except for the conjugation of deoxycholic acid with taurine, conjugation of these bile acids with glycine or taurine always decreased the choleretic properties of the bile acids. Therefore, it has been concluded that there is not a good correlation between the in vitro osmotic properties of bile acids and their ability to increase bile flow.     

Immunostimulant Activity of Picroliv, the Iridoid Glycoside Fraction of Picrorhiza kurroa, and its Protective Action against Leishmania donovani Infection in Hamsters1

Picroliv, a standardised fraction from root and rhizome of Picrorhiza kurroa, consisting of iridoid glycosides and shown to be responsible for its hepatoprotective activity, was studied for immunostimulant activity. Oral administration of Picroliv (10 mg/kg x 7 days) in mice prior to immunization with sheep red blood cells (SRBC) resulted in a significant increase in haemagglutinating antibody (HA) titre, plaque forming cells (PFC), and delayed hypersensitivity (DTH) response to SRBC. Picroliv enhanced the non-specific immune response characterized by an increase in macrophage migration index (MMI), [14C]-glucosamine uptake, phagocytosis of [14C]-leucine labelled Escherichia coli, chemiluminescence of peritoneal macrophages, and higher uptake of [3H]-thymidine in the lymphocytes of treated mice. It also induced a high degree of protection in golden hamsters against challenge infection with Leishmania donovani promastigotes.     

Differential effects of hydroxyacetophenone analogues on the transcytotic vesicular pathway in rat liver

Insertion of transporter proteins into the apical canalicular membrane via vesicular transport is one of several choleretic mechanisms. Based on different choleretic activities of hydroxyacetophenone analogues including 4-mono; 2,6-di and 2,4,6-trihydroxy-acetophenone (MHA, DHA and THA), the present study aims to determine if these compounds stimulated vesicular transport in hepatocytes. Hydroxyacetophenone was continuously infused into the duodenum of the bile fistula rat. Bile flow rate was allowed to stabilize and then followed by an intraportal injection of horseradish peroxidase, a marker of the transcytotic vesicle pathway. MHA which stimulates bile acid independent flow, showed a dose-dependent increase in both the early (paracellular) and late (transcellular) peak of horseradish peroxidase excretion in bile. THA, which stimulates both bile acid dependent flow and bile acid independent flow, did not alter the pattern of horseradish peroxidase excretion into bile. However, DHA, which is more hydrophobic and increases only bile acid dependent flow, decreased the late peak. The stimulating effects of MHA on bile flow and horseradish peroxidase excretion were markedly inhibited by colchicine, suggesting that its choleretic action involves stimulation of exocytosis, as well as increase in paracellular permeability. In contrast, the lack of a stimulatory effect of THA and DHA on biliary horseradish peroxidase excretion suggested that their choleretic action is not associated with vesicular exocytosis. These results demonstrate a variable effect of hydroxyacetophenones on the transcytotic vesicular pathway reflecting different choleretic mechanisms and therapeutic potential.     

Choleretic activity of phloracetophenone in rats: structure-function studies using acetophenone analogues

The relationship between the chemical structure and choleretic activity of phloracetophenone (2,4,6-trihydroxyacetophenone) was investigated in adult male rats. Fourteen acetophenone analogues, with different substituents on the benzene nucleus, were intraduodenally administered and bile samples were collected via a bile fistula. All of the compounds tested immediately induced choleresis. For the same number of substituents on the benzene ring, hydroxy analogues induced a greater choleresis. The number and position of hydroxy substituents on the benzene nucleus play an important role in determining choleretic activity and biliary secretion of bile acid, but had no relation to biliary excretion of cholesterol. The choleretic activity of the hydroxylated compounds was inversely related to hydrophobicity, as inferred by thin-layer chromatography (TLC). Among the hydroxylated acetophenone analogues, 2,4,6-trihydroxyacetophenone was identified as the most potent, with a choleretic activity of 231.8+/-6.1 microl/mmol/min. It induced both a high bile flow rate and a high bile salt output and led to lower plasma cholesterol levels. This bile had a low lithogenic potential. The results suggest that a structural requirement for high choleretic activity of 2,4,6-trihydroxyacetophenone is a substituent hydroxy group at 4-position. Additional hydroxy groups at 2- and 6-positions are essential for the induction of higher an output of bile acid, and possibly, other solid materials.     

肝复康滴丸对大鼠利胆作用的实验研究

目的:观察肝复康滴丸对大鼠的利胆作用,为临床应用提供理论依据。方法:利用胆管引流法测定肝复康滴丸对大鼠胆汁流量及胆固醇和胆红素分泌的影响。结果:肝复康滴丸各剂量组各个时间点均能增加胆汁流量,以中剂量组药后1h差异最为显著(P<0.01);各剂量组胆汁中胆红素及胆固醇含量均不同程度的降低,以中剂量组的差异最为显著(P<0.01)。结论:肝复康滴丸能增加胆汁流量,抑制胆固醇和胆红素的分泌,提示肝复康滴丸具有利胆作用。     

芒果苷利胆作用及对胆囊平滑肌痉挛的影响

目的：探讨芒果苷利胆作用及对胆囊平滑肌痉挛的影响.方法：利用胆管引流法测定芒果苷对大鼠胆汁的流量及成分的影响;通过对豚鼠胆囊肌条的收缩试验观察芒果苷对乙酰胆碱所致胆囊平滑肌痉挛的影响.结果：芒果苷4.74×10-5 mol·kg-1剂量组可显著提高大鼠的胆汁流量,显著提高胆汁中胆红素浓度（P ＜0.01）;2.37×10-5 mol·L-1剂量组可显著抑制由乙酰 胆碱引起的豚鼠胆囊痉挛（P＜0.01）.结论：芒果苷具有利胆作用,可缓解乙酰胆碱引起胆囊痉挛.     

Experimental study of the effect of intravenous administration of sorbitol on bile excretion

Experiments were made on dogs with chronic U-shaped gall bladder-duodenal fistulas. The animals received 10% sorbitol (0.6 g/kg) injections into the peripheral vein. Analysis of total bile acids cholesterol and total bilirubin in hourly portions of the bile showed that sorbitol known to produce a choleretic effect when administered enterally and intraduodenally failed to have a choleretic effect after intravenous injection.     

Taurolithocholate-induced increase in the intrabiliary pressure generated during retrograde intrabiliary infusion of saline in rats: Antagonism by taurocholate and glycocholate

Taurolithocholate (TLC) is known to produce cholestasis and certain bile acids antagonize this effect. This antagonistic relationship was studied by measuring intrabiliary pressure (IBP) and bile flow changes in pentobarbital-anesthetized male Sprague-Dawley rats weighing 329 ± 7 (SE) g. The IBP reflects the peak pressure generated during the retrograde intrabiliary infusion of saline at 2.3 μl/sec. When TLC was infused into the femoral vein at 0.46 μmol/min over a 35-min period, the IBP rose and the bile flow decreased. Upon stopping the infusion, IBP returned to control values in 30 min but the cholestasis persisted. Simultaneous infusion of taurocholate or glycocholate at 0.61 μmol/min with the TLC prevented the TLC-induced rise in IBP and the cholestasis. Infusion of 0.61 μmol dehydrocholate/min with the TLC did not antagonize the rise in IBP or the cholestasis. Because dehydrocholate was a more potent choleretic agent than taurocholate or glycocholate and it had no antagonistic effect on TLC-induced effects, it was evident that the antagonistic action of taurocholate and glycocholate was not due to their choleretic effect. In another experiment, an iv bolus injection of 100 μmol/kg, taurocholate and glycocholate alone produced a fall in IBP which lasted about 1 hr. Even though this latter kind of fall in IBP might have been consistent with an increase in biliary tree permeability, such an effect did not appear to play a role in the antagonistic effect of these bile salts against the taurolithocholate-induced change. The changes in IBP were likely the result rather than the cause of more fundamental alterations.     

Features of the choleretic action of caerulein

I.v. infusion of caerulein had a thorough choleretic effect in the chicken, stimulating secretion of bicarbonate and bile salts, both in the absence of enterohepatic circulation of bile salts, and in animals in which bile secretion was supported with i.v. or intraduodenal administration of exogenous bile salts. In the case of the intraduodenal route, both the concentration and output of bile salts were increased.A dose-response relation was evident, although more modest in the case of the bile salts output than in the bicarbonate output. A significant positive correlation between bile salts output and bile flow during caerulein stimulation was evident. The mechanism of the choleretic action of caerulein in the presence or absence of an enterohepatic circulation of bile salts is discussed.     

Effect of picroliv administration on hepatic microsomal mixed function oxidases and glutathione-conjugating enzyme system in cholestatic rats

The effect of Picroliv on hepatic microsomal mixed-function oxidases (MFO) and glutathione conjugating enzyme system in cholestatic rats was studied. Bile duct ligation in male rats for one weeks caused significant increase in both serum sorbitol dehydrogenase activity and serum bile acide concentration indicating cholestatic liver injury. Furthermore, a rise in the hepatic hydroxyproline level indicating collagen accumulation was observed. As a result of these alterations, the hepatic microsomal MFO system was imparied as evidenced by a decrease in cytochrome P-450 system content and in the activities of NADPH-cytochrome C reductase and aminopyrine demethylase. While the hepatic glutathione content remained unaffected, the cytosolic glutathione S-transferase activity was clearly suppressed due to subchronic cholestasis. Oral administration of Picroliv (25 mg/kg/day for 21 days)--a standardized irioid glycoside fraction of Picrorhiza kurroa in bile ligation induced cholestatic rats, singnificantly prevented the biochemical changes induced in liver and serum of cholestatic rats. These results suggested that picroliv has anti-cholestatic activity which may be attributed to antioxidant property or it's specific role in protein synthesis.