Dimethyl Diphenyl Bicarboxylate Research Articles

Comparative Analysis of the Antioxidative and Hepatoprotective Activities of Dimethyl Diphenyl Bicarboxylate in Four Animal Models of Hepatic Injury.

As a well-known hepatoprotective and antioxidant agent, dimethyl diphenyl bicarboxylate (DDB) has frequently been employed to remedy various liver diseases. However, it is still uncertain whether DDB exerts consistent hepatoprotective and antioxidative activities against varying degrees of hepatic damage. Therefore, DDB (100, 25, 5, or 50 mg/kg depending on the model) was administered to animals in four representative models of liver injury (CCl4 chemical acute model, DMN subchronic model, TAA chronic model, and restraint stress psychological acute model). Horizontal comparative analysis indicated that DDB significantly lowered the excess serum AST and ALT levels in the CCl4 and DMN models but not in the TAA and restraint stress models. In accordance with this result, DDB markedly reduced oxidative stress indices (hepatic MDA and ROS) but restored five main antioxidant components (GSH content, GSH-peroxidase, GSH-reductase, SOD, and catalase activity) in the CCl4 and DMN models. DDB failed to normalize oxidative stressors in the restraint stress-induced injury model and restore these five antioxidant components in the TAA model. Overall, our results produced a comprehensive overview of the effects of DDB on oxidative stressors and the main antioxidative components using four animal models. These findings will provide valuable clues to guide therapeutic clinical applications.

Hepatoprotective effect of Sophora moorcroftiana (Benth.) Benth.Ex baker seeds in vivo and in vitro

The leguminosae of Sophora moorcroftiana (Benth.) Benth.ex Baker is a drought-resistant endemic Sophora shrub species from the Qinghai-Tibet Plateau, and its seeds have hepatoprotective effects. To study the effect of S. moorcroftiana seeds on liver injury and the molecular mechanism underlying the beneficial effects, liquid chromatography-mass spectrometry was used to detect the main active components in the ethanol extract of S. moorcroftiana seeds (SM). Male mice were divided into six groups (n = 8): normal control (NC), CCl4, SM (50, 100, 200 mg/kg), and dimethyl diphenyl bicarboxylate (150 mg/kg) groups. Mice were treated as indicated (once/day, orally) for 14 days, and CCl4 (2 mL/kg) was administered intraperitoneally. The serum and liver of mice were used for biochemical assays. To explore the underlying mechanism, HepG2 cells were treated with SM, stimulated with tert-butyl hydroperoxide (t-BHP, 50 μM), and analyzed by Western blotting. The major active compounds of SM were alkaloids including 22 compounds. Serum alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) decreased in the SM (200 mg/kg) group. SM can activate the expression of pregnane X receptor (PXR) and downstream molecules cytochrome P4503A11 enzyme (CYP3A11), UDP glucuronosyltransferase 1 family polypeptide A 1 (UGT1A1), and inhibit the multidrug resistance protein 2 (MRP2). In addition, SM improved cell viability in t-BHP-induced HepG2 cells (64% to 83%) and decreased the activation of the mitogen-activated protein kinase (MAPK) pathway. The main compounds in SM were alkaloids. SM showed hepatoprotective effects possibly mediated by the suppression of oxidative stress through the MAPK pathway.

Hepatoprotective effect of methyl ferulic acid against carbon tetrachloride-induced acute liver injury in rats.

The present study aimed to investigate the hepatoprotective effects of methyl ferulic acid (MFA) against oxidative stress and apoptosis in acute liver injury induced by carbon tetrachloride (CCl4) in rats, as well as the underlying mechanisms. Sprague Dawley rats were treated with CCl4 after oral administration of MFA (25, 50, and 100 mg/kg) or dimethyl diphenyl bicarboxylate (200 mg/kg) for 7 days. The hepatoprotective effects of MFA were determined by analyzing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities as well as changes of oxidant parameters. Histopathological analysis was performed to determine the degree of hepatic injury. The mechanisms were investigated by detecting the levels of NADPH oxidase (NOX) trans-membrane subunit NOX4, its ligand p22phox, as well as caspase3, cleaved caspase3, B-cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), tumor necrosis factor (TNF)-α, interleukin (IL)-1, reactive oxygen species (ROS), thiobarbituric acid-reactive substances (TBARS), total anti-oxidant capacity (TAC), phosphorylated J-Jun N-terminal kinase (p-JNK) and p-p38 mitogen-activated protein kinase (MAPK) using semi-quantitative polymerase chain reaction, western blot analysis and colorimetric assays. MFA treatment significantly decreased serum enzymatic activities of ALT and AST. MFA markedly increased activities of liver superoxide dismutase, catalase and glutathione peroxidase, and reduced the malondialdehyde concentration. Histopathological examination demonstrated that MFA reduced lipid degeneration, cytoplasmic vacuolization, necrosis and inflammatory cell infiltration in the liversof CCl4-treated rats. MFA treatment markedly inhibited the expression of inflammatory factors TNF-α and IL-1β. Mechanistic study revealed that MFA decreased the TAC and the levels of ROS and TBARS. Furthermore, MFA treatment led to a reduction of the mRNA and protein expression of NOX4 and p22phox, as well as the protein levels of caspase3, cleaved caspase-3 and Bax, and an upregulation of p-JNK, p-p38 MAPK and Bcl-2 proteins in the liver. The present study demonstrated that MFA has hepatoprotective effects against CCl4-induced acute liver damage. MFA has anti-oxidant, anti-inflammatory and anti-apoptotic activities and was able to modulate the NOX4/p22phox/ROS-JNK/p38 MAPK signaling pathway.

Protection from diclofenac-induced liver injury by Yulangsan polysaccharide in a mouse model

Ethnopharmacological relevanceMillettia pulchra Kurz var-laxior (Dunn) Z. Wei, a wild-growing plant of the family Fabaceae is known to possess multifarious medicinal properties. Yulangsan polysaccharide (YLSPS) is a chief ingredient of its root, which has been used in Chinese traditional medicine with a long history for remedy of acute or chronic hepatitis and jaundice. Aim of the studyTo investigate the ability of the YLSPS to protect against diclofenac-induced hepatotoxicity in mice. Materials and methodsMice were orally treated with YLSPS daily 1h after the injection of diclofenac for 2 weeks. Dimethyl diphenyl bicarboxylate was used as a reference drug. ResultsYLSPS effectively reduced the elevated levels of serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and enhanced the reduction of superoxide dismutase, catalase, and glutathione peroxidase activities in the liver. Moreover, the content of malondialdehyde was reduced by treatment with YLSPS, and histological findings also confirmed the anti-hepatotoxic activity. In addition, YLSPS significantly inhibited proinflammatory mediators, such as tumor necrosis factor-alpha and interleukin 1 beta. YLSPS also enhanced mitochondrial antioxidants and inhibited cell death by preventing the down-regulation of Bcl-2 and the up-regulation and release of Bax along with caspase 9 and 3 activity; thus, these findings confirm the involvement of mitochondria in diclofenac-induced apoptosis. ConclusionThe results indicate that protective effects of YLSPS against diclofenac-induced acute hepatic injury may rely on its effect on reducing oxidative stress, suppressing inflammatory responses, and improving drug-metabolizing enzyme activity in the liver.

Hepatoprotective effects of Yulangsan polysaccharide against nimesulide-induced liver injury in mice

Ethnopharmacological relevanceYulangsan polysaccharide (YLSPS) is often used in popular folk medicine in the Guangxi Zhuang Autonomous Region of China as a chief ingredient of Millettia pulchra, which is used as a hepatic protection, anti-aging and memory improving agent. Aim of the studyThis study was designed to investigate the protective effects of polysaccharides from Millettia pulchra Kurz var.laxior (Dunn) (Yulangsan polysaecharide, YLSPS) against nimesulide-induced hepatotoxicities in mice. Materials and methodsLiver injury was induced in mice by administering nimesulide. Simultaneously, YLSPS was administered 2h prior to the administration of nimesulide. Dimethyl diphenyl bicarboxylate (DDB) was used as a reference drug. ResultsCompared with the nimesulide group, YLSPS significantly decreased the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and the content of bilirubin in the serum. The anti-oxidative effect of YLSPS was observed from the increase of the superoxide dismutase (SOD) and catalase and glutathione peroxidase (GSH-Px) activities in the liver, both of which were decreased by nimesulide. Moreover, the content of malondialdehyde (MDA) was reduced, and histological findings also confirmed the anti-hepatotoxic activity. In addition, YLSPS significantly inhibited proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6). Additionally, YLSPS also enhanced the mitochondrial antioxidant and inhibited dead cells by preventing the down-regulation of Bcl-2, up-regulation and release of Bax along with caspase 9 and 3 activity, confirming the involvement of mitochondria in the nimesulide-induced apoptosis. ConclusionThe protective effect of YLSPS against nimesulide-induced hepatic injury may rely on its ability to reduce oxidative stress and prevent nimesulide-induced hepatotoxicity by inhibiting critical control points of apoptosis.

Reversing effects of lignans on CCl4-induced hepatic CYP450 down regulation by attenuating oxidative stress

Oxidative stress has been proved to be a critical reason of regulating CYP450s under hepatic injury status. The study was aimed to investigate the effect of pretreatment of schisandra lignan extracts (SLE) and dimethyl diphenyl bicarboxylate (DDB) on expressions and activities of the main liver P450 isoenzymes in CCl4 induced liver injury rats and their anti-oxidative effects on both CCl4 induced liver injury rats and a CCl4 induced HepG2 cell injury model. Acute experimental liver injury induced by CCl4 caused drastically decreasing activities of the main liver P450 isoenzymes such as CYP1A2, CYP2C6, CYP2E1 and CYP3A2, as well as their protein expressions. Pretreatment of SLE (500mg/kg) and DDB (200mg/kg) twice a day for three days significantly decreased the losses of activities of CYP1A2, CYP2C6, CYP2E1 and CYP3A2. Similar results were observed in protein expressions. In addition, in the CCl4 induced HepG2 cells injury model and the CYP3A activity level correlated well with ROS level in several ingredients of SLE treated groups, especially in γ-schisandrin group. These results indicated that the reversion of P450 after SLE/DDB treatment were, on one hand, due to hepatoprotective effects of these lignans on livers; on the other hand, due to their regulation of P450 through anti-oxidative effect and γ-schisandrin might be the most powerful ingredient of SLE. Also, there might be potential interactions between SLE or DDB and co-administered medicines and it is necessary to adjust the dosage of co-administrated medicines in clinical medication of liver disease.

English

  The hepatoprotective effect of basil (Ocimum basilicum) extract against liver fibrosis-induced by carbon tetrachloride (CCl4) was studied in rats. Rats were allocated into five groups: Group I (control group); Group II [CCl4 group; rats were injected subcutaneously with CCl4 (1 ml/kg b.w.) twice weekly for 4 weeks (phenobarbital, 350 mg/L, was added to the drinking water throughout the experiment)]; Group III received daily oral doses of basil extract of 200 mg/kg b.w. along with CCl4 and phenobarbital for 6 weeks; Groups IV and V rats were treated with phenobarbital and CCl4 for 6 weeks then treated daily with oral dose of 200 mg/kg b.w basil extract, or by 300 mg/kg b.w dimethyl diphenyl bicarboxylate (DDB), respectively for 6 weeks. Basil-treatment significantly reduced the liver content of hydroxyproline and significantly increased the activity of hyaluronidase (HAase). The hepatic activity of superoxide dismutase (SOD) was stimulated while the lipid peroxidation was significantly reduced by the effect of basil extract. Treatment with CCl4 significantly increased the activities of transaminases [aspartate aminotransferase (AST), alanine aminotransferase (ALT)], and alkaline phosphatase (ALP). These activities were significantly decreased by basil extract. The higher levels of serum urea and creatinine in CCl4 group were significantly guarded by the protection of basil.   Key words: Carbon tetrachloride, liver fibrosis, antioxidant, Ocimum basilicum,dimethyl diphenyl bicarboxylate

Cytochrome P450 Dysregulations in Thioacetamide-Induced Liver Cirrhosis in Rats and the Counteracting Effects of Hepatoprotective Agents

Dysregulations of cytochromes P450 (P450s) under liver injury have been extensively studied. However, little is known about the possible reversing effects of hepatoprotective agents, the understanding of which is of great importance in guiding clinical dosage adjustment for patients with liver injury. This study aims to investigate the dysregulation patterns of major P450s in thioacetamide (TAA)-induced liver cirrhosis in rats and the potential counteracting effects of hepatoprotective agents schisandra lignans extract (SLE) and dimethyl diphenyl bicarboxylate (DDB). TAA intoxications for 6 weeks induced apparent liver injury and dramatically reduced the hepatic protein expressions of CYP1A2, CYP2C6, CYP2E1, and CYP3A2 to 18, 71, 30, and 21% of that in the normal control, respectively. Both SLE and DDB treatments could significantly reverse the TAA-induced loss of P450 protein levels, which may be ascribed to their hepatoprotective effects and direct P450-inducing effects that have been confirmed in healthy rats. However, the recovery of enzyme activities of most P450s by SLE and DDB treatment was less evident than that for the protein expression levels. TAA exhibited NADPH-, time-, and concentration-dependent inactivating effects on all of the four major P450 isozymes; both DDB and GSH showed little effects on counteracting such an inactivation efficacy. These findings provided a good explanation on the disproportional effects of hepatoprotective agents in recovering the protein levels and enzyme activities of TAA-induced dysregulated P450s.

Thioacetamide Intoxication Triggers Transcriptional Up-Regulation but Enzyme Inactivation of UDP-Glucuronosyltransferases

Thioacetamide (TAA) is a potent hepatotoxicant and has been widely used to develop experimental liver fibrosis/cirrhosis models. Although the liver toxicity of TAA has been extensively studied, little is known about its potential influence on UDP-glucuronosyltransferases (UGTs) associated with the development of liver fibrosis. The study presented here aimed to uncover the regulation patterns of UGTs in TAA-induced liver fibrosis of rats. Potential counteracting effects of hepatoprotective agents were also determined. TAA treatment for 8 weeks induced a significant transcriptional up-regulation of the major UGT isoforms, including UGT1A1, UGT1A6, and UGT2B1, accompanied with the dramatic elevations of most typical serum biomarkers of liver function and fibrosis scores. Upon TAA intoxication, the mRNA and protein levels of the major UGT isoforms were increased to 1.5- to 2.5-fold and 2.5- to 3.3-fold of that of the normal control, respectively. The hepatoprotective agents Schisandra spp. lignans extract and dimethyl diphenyl bicarboxylate could largely abolish TAA-induced up-regulation of all three UGT isoforms. However, enzyme activities of UGTs remained unchanged after TAA treatment. The dissociation of protein expression and enzyme activity could possibly be attributed to the inactivating effects of TAA, upon a NADPH-dependent bioactivation, on UGTs. This study suggests that the transcriptional up-regulation of UGTs may be an alternative mechanism of their preserved activities in liver fibrosis/cirrhosis.

Schisandrin B protects against solar irradiation-induced oxidative stress in rat skin tissue

Schisandrin B (Sch B) and schisandrin C (Sch C), but not schisandrin A and dimethyl diphenyl bicarboxylate, protected rat skin tissue against solar irradiation-induced oxidative injury, as evidenced by a reversal of solar irradiation-induced changes in cellular reduced glutathione and α-tocopherol levels, as well as antioxidant enzyme activities and malondialdehyde production. The cytochrome P-450-mediated metabolism of Sch B or Sch C caused ROS production in rat skin microsomes. Taken together, Sch B or Sch C, by virtue of its pro-oxidant action and the subsequent eliciting of a glutathione antioxidant response, may prevent photo-aging of skin.

Mourning for renowned pharmacologist Professor Geng-Tao Liu

At 22:08 h on February 27, 2010, Professor Geng-Tao Liu, a renowned pharmacologist affiliated with the Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, an academician of the Chinese Academy of Engineering, a doctoral tutor, and a member of World Journal of Gastroenterology (WJG) Editorial Board, passed away at Peking Union Medical College Hospital, at the age of 77 years (Figure ​(Figure11). Figure 1 Geng-Tao Liu, Professor, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China Professor Liu was born in 1932 in Shuangfeng, Hunan Province. He graduated from Hunan Medical College in 1956 and then started his research career in the Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences. He was elected a member of the 6-8th Council of Chinese Pharmacological Society. During his research career, Professor Liu successfully developed two novel anti-hepatitis drugs: dimethyl diphenyl bicarboxylate and bicyclol. He also made great contributions to the understanding of the pharmacology of Schisandra, Ganoderma lucidum, and Salvia miltiorrhiza. Professor Liu successfully developed Ganoderma Spore Powder Injection that has been used in China for over 30 years to treat a variety of neuromuscular ailments. To evaluate the pharmacological effects of Ganoderma lucidum, Professor Liu created two unique animal models: one for dermatomyositis and the other for elevated serum aldolase, which provide a basis for a scientific explanation of the therapeutic effects of Ganoderma lucidum against dermatomyositis. He also found that several schizandrins, particularly schisanhenol, have potent antioxidant activity. Professor Liu published over 200 papers and was granted multiple patents. He is the editor-in-chief of “Contemporary Pharmacology” and the editor of “Pharmacology of Traditional Chinese Herbs and Drug Innovation”. He was a member of the editorial board of 12 domestic and foreign academic journals. He was awarded nine scientific or technological prizes in China, such as “National Invention Award”, “Scientific and Technological Progress Award of the Ministry of Health”, and “Beijing Municipal Scientific and Technological Progress Award”. Professor Liu also won the titles of “National Young and Middle-aged Experts with Outstanding Contributions”, “Capital May 1st Labor Medal”, and “Beijing Municipal Outstanding Teacher”. Having tutored more than 40 postgraduates, Professor Liu enjoyed a great reputation in the field of pharmacology. Professor Liu took time out of his busy schedule to review six WJG articles and made a great contribution to WJG. Now, he has left us forever! We are deeply saddened by his passing and will turn our grief into strength to continue our efforts to establish WJG as one of the leading journals. Professor Liu, may you rest in peace.

Schisandrin B-Induced Glutathione Antioxidant Response and Cardioprotection Are Mediated by Reactive Oxidant Species Production in Rat Hearts

To investigate the involvement of reactive oxidant species (ROS), presumably arising from cytochrome P-450 (CYP)-catalyzed metabolism of schisandrin B (Sch B), in triggering glutathione antioxidant response, Sch B induced reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent and CYP-catalyzed reaction and associated ROS production were examined in rat heart microsomes. Sch B analogs were also studied for comparison. Using rat heart microsomes as a source of CYP, Sch B and schisandrin C (Sch C), but not schisandrin A and dimethyl diphenyl bicarboxylate (an intermediate compound derived from the synthesis of Sch C), were found to serve as co-substrate for the CYP-catalyzed NADPH oxidation reaction, with concomitant production of ROS. The stimulation of CYP-catalyzed NADPH oxidation reaction and/or ROS production by Sch B or Sch C correlated with the increase in mitochondrial reduced glutathione level and protection against ischemia/reperfusion (I/R) injury in rat hearts. The involvement of ROS in Sch B-induced cardioprotection was further confirmed by the suppressive effect produced by N-acetylcysteine or alpha-tocopherol pretreatment. Taken together, these results suggest that Sch B-induced glutathione antioxidant response and cardioprotection may be mediated by ROS arising from CYP-catalyzed reaction.

Histophysiological Evaluation of the Effect of Alpha-Tocopherol and Dimethyl Diphenyl Bicarboxylate on Arsenic-Induced Hepatotoxicity in Adult Male Albino Rats

Histophysiological Evaluation of the Effect of Alpha-Tocopherol and Dimethyl Diphenyl Bicarboxylate on Arsenic-Induced Hepatotoxicity in Adult Male Albino Rats

Protective role of dimethyl diphenyl bicarboxylate (DDB) against erythromycin induced hepatotoxicity in male rats

In this study, dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylene dioxybiphenyl-2,2′-dicarboxylate (DDB) was examined to justify its role in the hepatoprotection against erythromycin toxicity in male rats. Oral daily administration of toxic dose of erythromycin stearate (EE, 100 mg/kg body weight) was given to male rats for fourteen days to induce hepatotoxicity. It was found at the end of the experiment (14 days) that the total body weight was markedly decreased in rat treated with erythromycin stearate (EE). Hepatomegaly and splenomegaly were recorded in rats treated with erythromycin stearate (EE). The red blood cells (RBCs) count, haemoglobin content (Hb) and haematocrit value (Hct) were significantly reduced in rats treated with EE. The hepatotoxicities were monitored by increased level of plasma enzymes (aspartate aminotransferase; AST and alanine aminotransferase; ALT), total bilirubin, direct bilirubin, cholesterol, total lipids and glucose. The data obtained showed that oral administration of DDB (100 mg/kg body weight) has significantly prevented the occurrence of EE-induced liver damage. The biochemical data were supplemented by histopathological examination of the liver of control and treated rats. DDB showed a better hepatoprotective effect compared with ursodesoxycholic acid or Silymarin (Sil), as a reference drug.

Separation of atropisomers of anti-hepatitis drug dimethyl diphenyl bicarboxylate analogues by capillary electrophoresis with vancomycin as the chiral selector

Separation of atropisomers of analogues of the anti-hepatitis drug dimethyl diphenyl bicarboxylate (DDB) by capillary electrophoresis with vancomycin as the chiral selector is described. Among several tested chiral selectors, including various cyclodextrin derivatives as well as vancomycin, only the latter displayed the enantioselectivity to the studied atropisomers. However, relatively poor separation efficiency was obtained due to the adsorption of vancomycin on the capillary wall. This problem was overcome by modifying the capillary wall with a polycationic electrolyte named hexadimethrine bromide (HDB) to produce a positively charged coating, which minimized the adsorption of vancomycin on the capillary wall by electrostatic repulsion. Moreover, the positively charged coating could shorten the separation time by reversing the EOF because the reversed EOF migrated to the same direction as the negatively charged analyte. Effects of buffer pH, vancomycin and buffer concentrations and applied voltage on the separation were investigated and the optimal conditions were established as follows: 40 mM Tris–phosphate buffer (pH 6.0) containing 6.0 mM vancomycin and 0.001% HDB. Baseline separation of three racemic DDB analogues was obtained within 12 min under the optimal conditions.

Structural determinants of schisandrin B which enhance mitochondrial functional ability and glutathione status as well as heat shock protein expression in rat hearts and H9c2 cells.

Using an ex vivo model of isolated-perfused rat hearts and cultured H9c2 cells, the structure-activity relationships of schisandrin B (Sch B), and analogs lacking either the methylendioxy group or cyclooctadiene ring, schisandrin A (Sch A) and dimethyl diphenyl bicarboxylate (DDB), respectively, were investigated. Pretreatment with Sch B, but not with Sch A or DDB, protected against myocardial ischemia-reperfusion (I-R) injury in rats. Although Sch B pretreatment largely prevented H9c2 cells from menadione-induced cytotoxicity, Sch A pretreatment produced only a marginal protection. However, DDB pretreatment did not cause any detectable effect. The myocardial and cellular protection afforded by Sch B pretreatment correlated with increases in mitochondrial ATP generation capacity and/or reduced glutathione level as well as heat shock protein (Hsp)25/70 expression, under both control and oxidative stress conditions. The results indicate that the methylenedioxy group and the cyclooctadiene ring are important structural determinants of Sch B in enhancing mitochondrial functional ability and glutathione status, as well as tissue Hsp 25/70 expression, thereby protecting the myocardium against I-R injury.

Role of cytochrome P-450 in schisandrin B-induced antioxidant and heat shock responses in mouse liver

In order to explore the role of cytochrome P-450 ( P-450) in schisandrin B (Sch B)-induced antioxidant and heat shock responses, the effect of 1-aminobenzotriazole (ABT, a broad spectrum inhibitor of P-450) on hepatic mitochondrial glutathione antioxidant status (mtGAS) and heat shock protein (Hsp)25/70 expression was examined in Sch B-treated mice. The non-specific and partial inhibition of cytochrome P-450 ( P-450) by ABT pretreatment significantly caused a protraction in the time-course of Sch B-induced enhancement in hepatic mitGAS and Hsp25/70 expression in mice. Using mouse liver microsomes as a source of P-450, Sch B, but not dimethyl diphenyl bicarboxylate (a non-hepatoprotective analog of Sch B), was found to serve as a co-substrate for the P-450-catalyzed NADPH oxidation reaction, with a concomitant production of oxidant species. Taken together, the results suggest that oxidant species generated from P-450-catalyzed reaction with Sch B may trigger the antioxidant and heat shock responses in mouse liver.

Effect of Bifendate (DDB) On Normal and Diseased Liver of Adult Male Albino Rats: An Experimental Study.

Background: Fructus Schizandrae Sinensis bail, a traditional Chinese medicine, has been shown to lower the elevated serum level of liver enzymes of patients suffering from chronic active hepatitis. A synthetic derivative compound of Schisandrian, Dimethyl Diphenyl Bicarboxylate (DDB) is now used widely in clinical fields as a hepatoprotective drug. Thus it is important to know whether DDB has a beneficial effect on damaged liver or not. Objective: To evaluate the protective effect of DDB on induced liver tissue injury in rats. Design: Experimental study. Setting: National Hepatology and Tropical Medicine Research Institute. The study was conducted from October (2004) to February (2005). Materials and methods: 120 male albino rats aged 6-8 weeks, weight 150-200g were grouped in six groups, 20 rats per group. Group 1 received food and water only, group 2 received food, water and DDB intragastric 6mg/kg daily for 12 weeks, group 3 received 20% ethanol instead of water, group 4 received 20% ethanol instead of water plus DDB, group 5 received thioacetamide (TAA) in a dose of 200mg/kg body weight intraperitoneal injection, group 6 received thioacetamide plus DDB at the same dose of the above group. At the end of the trial, blood samples were taken from all groups for biochemical analysis. Liver tissue excised from each rat was fixed in 10% neutral formalin, embedded in paraffin, and stained with Hematoxylin and Eosin, as well as Masson’s trichome stain, for evaluation of hepatic injury and/or fibrosis. Results: Statistical elevation of serum hepatic enzymes was noticed in rats received alcohol, Thioacetamide and alcohol + DDB (groups III, V and IV respectively) compared to the corresponding control (P= 0.000). On the other hand, administration of DDB to TAA treated group (group VI) induced significant improvement of liver function tests compared to other groups (P= 0.000). Histopathologically, the control livers showed normal lobular architecture without any pathological changes. Liver sections of animals administered alcohol, TAA respectively showed chronic inflammatory reaction, fat accumulation, hepatic parenchymal necrosis and/or hepatic fibrosis. Administration of DDB resulted in improvement of the pathological changes induced by TAA (group VI), but not that induced by alcohol (group IV). Conclusion: Our results revealed that DDB has antitoxic effect against TAA and ameliorates the dangerous effect on the liver parenchyma, while it has no beneficial effect on alcoholic liver disease.

Effect of Bifendate (DDB) On Normal and Diseased Liver of Adult Male Albino Rats: An Experimental Study.

Background: Fructus Schizandrae Sinensis bail, a traditional Chinese medicine, has been shown to lower the elevated serum level of liver enzymes of patients suffering from chronic active hepatitis. A synthetic derivative compound of Schisandrian, Dimethyl Diphenyl Bicarboxylate (DDB) is now used widely in clinical fields as a hepatoprotective drug. Thus it is important to know whether DDB has a beneficial effect on damaged liver or not. Objective: To evaluate the protective effect of DDB on induced liver tissue injury in rats. Design: Experimental study. Setting: National Hepatology and Tropical Medicine Research Institute. The study was conducted from October (2004) to February (2005). Materials and methods: 120 male albino rats aged 6-8 weeks, weight 150-200g were grouped in six groups, 20 rats per group. Group 1 received food and water only, group 2 received food, water and DDB intragastric 6mg/kg daily for 12 weeks, group 3 received 20% ethanol instead of water, group 4 received 20% ethanol instead of water plus DDB, group 5 received thioacetamide (TAA) in a dose of 200mg/kg body weight intraperitoneal injection, group 6 received thioacetamide plus DDB at the same dose of the above group. At the end of the trial, blood samples were taken from all groups for biochemical analysis. Liver tissue excised from each rat was fixed in 10% neutral formalin, embedded in paraffin, and stained with Hematoxylin and Eosin, as well as Masson’s trichome stain, for evaluation of hepatic injury and/or fibrosis. Results: Statistical elevation of serum hepatic enzymes was noticed in rats received alcohol, Thioacetamide and alcohol + DDB (groups III, V and IV respectively) compared to the corresponding control (P= 0.000). On the other hand, administration of DDB to TAA treated group (group VI) induced significant improvement of liver function tests compared to other groups (P= 0.000). Histopathologically, the control livers showed normal lobular architecture without any pathological changes. Liver sections of animals administered alcohol, TAA respectively showed chronic inflammatory reaction, fat accumulation, hepatic parenchymal necrosis and/or hepatic fibrosis. Administration of DDB resulted in improvement of the pathological changes induced by TAA (group VI), but not that induced by alcohol (group IV). Conclusion: Our results revealed that DDB has antitoxic effect against TAA and ameliorates the dangerous effect on the liver parenchyma, while it has no beneficial effect on alcoholic liver disease.

Hepatoprotective effect of lactic acid bacteria, inhibitors of β-glucuronidase production against intestinal microflora

The hepatoprotective activity of lactic acid bacteria (Lactobacillus brevis HY7401, Lactobacillus acidophilus CSG and Bifidobacterium longum HY8001), which inhibited beta-glucuronidase productivity of intestinal microflora, on t-BHP- or CCl4-induced hepatotoxicity of mice were evaluated. These oral administration of lactic acid bacteria lowered beta-glucuronidase production of intestinal microflora as well as Escherichia coli HGU-3. When lactic acid bacteria at a dose of 0.5 or 2 g (wet weight)/kg was orally administered on CCl4-induced liver injury in mice, these bacteria significantly inhibited the increase of plasma alanine transferase and aspartate transferase activities by 17-57% and 57-66% of the CCl4 control group, respectively. These lactic acid bacteria also showed the potent hepatoprotective effect against t-BHP-induced liver injury in mice. The inhibitory effects of these lactic acid bacteria were more potent than that of dimethyl diphenyl bicarboxylate (DDB), which have been used as a commercial hepatoprotective agent. Among these lactic acid bacteria, L. acidophilus CSG exhibited the most potent hepatoprotective effect. Based on these findings, we insist that an inhibitor of beta-glucuronidase production in intestine, such as lactic acid bacteria, may be hepatoprotective.