Elevated Plasma Alanine Aminotransferase Research Articles

Molecular mechanism of trichloroethylene-induced hepatotoxicity mediated by CYP2E1

Cytochrome P450 (CYP) 2E1 was suggested to be the major enzyme involved in trichloroethylene (TRI) metabolism and TRI-induced hepatotoxicity, although the latter molecular mechanism is not fully understood. The involvement of CYP2E1 in TRI-induced hepatotoxicity and its underlying molecular mechanism were studied by comparing hepatotoxicity in cyp2e1 +/+ and cyp2e1 −/− mice. The mice were exposed by inhalation to 0 (control), 1000, or 2000 ppm of TRI for 8 h a day, for 7 days, and TRI-hepatotoxicity was assessed by measuring plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histopathology. Urinary metabolites of trichloroethanol and trichloroacetic acid (TCA) were considerably greater in cyp2e1 +/+ compared to cyp2e1 −/− mice, suggesting that CYP2E1 is the major P450 involved in the formation of these metabolites. Consistent with elevated plasma ALT and AST activities, cyp2e1 +/+ mice in the 2000 ppm group showed histopathological inflammation. TRI significantly upregulated PPARα, which might function to inhibit NFκB p50 and p65 signalling. In addition, TRI-induced NFκB p52 mRNA, and significantly positive correlation between NFκB p52 mRNA expression and plasma ALT activity levels were observed, suggesting the involvement of p52 in liver inflammation. Taken together, the current study directly demonstrates that CYP2E1 was the major P450 involved in the first step of the TRI metabolism, and the metabolites produced may have two opposing roles: one inducing hepatotoxicity and the other protecting against the toxicity. Intermediate metabolite(s) from TRI to chloral hydrate produced by CYP2E1-mediated oxidation may be involved in the former, and TCA in the latter.

Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice

Ezetimibe is a novel cholesterol and plant sterol absorption inhibitor that reduces plasma low-density lipoprotein–cholesterol by selectively binding to the intestinal cholesterol transporter, Niemann-Pick C1-Like 1. Mice deficient in Niemann-Pick C1-Like 1 are protected from high fat/cholesterol diet-induced fatty liver as well as hypercholesterolemia. The object of the present study was to determine whether ezetimibe treatment could reduce hepatic steatosis in diet-induced obese mice. C57BL/6J mice were fed a high fat/cholesterol containing semi-purified diet (45% Kcal fat and 0.12% cholesterol) for 7 months after weaning. These mice were not only obese, but also developed hepatomegaly and hepatic steatosis, with varying degrees of liver fibrosis and steatohepatitis. About 87% of the mice on the high fat/cholesterol diet for 7 months had elevated plasma alanine aminotransferase activity, a biomarker for non-alcoholic fatty liver disease. Chronic administration of ezetimibe for 4 weeks significantly reduced hepatomegaly by decreasing hepatic triglyceride, cholesteryl ester and free cholesterol in diet-induced obese mice fed high fat/cholesterol diet for 7 months. Chronic ezetimibe treatment also significantly decreased plasma alanine aminotransferase activity. These results suggest that ezetimibe may be a novel treatment for high fat/cholesterol-induced non-alcoholic fatty liver disease.

Prophylactic effect of green tea polyphenols against liver and kidney injury induced by fenitrothion insecticide

The ameliorative effect of daily administrated dose of green tea extract (60 mg polyphenols/animal/day) was investigated on albino rats Rattus norvegicus (150–180 gm) intoxicated with 1/30 and 1/60 LD 50 fenitrothion organophosphate insecticide for 28 days. Blood samples were taken at 14 and 28 days for further biochemical parameters. Histopathological studies were carried out in the liver and kidney at the end of the experiment. Significant inhibition in plasma cholinesterase (ChE), a biomarker of Ops, was recorded. Damage in the liver and kidney tissues was observed and confirmed with elevation of plasma alanine aminotransferase (ALT), aspartate aminotaransferase (AST), albumin, urea and creatinine, as well as an elevation in the oxidative stress (OS) marker malondialdehyde (MDA). Decrease in total glutathione (GSH) content in erythrocytes and fluctuation in glutathione S-transferase (GST) activity in plasma was also observed. Green tea supplementation (60 mg/animal/day) partially counteracts the toxic effect of fenitrothion on oxidative stress parameters and repairs tissue damage in the liver and kidney, especially when supplemented to 1/60 LD 50 intoxicated animals depending on the duration. It seems that enzyme and metabolite markers of these organs need more time to be restored to the control level.

Synthetic Derivatives of Osthole for the Prevention of Hepatitis

Prevention of hepatitis is a worldwide issue. For most patients with liver disease, hepatoprotective drugs are required. But there are only a few hepatoprotective drugs available. Osthole is a coumarin compound and protects the liver from hepatitis by preventing the development of apoptosis. However, osthole exhibits low water solubility, and some structural modifications are required for sufficient hepatoprotection upon oral administration. We synthesized 28 osthole derivatives, and then studied their effects by using mice concanavalin A (Con A) -induced hepatitis. The osthole derivatives No.1, 9 and 19 showed stronger inhibition of Con A-induced elevation of plasma alanine aminotransferase (ALT). Oral administration of osthole at the dose of 100 mg/kg (n=10) inhibited 38.0% of the Con A-induced elevation of plasma ALT. In contrast, oral administration of Nos. 1, 9 and 19 at the dose of 100 mg/kg (n=5) caused 68.7%, 62.5% and 88.3% inhibition of the Con A-induced elevation of plasma ALT, respectively. These synthetic osthole derivatives could contribute to the development of hepatoprotective drugs effective for various types of liver diseases on oral administration.

Metabolism and hepatic toxicity of flutamide in cytochrome P450 1A2 knockout SV129 mice

Flutamide, a nonsteroidal antiandrogen used for treatment of prostate cancer, causes a temporary increase in transaminase and in some cases severe liver dysfunction. It is dominantly metabolized by cytochrome P450 (CYP) 1A2 into 2-hydroxyflutamide (OH-flutamide), which has stronger antiandrogenic activity without obvious cytotoxicity to cultured hepatocytes. We hypothesized that another subsidiary metabolite might be responsible for induction of hepatotoxicity. Flutamide was administered daily to CYP1A2 knockout mice and parental SV129 mice to compare pharmacokinetics and appearance of hepatic toxicity. In the CYP1A2 knockout mice, the plasma concentration of flutamide maintained at a high level and OH-flutamide stayed low; a higher amount of FLU-1, an alternative metabolite of flutamide, was detected in urine. Simple repetitive administration of 800 mg/kg of flutamide for 28 days to CYP1A2 knockout mice did not show abnormal elevation of plasma alanine aminotransferase (ALT). However, after the knockout mice were fed with an amino acid-deficient diet for 2 weeks, which reduced the glutathione (GSH) content to 27% of the initial, administration of 400 mg/kg of flutamide increased ALT to over 200 IU/l and histopathologically moderate hepatitis developed. Since FLU-1 itself did not show cytotoxicity or reduce GSH content in vitro, a further metabolized molecule must cause the hepatotoxicity. Blockade of CYP1A2 produced an unknown potential hepatotoxic molecule through FLU-1, and GSH might play an important role in diminishing the reactive hepatotoxic metabolite.

Serum adiponectin levels and enzyme markers of liver dysfunction in diabetic and non-diabetic Caribbean subjects

Low adiponectin levels are associated with elevated plasma alanine aminotransferase, a marker of reduced hepatic insulin sensitivity and a risk factor for type 2 diabetes. This study aims to determine the relationship between serum adiponectin level and alanine aminotransferase in diabetic and non-diabetic subjects. Fifty-six type 2 diabetic patients and 33 non-diabetic subjects participate in the study. Baseline plasma concentrations of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and glucose are measured on a chemistry analyser. Insulin and adiponectin are measured using enzyme-linked immunoassay techniques and insulin resistance is determined using the homeostatic model assessment method. Diabetic patients showed significantly lower levels of serum adiponectin than did the non-diabetic subjects, whereas levels of alanine aminotransferase and alkaline phosphatase were similar in both groups. While female non-diabetic subjects showed higher serum adiponectin levels than did female diabetic patients, alanine aminotransferase level did not differ (P>0.05). No significant relationship was seen between adiponectin and alanine aminotransferase in diabetic and non-diabetic subjects (P>0.05). Serum adiponectin levels were higher in non-diabetic subjects but there was no significant correlation between adiponectin and alanine aminotransferase in both groups of subjects. The data suggest that low serum adiponectin level may not be a suitable marker for impaired liver function in diabetic patients.

Bright Liver and Alanine Aminotransferase Are Associated with Metabolic Syndrome in Adults

The metabolic syndrome has become a significant health problem worldwide. In this study, we investigated the relationship between the metabolic syndrome, bright liver (BL) by ultrasonography (US), and plasma alanine aminotransferase (ALT) levels among apparently healthy adults. A total of 15,430 nonalcoholic healthy adults without hepatitis B or C were recruited from four nationwide MJ Health Screening Centers in Taiwan in 2000. Metabolic syndrome was defined using the National Cholesterol Education Panel (NCEP) metabolic syndrome criteria or modified NCEP criteria. Based on liver US, subjects were classified into either having BL or not. The relationship between the metabolic syndrome, BL, and ALT levels was examined using multivariate logistic regression analysis. The crude OR of the metabolic syndrome was 13.92 (12.19 using modified NCEP criteria), and the age-BMI-sex-adjusted OR was 3.77 (3.71 using modified NCEP criteria) in subjects with BL vs. subjects without BL, respectively. The ORs of the metabolic syndrome were significantly higher in subjects with elevated ALT levels than in those with normal ALT levels. After adjustment for age, sex, and BMI, BL and elevated ALT level were independently associated with increased risk of the metabolic syndrome. Presence of BL and elevated plasma ALT level was independently associated with increased risk of the metabolic syndrome in adults. These factors contribute to a list of well-known risk factors, including obesity, aging, and male sex, and thus can be applied as an additional evaluation for the metabolic syndrome in a clinical setting.

Macrophage inflammatory protein-1α plays a crucial role in concanavalin A-induced liver injury through induction of proinflammatory cytokines in mice

: The chemokines play roles in the development of immune mediated liver diseases. In this study, we investigate the involvement of macrophage inflammatory protein-1alpha (MIP-1alpha), one of the CC chemokines in concanavalin A (Con A)-induced liver injury in mice. : Liver injury was induced by intravenous injection of Con A. Anti-mouse MIP-1alpha antibody, recombinant murine-MIP-1alpha and gadolinium chloride (GdCl(3)) were administrated prior to Con A injection. Plasma alanine aminotransferase (ALT), MIP-1alpha, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) levels were determined and histological assessment of the liver was performed. : Plasma MIP-1alpha level was elevated after Con A injection. The elevated plasma ALT level, mortality rate and histological change after Con A injection were inhibited by anti-MIP-1alpha antibody pretreatment. The elevated plasma ALT level after Con A injection was further enhanced by recombinant murine-MIP-1alpha. The elevated plasma TNF-alpha and IFN-gamma levels after Con A injection were inhibited by anti-MIP-1alpha antibody, and enhanced by recombinant murine-MIP-1alpha. GdCl(3) pretreatment inhibited the elevated plasma MIP-1alpha and ALT levels. : These findings suggest that MIP-1alpha is produced from Kupffer cells after Con A injection, and this CC chemokine plays a crucial role in Con A-induced liver injury through induction of proinflammatory cytokines.

Preventive effect of Thea sinensis melanin against acetaminophen-induced hepatic injury in mice.

The preventive effect of Thea sinensis melanin (TSM) against overdoses of N-acetyl-p-aminophenol (NAPAP) was studied on ICR mice. Animals were given 400 mg/kg intraperitoneally (i.p.) of NAPAP, and TSM was injected i.p. in doses 10-40 mg/kg 2 h before intoxication. The protective effects were evidenced by a complete blockage of the NAPAP-induced elevation of plasma alanine aminotransferase (ALT) activity, decreased concentration of thiobarbituric acid reactive substances (TBARS) to the control level, and a partial prevention of reduced glutathione (GSH) depletion in the liver tissue. Preadministration of TSM also caused restoration of superoxide dismutase (SOD) activity and resumed content of coenzymes Q9 and Q10. TSM by itself, however, did not affect the hepatic functional parameters, including serum ALT, TBARS, GSH, SOD, or coenzymes Q in the liver. Administration of TSM caused a dose-dependent inhibition of N-nitrosodimethylamine demethylase activity with ED50 of 15.8 mg/kg. Activities of ethoxyresorufin O-dealkylase and pentoxyresorufin O-alkylase isozymes were changed insignificantly. The immune suppressive effect of NAPAP on the in vivo antibody-forming cell responses was demonstrated using ICR-sensitized mice with sheep red blood cells. The joint effect of TSM and NAPAP indicated the capability of TSM to recover immunity of the animals to the level of intact mice. Results obtained demonstrate that TSM preadministration can prevent the multiple toxic effects of NAPAP.

Silymarin protects against liver damage in BALB/c mice exposed to fumonisin B1 despite increasing accumulation of free sphingoid bases.

Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium verticillioides found on corn and corn-based foods. It causes equine leukoencephalomalacia, porcine pulmonary edema, and liver and kidney damage in most animal species. Fumonisin B(1) perturbs sphingolipid metabolism by inhibiting ceramide synthase activity, leading to the production of cell signaling factors including tumor necrosis factor alpha (TNF-alpha). The signal pathways of TNF-alpha are important factors in the pathogenesis of FB(1) hepatotoxicity. In the present study, female BALB/c mice were treated daily with 750 mg/kg silymarin by gavage and 2.25 mg/kg FB(1) subcutaneously for 3 days. Then, 1 day after the last FB(1) injection, the mice were euthanized and blood and tissues were sampled for analyses. Silymarin significantly diminished FB(1)-induced elevation of plasma alanine aminotransferase and aspartate aminotransferase activities and the number of apoptotic hepatocytes, while it augmented hepatocyte proliferation indicated by an increase in proliferating cells. Silymarin dramatically potentiated FB(1)-induced accumulation of free sphinganine and sphingosine in both liver and kidney. Silymarin itself slightly increased expression of hepatic TNF-alpha; however, it prevented the FB(1)-induced increases in TNF-alpha, TNF receptor 1, TNF receptor-associated apoptosis-inducing ligand, lymphotoxin beta, and interferon gamma. The induction of transforming growth factor beta1 expression in liver following FB(1) treatment was not affected by silymarin. These findings suggest that silymarin protected against FB(1) liver damage by inhibiting biological functions of free sphingoid bases and increasing cellular regeneration.

Gender-related differences in concanavalin A-induced liver injury and cytokine production in mice

Background/aim: Concanavalin A (Con A) activates T cells and causes T cell-mediated liver injury in mice. Since autoimmune diseases predominantly occur in women, female is considered to have enhanced immune responses and T cell functions. We investigated the presence of gender-related differences on Con A-induced liver injury and cytokine production in mice. Methods: Male and female BALB/c mice were given Con A (15 mg/kg) intravenously at 7 weeks of age. Plasma alanine aminotransferase (ALT), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin (IL)-4 and IL-10 levels were determined 0, 2, 4, 6, 8 and 24 h after Con A administration. To investigate the effects of sex hormones on liver injury and cytokine production, female and male mice were castrated at 3 weeks of age and were administered Con A 4 weeks after the operation. Results: Plasma ALT level of females was significantly higher at 8 and 24 h after Con A administration than those of males. Plasma levels of TNF-α and IFN-γ at 2, 4, 6 and 8 h, IL-4 at 2 h, but not IL-10, after Con A administration were significantly elevated in females than those of males. Furthermore, the elevated plasma ALT, TNF-α and IFN-γ levels decreased significantly by an ovariectomy. In contrast, those markers were exacerbated by an orchiectomy compared with sham operation. Conclusion: These findings indicate that Con A induces more severe liver injury in female mice than in male mice, and suggest that the effect of sex hormones on cytokine production may play a role in gender-related difference on Con A-induced liver injury.

L-carnitine alleviates alcohol-induced liver damage in rats: role of tumour necrosis factor-alpha.

Excessive alcohol intake induces hepatic fatty infiltration, which has been suggested to sensitize the liver to further damage. To test this hypothesis, L-carnitine, a constitutional lipotropic compound, was administered to rats chronically treated with ethanol by liquid diet feeding for 10 weeks. Ethanol administration caused marked steatosis, mild inflammation and elevated plasma alanine aminotransferase and tumour necrosis factor alpha (TNF-alpha) concentrations. Dietary supplementation with L-carnitine significantly reduced all these parameters as well as the hepatic concentration of thiobarbituric acid reactive substances, an indicator of lipid peroxidation products. Pretreatment with L-carnitine also significantly blunted ethanol-induced stimulation of TNF-alpha release by isolated Kupffer cells. This study provides direct support for the notion that steatosis sensitizes the liver to further damage and suggests an involvement of TNF-alpha in this process.

Osthole prevents anti-Fas antibody-induced hepatitis in mice by affecting the caspase-3-mediated apoptotic pathway

Fas (Apo-1/CD95) ligand, which is a type II membrane protein, is a major inducer of apoptosis. Osthole is a coumarin derivative present in medicinal plants. The effect of osthole on hepatitis induced by anti-Fas antibody in mice was studied. Pretreatment of mice with osthole (10, 50, and 100 mg/kg, i.p.) prevented the elevation of plasma alanine aminotransferase (ALT) caused by anti-Fas antibody (175 μg/kg, i.v.). Administration of osthole to mice even at a dose of 10 mg/kg significantly inhibited of anti-Fas antibody-induced elevation of plasma ALT. Capase-3 is a cysteine protease, and treatment of mice with anti-Fas antibody caused an elevation of caspase-3 activity at 3.5 and 6 hr. Pretreatment of mice with osthole (100 mg/kg, i.p.) inhibited the elevation of caspase-3 activity caused by anti-Fas antibody. However, the addition of osthole (up to 10 −4 M) to a liver cytosol fraction isolated from mice treated with anti-Fas antibody did not inhibit caspase-3 activity in vitro. Thus, treatment of mice with osthole inhibited caspase-3 activity by an effect upstream of caspase-3 activation. The livers of mice treated with anti-Fas antibody contained apoptotic and dead cells; osthole attenuated the development of this apoptosis and cell death. The present results show that osthole prevented anti-Fas antibody-induced hepatitis by inhibiting the Fas-mediated apoptotic pathway.

Antithrombin III prevents concanavalin A-induced liver injury through inhibition of macrophage inflammatory protein-2 release and production of prostacyclin in mice

Background/Aims: Recently, we have reported that macrophage inflammatory protein-2 (MIP-2) plays a pivotal role in concanavalin A (Con A)-induced liver injury. In this study, we investigated the effect of antithrombin III (AT-III) on liver damage, and production of MIP-2 and prostacyclin in this model. Methods: Liver injury was induced by intravenous injection of Con A (15 mg/kg) and AT-III was administered (50, 250 and 500 units/kg, iv) 30 mm before Con A injection. Plasma levels of alanine aminotransferase (ALT), MIP-2 and 6-keto-prostaglandin F1α (6k-PG-F1α), stable metabolite of prostaglandin I 2 (prostacyclin), were determined. Results: The elevated plasma ALT levels 8, 16, 24 h after Con A injection were inhibited by AT-III pretreatment. The elevated plasma MIP-2 levels were significantly inhibited by AT-III pretreatment compared with vehicle treatment. The inhibitory effect of AT-III on plasma ALT and MIP-2 in Con A-induced liver injury was attenuated by indomethacin (5 mg/kg, ip). Plasma concentration of 6k-PG-F1α at 2 h after AT-III injection was significantly elevated compared with baseline and vehicle pretreatment. Conclusions: These findings suggest that AT-III prevents Con A-induced liver injury through an inhibition of MIP-2 release and a production of prostacyclin.

Inhibitory effect of M50054, a novel inhibitor of apoptosis, on anti-Fas-antibody-induced hepatitis and chemotherapy-induced alopecia

M50054, 2,2′-methylenebis (1,3-cyclohexanedione), was identified as a novel inhibitor of apoptosis (programmed cell death) using an in vitro cell death assay system induced in human Fas-expressing WC8 cells by soluble human Fas ligand. Furthermore, M50054 inhibited the apoptotic cell death of U937, a human monocytic leukemic cell line, induced by anticancer agents such as etoposide; it was also confirmed that M50054 inhibited apoptotic features such as DNA fragmentation and phosphatidylserine exposure in these cells. These anti-apoptotic effects were attributable to inhibition of caspase-3 activation. Additionally, M50054 significantly inhibited anti-Fas-antibody-induced elevation of plasma alanine aminotransferase and aspartate aminotransferase. Alopecia (hair loss) symptoms were also significantly improved with topical treatment with M50054. In conclusion, M50054 inhibits apoptosis induced by a variety of stimuli via inhibition of caspase-3 activation, and may thus be effective for hepatitis and chemotherapy-induced alopecia.

Prevention of concanavalin A-induced mice hepatitis by molsidomine.

Molsidomine is effective in reducing portal hypertension in cirrhosis, but its effect on hepatitis is not known. In the present study, the effect of molsidomine on hepatitis was examined using mouse concanavalin A (Con A)-induced hepatitis and mouse anti-Fas antibody-induced hepatitis. Treatment of mice with Con A caused elevation of plasma alanine aminotransferase (ALT) at 8 and 24 h (n=4). Pretreatment of mice with molsidomine (3, 10, 30 and 100 mg/kg, i.p.) prevented Con A-induced hepatitis. Treatment of mice with anti-Fas antibody (150 microg/kg, i.v.) caused elevation of plasma ALT at 3.5 h. Pretreatment mice with molsidomine (10 mg/kg, i.p.) showed only 47% inhibition of anti-Fas antibody caused elevation of plasma ALT. The present results showed effectiveness of molsidomine in preventing Con A-induced mice hepatitis.

Minimal effect of cytokine-independent hepatitis induced by anti-Fas antibodies on hepatic cytochrome P450 gene expression in mice.

The effect of cytokine-independent hepatitis on cytochrome P450 (CYP) gene expression remains unknown. Treatment of mice with anti-Fas antibodies (150 microg/kg, i.v.) caused elevated plasma alanine aminotransferase activity at 4 and 24 h after treatment. Under normal reverse-transcription polymerase chain reaction (RT-PCR) amplification conditions, no effect of anti-Fas antibody-induced hepatitis on hepatic CYP 2E1 and 3A gene expression was observed. But lower cycle RT-PCR amplification revealed slight suppression of hepatic CYP 2E1 gene expression. The present results showed that cytokine-independent hepatitis induced by anti-Fas anti-bodies had only a minimal effect on the suppression of CYP gene expression in the liver.

Expression of the inducible form of the nitric oxide synthase gene in the livers of mice with chronic hepatitis.

The interferon-gamma (IFN-gamma) transgenic mouse expresses the exogenous IFN-gamma gene in the liver and develops chronic hepatitis. For the present experiment, four IFN-gamma transgene (+) mice of 48 weeks of age and 16 IFN-gamma transgene (+) mice of 8 weeks of age were used. The four IFN-gamma transgene (+) mice of 48 weeks of age showed significantly elevated plasma alanine aminotransferase (ALT) and expressed the inducible form of nitric oxide synthase (iNOS) mRNA in the liver. Of the 16 IFN-gamma transgene (+) mice of 8 weeks of age, iNOS mRNA was expressed in the livers of three. These three mice exhibited higher plasma ALT levels than the other mice of 8 weeks of age. The present results suggest that iNOS mRNA expression in the liver might be correlated with the progression of hepatitis.

Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors

Squalene synthase (SQS; EC 2.5.1.21) plays an important role in the cholesterol biosynthetic pathway. We discovered ER-28448, 5-{N-[2-butenyl-3-(2-methoxyphenyl)]-N-methylamino}-1,1-penthylidenebis(phosphonic acid) trisodium salt, as a potent and selective inhibitor of SQS. ER-28448 inhibited SQS in rat liver microsome with an IC50 value of 3.6 nm. We also prepared ER-27856, the tripivaloyloxymethyl ester prodrug of ER-28448. Although less active than ER-28448 in a liver microsome assay, ER-27856 more potently inhibited cholesterol biosynthesis in rat hepatocytes; and ER-27856 orally inhibited de novo cholesterol biosynthesis in Sprague-Dawley rats, with an ED50 value of 1.6 mg/kg. In HepG2 cells, ER-27856 upregulated low density lipoprotein receptor activity to 2.1 times that of control. A time-course study indicated that the inhibitory effect of ER-27856 on cholesterol biosynthesis in rats continued for up to 8 h. In a study of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMGRIs), atorvastatin actively suppressed cholesterol biosynthesis for 8 h, whereas the effect of pravastatin and simvastatin diminished at 4 and 8 h, respectively. In rhesus monkeys, 4 days of oral administration of ER-27856 lowered plasma total cholesterol (TCHO) more potently than did these HMGRIs. Whereas atorvastatin significantly elevated plasma alanine aminotransferase, a marker of hepatotoxicity, to 3.7 times at 100 mg/kg, ER-27856 increased the level only 1.4 times at 10 mg/kg, at which doses the hypocholesterolemic effect was equivalent. During 28 days of administration, ER-27856 reduced TCHO and non-high density lipoprotein (non-HDL) cholesterol by 72 and 95%, respectively.These results demonstrate that ER-27856 had more potent hypocholesterolemic activity and less hepatotoxic effect than HMGRIs. ER-27856 may contribute to the treatment of hypercholesterolemic patients.

Protective effects of soyasapogenol A on liver injury mediated by immune response in a concanavalin A-induced hepatitis model

The present study was carried out to analyze the effects of soyasapogenol A on the liver injury mediated by the immune response in concanavalin A-induced hepatitis in mice. Soyasapogenol A reduced the number of infiltrating inflammatory cells in the liver and significantly lowered the elevated level of plasma tumor necrosis factor-α (TNF-α) 2 h after concanavalin A treatment, and then markedly reduced the elevated plasma alanine aminotransferase activity and decreased the number of apoptotic bodies in the liver parenchymal cells but not in the sinusoidal cells at 24 h. Since the effect of soyasapogenol A on the elevated plasma TNF-α level was not appreciable compared to the preventive effect of soyasapogenol A on the elevated plasma alanine aminotransferase level, these results suggest that soyasapogenol A directly prevents apoptosis of hepatocytes, and secondly, inhibits the elevation of plasma TNF-α, which consequently resulted in the prevention of liver damage in the concanavalin A-induced hepatitis model.