Increase In Glutamic Oxaloacetic Transaminase Research Articles

Beyond soybean meal: investigating the effects of dietary protein alternatives on gut health, liver function and microbiota in traditional slow-growing chicken breeds

The use of soybean meal in animal feed is crucial for nutrition but has a significant environmental impact, especially related to deforestation and biodiversity loss. With the increasing demand for sustainable agricultural practices, it becomes essential to explore alternatives to soybean meal. This study evaluated the effect of a soy-free diet, replaced with fava beans and pea protein, on an Italian slow-growing chicken breed: the Bianca di Saluzzo. The results indicate that the experimental diet did not compromise the growth, final weight or intestinal health of the animals, demonstrating a good tolerance and adaptability of the breed to these alternative ingredients. Furthermore, the analysis of the intestinal microbiota showed a positive impact, with an increase in organic acids such as succinic and citric, which could improve intestinal health and metabolic efficiency. Some changes in liver enzyme levels were observed, such as the increase in glutamate-oxaloacetate transaminase, an enzyme involved in amino acid metabolism. This increase could indicate a higher efficiency in protein metabolism, suggesting that the diet based on alternative ingredients could support an improvement in liver metabolism. Although this aspect deserves further investigation, it could represent a positive effect of the diet on liver function and overall health of the animals. Further studies are needed to fully understand the long-term implications of these dietary modifications, particularly in relation to the gut microbiota and metabolism.

5-Hydroxyndole-3-acetic acid suppresses activation of glutamate oxaloacetate transaminase 1 linked to Th1/17 cell differentiation and ameliorates rheumatoid arthritis

Abstract It has been established that cell proliferation and survival activities can be controlled according to metabolic resources in inflammation. However, it is not clear how T cell-mediated inflammatory immune responses in rheumatoid arthritis (RA) affect the activity and regulation of inflammatory cells by meeting biosynthesis and bioenergy requirements. This study evaluated the effect of serotonin-derived metabolite 5-Hydroxyndole-3-acetic acid (5-HIAA) on the increase in glutamate oxaloacetate transaminase 1 (GOT1) by the differentiation of Th1, Th17, or Th1/17 cells. The differentiation of Th1, Th17, or Th1/17 cells increased GOT1 and showed that GOT1 promotes the differentiation of Th1, Th17, or Th1/17 cells. Conversely, selective inhibition of GOT1 using 5-HIAA blocked the differentiation of Th1, Th17, or Th1/17 cells. Furthermore, inhibition of GOT1 using 5-HIAA ameliorated RA through up-regulation of regulatory T cells (Foxp3+CD4+), suppression of pro-inflammatory cytokines, and inhibition of Th1/17 responses in mouse joints. Therefore, targeting glutamate-dependent metabolic pathways would be an effective therapeutic strategy for rheumatoid arthritis and a wide spectrum of autoimmune diseases. Supported by 21st Century Medical Science Creative Human Resource Development Center

Changes in Serum Blood Parameters in Farmed Rainbow Trout (Oncorhynchus mykiss) Fed with Diets Supplemented with Waste Derived from Supercritical Fluid Extraction of Sweet Basil (Ocimum basilicum)

The antimicrobial and immunostimulant proprieties of aromatic plant extracts have been widely described, but their effects on serum blood biochemistry in fish have not. For this study, we assessed the changes in serum blood biochemical parameters in rainbow trout fed with a fish diet supplemented with a basil supercritical extract (F1-BEO). Our hypothesis was that treatment and time would be associated with changes in 10 serum blood biochemical parameters. F1-BEO was added to a commercial feed (0.5, 1, 2, 3% w/w). The fish were fed for 30 days, and the blood samples were collected at 2 time points (15 and 30 days). A two-way ANOVA showed a significant effect of treatment, time, and interaction treatment × time on creatinine, urea, total protein, albumin, magnesium, and phosphorus (p < 0.05), a significant effect of both time and interaction treatment × time on cholesterol (CHOL), glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) levels, and a significant effect of time on triglycerides (p < 0.05). While changes in several of the parameters were observed, the levels remained within the normal range for rainbow trout. Notably, after 30 days there was a significant decrease in CHOL in fish treated with 0.5% and 1% w/w F1-BEO (p < 0.05). The statistically non-significant increase in GOT and GPT in the fish fed with F1-BEO up to 3% w/w indicated a positive effect of basil on liver health. Our findings suggest a potential use for basil extracts (for example., F1-BEO) in fish feed to reduce antibiotic use and improve fish welfare.

Effectiveness of aqueous extract of marjoram leaves in the treatment of aspartame liver toxicity

Background and objectives Although there are several toxicological studies on aspartame (ASP), its histopathological effects on the liver have received little attention. Natural marjoram [Origanum majorana (OM)] is extensively studied for its ability to protect cells from damages. The present study was to evaluate the chronic effects of ASP, and marjoram as well as the protective effect of aqueous extract of marjoram leaves (OM) against ASP-induced liver toxicity. Materials and methods Seventy-two female albino rats (180±20 g) were divided into nine groups: G1 as a control, G2 and G3 received ASP, G4 and G5 were administrated water extract OM, and G6, G7, G8, and G9 were treated with ASP+OM. Serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, vascular endothelial growth factor levels, and histological examination of the liver tissues were detected for all groups. Results and conclusion ASP caused a significant increase in glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and vascular endothelial growth factor levels. A combination of OM (100 or 300 mg/rat) with ASP (50 or 100 mg/rat) improved most of the previous parameters. Histological examination of the liver showed some abnormality, but no significant morphological changes in G6, G7, G8, and G9. The treated rats (G2 and G3) showed hepatic fibrosis, nuclear changes, hepatocyte degeneration disruption hepatic cords, and cytoplasmic vacillations. ASP groups treated with OM showed improvement of many hepatic changes. Thus, OM may have a protective effect on ASP hepatotoxicity.

Potential effects of low molecular weight phthalate esters (C16H22O4 and C12H14O4) on the freshwater fish Cyprinus carpio.

The aim of the present study is to assess the toxic effect of dibutyl phthalate (DBP) and diethyl phthalate (DEP) on the freshwater fish Cyprinus carpio. The median lethal concentrations of DBP and DEP for 96 h are found to be 35 and 53 mg L-1, respectively. Fish were exposed to 3.5 mg L-1 (Treatment I) and 1.75 mg L-1 (Treatment II) of DBP and 5.3 mg L-1 (Treatment I) and 2.65 mg L-1 (Treatment II) of DEP for a period of 35 days. The DBP and DEP exposed fish show a concentration based toxic effect on the selected parameters of this study. The hematological parameters, such as hemoglobin (Hb), hematocrit (Hct) and erythrocyte (RBC), were found to decrease in the DBP and DEP treated fish, whereas their leucocyte (WBC) count increased compared to that of the control groups. A biphasic response is noted in the erythrocyte indices, such as mean cellular volume (MCV), mean cellular hemoglobin (MCH) and mean cellular hemoglobin concentration (MCHC), throughout the study period. Exposure to DBP and DEP caused a significant (p < 0.05) decrease in sodium (Na+), potassium (K+), and chloride (Cl-) levels in the gill and brain of the fish throughout the study period when compared to that of their respective controls. The plasma protein level decreased in all the treatments, whereas the plasma glucose level significantly increased in the DBP and DEP exposed fish. Maximum inhibition of Na+/K+-ATPase activity was noticed in the gill and brain of the fish exposed to DBP and DEP. The cholinesterase (ChE) activity in the brain of the fish significantly decreased throughout the study period. A significant (p < 0.05) increase in glutamate oxaloacetate transaminase (GOT) and glutamic pyruvate transaminase (GPT) activity was noted in the fish exposed to both toxicants. The antioxidant enzymatic parameters such as superoxide dismutase (SOD) and catalase (CAT) activities were found to decrease in the gill and liver of the DBP and DEP treated fish, whereas a significant (p < 0.05) increase in lipid peroxidation (LPO) was observed. The above mentioned parameters could be used as potential biomarkers in clinical trials for the assessment of plasticizers. This study provides indispensable information towards future research on the effect of plasticizers on non-target organisms including humans.

Liver damage in automotive and industrial workers of the glass.

High doses of organic solvents can cause hepatic disease. We investigated whether exposure to low doses of solvents in automotive and industrial workers may lead to changes in liver tests. We studied the liver parameters (glutamic oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), gamma-glutamyl-traspeptidasi (γ-GT), alkaline phosphatase (PHA), total (TB) and direct bilirubin (DB) of 24 workers exposed to organic solvents and of 30 unexposed controls. A significant increase of GOT, GPT and γ-GT was found in exposed workers compared to unexposed controls workers. The ratio GPT/GOT was significantly higher among the exposed compared to controls. The results confirmed the hypothesis that exposure to low doses of solvents may determine a liver damage.

Risk factors for liver abscess formation in patients with blunt hepatic injury after non-operative management.

To identify risk factors for liver abscess formation in patients with blunt hepatic injury who underwent non-operative management (NOM). From January 2004 to October 2008, retrospective data were collected from a single level I trauma center. Clinical data, hospital course, and outcome were all extracted from patient medical records for further analysis. A total of 358 patients were enrolled for analysis. There were 13 patients with liver abscess after blunt hepatic injury. Patients with abscess had a significant increase in glutamic oxaloacetic transaminase (GOT, p=0.006) and glutamic pyruvic transaminase (GPT, p<0.0001), and a decrease in arterial blood pH (p=0.023) compared to patients without abscess in the univariate analyses. In addition, high-grade hepatic injury and transarterial embolization (TAE, p<0.001) were also risk factors for liver abscess formation. Five factors (GOT, GPT, pH level in the arterial blood sample, TAE, and high-grade hepatic injury) were included in the multivariate analysis. TAE, high-grade hepatic injury, and GPT level were statistically significant. The odds ratios of TAE and high-grade hepatic injury were 15.41 and 16.08, respectively. A receiver operating characteristic (ROC) analysis was used for GPT, and it suggested cutoff values of 372.5 U/L. A prediction model based on the ROC analysis had 100% sensitivity and 86.7% specificity to predict liver abscess formation in patients with two of the three independent risk factors. TAE, high-grade hepatic injury, and a high GPT level are independent risk factors for liver abscess formation.

Effect of activated human protein C on disseminated intravascular coagulation induced by lipopolysaccharide in rats.

Protein C is the zymogen of an anticoagulant serine protease and is converted to its active form (activated protein C: APC) by thrombin in the presence of thrombomodulin. APC plays an important role in regulating coagulation and fibrinolysis by inactivating not only blood coagulation factors Va and VIIIa but also type-1 plasminogen activator inhibitor (PAI-1). The aim of the present study was to examine the effect of a human APC product (designated as CTC-111), compared with that of heparin, on the disseminated intravascular coagulation (DIC) induced by lipopolysaccharide (LPS) in rats. LPS (1 mg/kg/h) infusion was performed through a femoral vein for 4 h. One-fifth amount of the total dosage of CTC-111 or heparin was injected into the other femoral vein, followed by a 4-h infusion of the remainder. Both CTC-111 (10,000-100,000 U/kg) and heparin (400-800 IU/kg) inhibited the decrease in platelet count and fibrinogen level equally. The prolonged activated partial thromboplastin time and prothrombin time observed in DIC rats were further elongated in both CTC-111- and heparin-treated rats. But, this prolongation was less in CTC-111-treated rats than in the heparin-treated ones. Heparin inhibited the increase in fibrin and fibrinogen degradation products more prominently than CTC-111. On the other hand, CTC-111 strongly inhibited the increase in PAI-1 activity but heparin did not. These results suggest that CTC-111 may enhance fibrinolysis through its direct inhibitory effect on PAI-1. The parameters for liver or renal damage, i.e., plasma glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), creatinine (Cre) and blood urea nitrogen (BUN), were significantly increased by LPS infusion. Both CTC-111 (100,000 U/kg) and heparin (800 IU/kg) decreased the increase in GOT and GPT levels significantly, whereas neither affected the increase in Cre or BUN. From these results, the activation of the blood coagulation system might partially contribute to the progression of liver damage caused by LPS, and might be less involved in the progression of renal damage in this model. In conclusion, CTC-111 showed both anticoagulant and profibrinolytic activity in the LPS-induced DIC model without excessive prolongation of coagulation time. From these results, CTC-111 is expected to be a useful remedy for DIC without the risk of bleeding.

Activities of alkaline phosphatase, glutamate oxaloacetate transaminase and glutamate pyruvate transaminase in liver and serum of &lt;I&gt;Trypanosoma brucei&lt;/I&gt;-infected rats treated with honey

Alkaline phosphatase, glutamate oxaloacetate transaminase and glutamate pyruvate transaminase activities were assessed in rats highly infected with federe strain of Trypanosoma brucei and treated with honey. Therapeutic effect of honey on parasitaemia was also assessed. Results show an extension in the life span of infected but treated rats from 12 days for control to 19 days for infected honey-treated rats. Parasitaemia was also effectively lowered. Alkaline phosphatase activity was increased in the serum but not significantly different in the liver. Glutamate oxaloacetate transaminase and glutamate pyruvate transaminase were also increased in the serum but there is decrease in glutamate pyruvate transaminase activity in the liver. There were no significant differences in glutamate oxaloacetate transaminase activity in the liver. Results suggest that, honey could be a potential agent in the management of African trypanosomosis. However, it leads to decrease in glutamate pyruvate transaminase activity in the liver suggesting liver damage. Increase in glutamate oxaloacetate transaminase and alkaline phosphatase activities in the serum also suggest possible damage to other organs where these maybe abundant. Keywords : honey, alkaline phosphatase, transaminase, sleeping sickness Biokemistri Vol. 17(2) 2005: 185-191

Inhibition of Matrix Metalloproteinase on Hepatic Transforming Growth Factorβ1 and Caspase-3 Activation in Hemorrhage

Hemorrhage initiates an inflammatory response that induces the systemic release of cytokines and sequestration of polymorphonuclear neutrophils. Sequestered polymorphonuclear neutrophils release proteases, including matrix metalloproteinases (MMPs) that degrade elements of the extracellular matrix, contributing to the morbidity and mortality seen from hemorrhage. Activation of MMPs may be associated with changes in transforming growth factor beta1 (TGF-beta1) and caspase-3 signaling pathways. In this study, the authors examined hemorrhage-induced changes in the expression of rat hepatic MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-l), TGF-beta1, and caspase-3 activities in the presence and absence of the MMP inhibitor hydroxamate. Hemorrhagic shock was induced in fasted, anesthetized, and cannulated rats by rapid phlebotomy to a mean arterial pressure level of 40 mm Hg, maintained for 90 minutes by withdrawal and infusion of blood, followed by a resuscitation period of lactated Ringer's infusion. Rats received either hydroxamate (25 mg/kg) or vehicle by gavage before hemorrhage. Twenty-four hours after resuscitation, plasma and liver samples were collected. Liver MMP-9, TGF-beta1, and caspase-3 levels were quantified by Western immunoblotting. Plasma glutamic oxaloacetic transaminase (GOT) and plasma glutamic pyruvic transaminase (GPT) were determined enzymatically. Plasma GOT, plasma GPT, and liver MMP-9, TGF-beta1, and caspase-3 levels were all significantly elevated at 24 hours postresuscitation when compared with the control values. Hepatic TIMP-1, an in vivo inhibitor of MMP-9, was unaltered at 24 hours. Hydroxamate treatment reduced GOT, GPT, MMP-9, TGF-beta1, and caspase-3 levels at 24 hours. The mortality of hemorrhaged untreated rats was 29% after 24 hours, and pretreatment with hydroxamate reduced mortality to 0%. These results indicate the beneficial effects of MMP inhibitor in preventing an increase in GOT, GPT, MMP-9, TGF-beta1, and caspase-3 activity with the potential for improvement of hepatic injury due to hemorrhage.

Influence of hypothermic conditions on primary porcine hepatocyte-entrapped hollow fiber bioreactors

Transportation of bioartificial liver (BAL) device with viable cells and higher metabolic functions are necessary. The aim of this study is to evaluate hypothermic (4 °C) influence on the performance of hepatocyte-entrapped hollow fiber bioreactors, as well as the effects on cell function with or without medium supplement. Oxygen consumptions were stable at average of 15–25 mmHg per cartridge during 8 h normothermic incubation after cold-perfusion and cold-non-perfusion. All groups showed increase in glutamic oxaloacetic transaminase (GOT) and lactate dehydrogenase (LDH) level. Urea production and albumin synthesis were only slightly higher in cold-perfusion groups than that of the cold-non-perfusion groups and the control. There were no significant differences in the metabolic functions of bioreactors between each study groups during normothermic operation. Our study suggests that the use of a preliminary cold-storage step prior to normal culture condition or clinical therapy can prolong the transportation time without changing various functions of the BAL device.

Hepatotoxic and haematological effects of Nigerian Bonny light crude oil in male albino rats

The effect of Bonny light crude oil was assessed in adult albino rats. The rats were administered with 200, 400, and 800 mg/kg of the crude oil orally for 7 days. Fluid intake was measured daily, and the initial and final animal body weight recorded. Oral crude oil at these doses produced no effect on feed and fluid intake between the test groups and the control group. There was a significant decrease in body weight compared to the control group after 7 days of treatment with the different doses of crude oil. The toxic effects of the liver and hematological effects were assessed. The packed cell volume (PCV) and total white blood cell (WBC) of the 200 mg/kg group were significantly decreased compared to the respective control values. Administration of 200, 400, and 800 mg/kg of Bonny light crude oil, caused a significant dose-dependent increase in glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) levels, but a significant decrease in the alkaline phosphatase (AP) level compared to the control. Histological examination indicates that crude oil induced severe pathologic changes in the forms of necrosis and oedema.

Inhibition of matrix metalloproteinases by chemically modified tetracyclines in sepsis.

Sepsis precipitates a systemic inflammatory stimulus that causes systemic release of cytokines and sequestration of polymorphonuclear neutrophils, resulting in degranulation of matrix metalloproteinases (MMPs), which causes extracellular matrix basement membrane degradation. One of the important anti-inflammatory properties of tetracyclines is their ability to inhibit MMPs. In this study, we focused on the regulation of MMPs in sepsis and their reduction by treatment with nonantimicrobial chemically modified tetracyclines (CMTs), which retain their anti-inflammatory activity. Sepsis was induced by cecal ligation and puncture (CLP) method. At 24 h and 1 h before CLP, some rats received CMT-3 (25 mg/kg), another group of rats received hydroxamate (H; an inhibitor of MMP; 25 mg/kg), and untreated rats received saline by gavage. At 0 h, 0.5 h, 1.5 h, and 24 h after CLP, blood and liver samples were collected. Plasma and liver MMP-9 by zymography and Western immunoblotting, plasma nitric oxide by measuring nitrate level, plasma glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) by enzymatic method, and liver gelatinase by radiolabeled gelatin lysis assay and 24 h mortality were determined. Plasma MMP-9 (92 kDa), nitrate, and GOT and GPT levels were elevated compared with the time 0 level and reached peak at 1.5 h CLP and remained high for 24 h. Both CMT-3 and H treatment reduced GOT,GPT, 92-kDa gelatinase, and nitrate levels throughout the 24 h. CMT-3 and H are equally effective in sepsis treatment. The 24-h mortality for CLP rats was 30%, whereas pretreatment with CMT-3 and H resulted in 0% mortality. Hepatic MMP-9 and gelatinase activity increased significantly after CLP, and pretreatment with CMT-3 and H inhibited these expressions. These results indicate the beneficial effect of CMT-3 in preventing the increase in GOT, GPT, NO, MMP-9, gelatinase activity, and the ensuing septic shock.

Isquemia hepática normotérmica em ratos: estudo da lesão celular através do uso de clampeamento pedicular contínuo e intermitente

OBJETIVO: Avaliar as alterações bioquímicas decorrentes da isquemia hepática normotérmica, seguida de reperfusão em duas modalidades de clampeamento da tríade portal em ratos. MÉTODO: Trinta ratos Wistar machos pesando entre 250 e 320 gramas foram divididos em três grupos de 10 animais cada. Induzimos 40 minutos de isquemia hepática por clampeamento pedicular contínuo (grupo I) ou intermitente (grupo II). No grupo controle não houve clampeamento. Como parâmetro de lesão hepatocelular adotamos a concentração plasmática de: transaminase glutâmico oxalacética (TGO), transaminase glutâmico pirúvica (TGP) e lactato desidrogenase (LDH). Colhemos as amostras de sangue no início (T1) e no final da cirurgia (T2). Todos os animais foram submetidos ao mesmo tempo operatório: 60 minutos. RESULTADOS: Não houve diferença estatística nos valores iniciais (T1) das três enzimas nos três grupos. Todos apresentaram aumento significativo das enzimas do momento 1 (T1) para o momento 2 (T2). Houve diferença estatística no aumento médio de TGO e TGP entre os três grupos, sendo o maior aumento encontrado no grupo I e o menor, no grupo controle. Não houve diferença significativa, em relação à LDH, entre o grupo II e o grupo controle. No grupo I, entretanto, houve aumento significativo em relação aos demais. Conclusão: Comparado ao clampeamento contínuo, para um período total de 40 minutos de isquemia, o clampeamento da tríade portal em ratos realizado de forma intermitente, com ciclos de 10 minutos de isquemia e 5 minutos de reperfusão, provoca menor dano hepatocelular, o que foi constatado pela menor alteração enzimática.

Evaluation of oxidative stress during apoptosis and necrosis caused by d-galactosamine in rat liver

Eighteen and twenty-four hours after intraperitoneal administration of d-galactosamine (1 g/kg body weight) to rats, the activity of caspase-3-like protease in the liver increased significantly compared with that in the control group given saline. Histological examinations including the in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method found apoptotic hepatocytes 18 hr after the administration of d-galactosamine. Caspase-3 activity was barely detectable in the plasma of control rats, but increased significantly 24 hr after drug administration along with a dramatic increase in glutamate-oxaloacetate transaminase (GOT). These results indicated that d-galactosamine causes apoptosis in the liver by activating caspase-3, which is released to the plasma by secondary necrosis. The concentration of lipid hydroperoxides in the liver increased significantly 24 hr after d-galactosamine administration. In contrast, the concentration of vitamin C in the liver decreased significantly 18 and 24 hr after d-galactosamine administration. These results suggest that d-galactosamine induces severe oxidative stress in the liver, leading to extensive necrosis.

Hepatoprotective and antioxidative properties of Salacia reticulata: preventive effects of phenolic constituents on CCl4-induced liver injury in mice.

The hepatoprotective effects of the hot water (SRHW) and methanolic (SRM) extracts from the roots and stems of Salacia reticulata were examined using an oxidative stress-induced liver injury model. Both SRHW and SRM extracts (400 mg/kg, p.o.) significantly suppressed the increase in glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activities in carbon tetrachloride (CCl4)-treated mice. These extracts also inhibited CCl4-induced thiobarbituric acid-reactive substance (TBA-RS) formation, which indicates increased lipid peroxidation in the liver. A good correlation (r=0.945, p<0.01) was observed between the amount of phenolic compounds in the extracts and their inhibitions of TBA-RS formation. The IC50 values of the extracts on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging were less than 10 microg/ml and the antioxidative activities of six phenolic compounds from the roots of S. reticulata were examined. Mangiferin, (-)-4'-O-methylepigallocatechin, and (-)-epicatechin-(4beta-->8)-(-)-4'-O-methylepigallocatechin, which a principal phenolic compounds, showed potent scavenging activity on DPPH radicals and their concentrations required for 50% reduction of 40 microM DPPH radicals were 5.9, 10, and 3.2 microM, respectively. On the other hand, against the CCl4-induced serum GOT and GPT elevations and TBA-RS formation in mice, mangiferin and (-)-4'-O-methylepigallocatechin showed potent activity at a dose of 100 mg/kg, but (-)-epicatechin-(4beta-->8)-(-)-4'-O-methylepigallocatechin did not. These results suggest that the antioxidative activity of the principal phenolic compounds is involved in the hepatoprotective activity of S. reticulata.

Evaluation of oxidative stress during apoptosis and necrosis caused by carbon tetrachloride in rat liver

After 12, 18, and 24 h of oral administration of carbon tetrachloride (as a 1:1 mixture with mineral oil: 4 ml/kg body weight) to rats, the activity of caspase-3-like protease in the liver increased significantly compared to that in the control group that was given mineral oil (4 ml/kg). In plasma, the activity of caspase-3 was barely detectable in the control rat, but increased significantly 24 h after drug administration along with a dramatic increase in glutamate oxaloacetate transaminase. These results indicate that carbon tetrachloride causes apoptosis in the liver by activating caspase-3, which is released to plasma by secondary necrosis. After 18 and 24 h of carbon tetrachloride administration, the liver concentration of hydrophilic vitamin C was decreased significantly, while that of hydrophobic vitamin E was not affected. The plasma concentration of vitamins C and E was not influenced significantly. These results suggest that carbon tetrachloride induces oxidative stress mainly in the aqueous phase of the liver cell.

28-day repeated oral toxicity study of a hypolipidemic agent, NK-104 in rats.

NK-104, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, was administered orally to Wistar rats at a dose of 2, 10, 50 or 100 mg/kg for 28 days consecutively, and the toxicity of NK-104 and its recovery with 2 weeks cessation of drug treatment were examined. As major clinical signs, loose stool, diarrhea, crouching and emaciation were observed in both sexes at 50 or 100 mg/kg, and all females at 100 mg/kg died or became moribund due to severe emaciation before the completion of treatment. The suppression of body weight gain or decrease in body weight was observed in the female dose group at 50 mg/kg and both sexes at 100 mg/kg. Decreased food intake was observed in both sexes at 100 mg/kg. Moreover, an increase in cholinesterase (Ch.E) in the male dose groups at 50 and 100 mg/kg and an increase in glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) in the female dose group at 50 mg/kg were observed in blood chemistry testing. Macroscopic examination showed thickening of the forestomach mucosa in the groups of 10 mg/kg or more. Microscopic examination revealed hyperkeratosis and hypertrophy of the spinous layer associated with both cell infiltration of the mucosal propria and submucosal edema. In addition, skeletal muscle lesions including atrophy, vacuolation and focal necrosis were observed in the female dose groups at 50 and 100 mg/kg. The above-mentioned microscopic changes were not observed on cessation of drug treatment. The non-toxic dose level of NK-104 in the 28-day repeated oral toxicity study using rats was determined to be 2 mg/kg.

Comparison of Postoperative Liver Dysfunction Following Halothane and Sevoflurane Anesthesia in Women Undergoing Mastectomy for Cancer

The incidence of an abnormal increase in the serum levels of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) following anesthesia with halothane and 65% nitrous oxide in oxygen (halothane group) or with sevoflurane and 65% nitrous oxide in oxygen (sevoflurane group) was compared in women undergoing surgery for breast cancer. An abnormal increase in GOT and GPT, both defined as higher than 50 IU, occurred postoperatively in 2 of the 150 patients (1.7%) in the sevoflurane group, and in 37 of the 200 (18.5%) in the halothane group (P<0.001). The elevated levels of serum transaminases after sevoflurane ranged from 50 to 65 IU whereas those after halothane ranged from 50 to 1000 IU, except for a value greater than 5000 IU in 1 patient. In the halothane group, there was a significant association between postoperative increases in serum transaminases and previous exposure to inhalation anesthetics, postoperative mitomycin therapy, and radiation therapy (all P<0.001). The results of multivariate analysis, when data from all patients were taken together, showed that the type of anesthetic (halothane) was the highest factor related to postoperative increases in GOT and GPT (odds ratio 35.85; 95% confidence interval 5.92–217.37), followed next by prior exposure to inhalation anesthetics (8.65; 2.96–25.27), postoperative radiation therapy (4.37; 1.70–11.19), and postoperative mitomycin therapy (3.56; 1.23–10.35). These data suggest that sevoflurane is less likely to cause anesthesia-related liver dysfunction than halothane.

Effects of a highly selective synthetic inhibitor of plasma kallikrein on disseminated intravascular coagulation in rats

We found a new, highly selective plasma kallikrein inhibitor, trans-4-aminomethyl-cyclohexanecarbonylphenylalanine 4-carboxymethylanilide hydrochloride, called PKSI-527 in our laboratories. This study was conducted to evaluate PKSI-527, on thromboplastin (TP)- and endotoxin (LPS)-induced disseminated intravascular coagulation (DIC) in rats. PKSI-527 was infused intravenously at 0.1 mg/kg/min for 250 min. Three of the parameters of the coagulation and fibrinolysis system, fibrinogen level, platelet counts and fibrin(ogen) degradation products (FDP) level were assayed. PKSI-527 prevented the change in the coagulation and fibrinolysis system in LPS-induced DIC, however it was not clearly effective in TP-induced DIC. The parameters of organ failure, such as serum glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), creatine phosphokinase (CPK), lactate, blood urea nitrogen and β-glucuronidase, were assayed. Although the changes in the fibrinogen level, platelet counts and FDP level were almost the same in both models, the parameters of organ failure apparently increased in LPS-induced DIC more so than in TP-induced DIC. PKSI-527 significantly suppressed the increases in GOT and GPT in LPS-induced DIC. These results indicate that plasma kallikrein may play a significant role in LPS-induced DIC. Therefore, PKSI-527, as a synthetic plasma kallikrein inhibitor may be a valuable tool to explore the mechanism of DIC and the accompanying organ failure.