Modulation of endotoxin stimulated interleukin-6 production in monocytes and Kupffer cells by S-adenosylmethionine (SAMe)

Interleukin-6 (IL-6) is a multifunctional cytokine having primarily anti-apoptotic and anti-inflammatory effects. Recent reports have documented that IL-6 plays a key role in liver regeneration. Intracellular deficiency of S-adenosylmethionine (SAMe) is a hallmark of toxin-induced liver injury. Although the administration of exogenous SAMe attenuates liver injury, its mechanisms of action are not fully understood. Here we investigated the effects of exogenous SAMe on IL-6 production in monocytes and Kupffer cells. RAW 264.7 cells, a murine monocyte cell line, and isolated rat Kupffer cells were stimulated with lipopolysaccharide (LPS) in the absence or presence of exogenous SAMe. IL-6 production was assayed by ELISA and intracellular SAMe concentrations were measured by HPLC. We have found that exogenous SAMe administration enhanced both IL-6 protein production and gene expression in LPS-stimulated monocytes and Kupffer cells. Cycloleucine (CL), an inhibitor for extrahepatic methionine adenosyltransferases (MAT), inhibited LPS-stimulated IL-6 production. The enhancement of LPS-stimulated IL-6 production by SAMe was inhibited by ZM241385, a specific antagonist of adenosine (A2) receptor. Our results demonstrate that SAMe administration may exert its anti-inflammatory and hepatoprotective effects, at least in part, by enhancing LPS-stimulated IL-6 production.     

Hepatic and renal changes in albino rats caused by the administration of chromium (VI) in drinking water

The effects of sodium chromate administered in drinking water on liver and kidney of albino rats have been studied, through investigation of histological alterations and monitoring changes on serum urea levels and transaminases (GOT and GPT). Measurements have been done after 4, 8 and 12 weeks of treatment. The liquid intake of treated animals decreases with time. The amount of water drunk by treated rats is 1/2 of that drink by controls after 12 weeks. The histological alterations in liver and kidney are similar to those described elsewhere. Serum urea level is always higher in treated animals than in controls. GOT levels are similar in both treated and control rats, although always higher in the treated ones. GPT levels increase significantly after 12 weeks of treatment.     

Effect of dimethylsulphoxide on the functional characteristics of isolated perfused rat liver

Exposure of rat liver, perfused with 7% BSA in Krebs-Ringer bicarbonate buffer, to 1.4 m Me₂SO at 35 °C had no effect on the release of potassium from the livers, but the rate of urea synthesis fell from 0.6 to 0.1 μmol/min. Bile production also decreased and the total amount collected during perfusion was only half that produced by controls. After perfusion for 4 hr at 35 °C control livers and those exposed to Me₂SO started to release GOT into the perfusate but livers exposed to the cryoprotective compound released the enzyme at a faster rate.Exposure of livers to Me₂SO at 5 °C resulted in potassium being released at a slower rate (0.98 μmol/min) than from cooled controls (1.19 μmol/min) and urea synthesis was decreased from 0.8 to 0.2 μmol/min. Bile production also declined but, because bile flow normally ceases during hypothermia, the effect on this aspect of liver function was probably less than was found at 35 °C. Release of GOT from livers exposed to Me₂SO at 5 °C was quite different from that observed at 35 °C; the enzyme appeared in the perfusate after about 8 hr and it was present in much lower concentration than was found with appropriately cooled controls which started to release the enzyme after 6 hr.Thus, exposure of rat liver to Me₂SO at 5 °C appears to be slightly less damaging than exposure at 35 °C and it may even have a beneficial effect on some aspects of liver function in vitro.     

高效氯氰菊酯对欧洲鲫鱼血清谷丙转氨酶和谷草转氨酶活性的影响

Synthetic pyrethroids are considered as possible sub-stitutesfor some organophosphate carbamates or organochlo-rine insecticides,and have been used extensivelyfor morethantwo decades[1].Pyrethroids are preferred over otherinsecticides because of their easy degradation into non-toxic or less toxic metabolites under natural conditions.Consequently,there has recently beena dramatic increaseinthe use of pyrethroid pesticides to control insect pests.However,synthetic pyrethroids were also reported …     

Protective effect of soybean against hepatocarcinogenesis induced by DL-ethionine

There has been increasing interest in the value of using soybean to delay or reduce the tumor incidence. This study was undertaken to investigate the possible protective effects of soybean against hepatocarcinogenesis induced by DL-ethionine. Accordingly, we measured biochemical changes occurring in serum and liver of rats treated with DL-ethionine in the presence or absence of soybean. Male albino rats were fed a control diet containing the hepatocarcinogen, DL-ethionine, or the control diet plus soybean 30%, or the control diet plus soybean plus DL-ethionine 0.25% for three months and then returned to a control diet for up to nine months. Rats fed a control diet plus DL-ethionine showed a gradual decrease in liver DNA, RNA, total protein, and liver weight and enzyme activities of liver transaminases (GOT and GPT) and alkaline phosphatase over the 7-month study period. This was followed by a large increase in the liver parameters at the end of the 9(th) month, except for 5'-nucleotidase and glucose-6-phosphatase that showed a large decrease. On the other hand, a gradual increase in the serum enzyme activities of GOT, GPT, 5-nucleotidase, alkaline phosphatase, and in the albumin/globulin (A/G) ratio is observed in the group of rats fed a control diet plus DL-ethionine compared to the control group over 8 months, and this was followed by a large increase in all serum parameters studied at nine-months. The administration of 30% soybean to the rat diet in addition to DL-ethionine maintained all parameters studied at near control values until the end of the 9(th) month. This study suggests that soybean has a protective effect against the hepatocarcinogenesis induced by DL-ethionine.     

Studies on glutamic-oxalacetic (GOT) and glutamic-pyruvic (GPT) transaminases of swine kidney worm Stephanurus dentatus (Diesing, 1839). I. Assay and general properties.

Biochemical studies on the two transaminases GOT and GPT of swine kidney worm Stephanurus dentatus have been made. GOT has been found much more active than GPT. Enzyme activities are based on the formation of oxaloacetate (GOT) or pyruvate (GPT) from aspartic acid and alanine respectively with oxoglutarate. A linear relationship is observed between the enzyme concentration and activity. GOT shows a maximum activity at pH 8.0 and Michaelis constant 9 X 10(-3) M for male and 2.9 X 10(-3) M for female. GPT has an optimum pH of 7.5 and a Michaelis constant 19 X 10(-3) M for male and 8 X 10(-3) M for female. The optimum temperature for both GOT and GPT was 60 degrees C.     

Serum and liver enzyme changes in rats after short term exposure to dichlorvos

Rat serum and liver ICDH, OCT, GOT and GPT activities are significantly elevated 2-6 hr after i.p. injections of single doses (2.5 mg/kg body wt) of dichlorvos. ICDH, OCT, GOT and GPT activities are significantly increased in serum and liver of rats receiving daily injections (0.25 mg/kg body wt) for 7 days. Although liver SD is significantly elevated in the single and repeated dosage study, serum SD appears unaffected at these levels of dichlorvos toxicity. Changes in serum OCT activity estimations maybe a useful single parameter for screening pesticides for potential hepatotoxic effects in humans and farm animals.     

The role of thromboxane A2 [TxA2] in liver injury in mice

The role of thromboxane A2 (TxA2) in CCl4-induced liver disease was investigated in mice. Significant elevation of TxB2 in the liver was observed 6 hours after the injection of CCl4. Administration of OKY-046, a selective TxA2 synthetase inhibitor (10 and 50 mg/kg) and ONO-3708, a TxA2 receptor antagonist, (0.5, 1 and 2 mg/Kg) suppressed the elevation of serum GOT and GPT levels and histopathological changes of the liver. In addition, OKY-046 inhibited the elevation of TxB2 in the liver. When U-46619, a stable TxA2 mimetic was injected i.v. into the mice, clear elevation of serum GOT and GPT levels and histopathological score of the liver were observed. These results suggest that TxA2 play a role for the onset of CCl4-induced liver injury in mice.     

Effect of some--SH and other reagents on aspartate aminotransferase and L-alanine aminotransferase of Paramphistomum explanatum Fischoeder, 1901.

Studies on aspartate aminotransferase (GOT) and L-alanine aminotransferase (GPT) of Paramphistomum explanatum have shown that GPT activity has more than twice the activity of GOT. The effect os some--SH reagents like cadmium, mercury, silver and iodoacetamide revealed that both enzymes were inhibited except that GOT was insensitive to cadmium ions. GPT was found to be much more sensitive to--SH reagents than GOT. There was unusual reaction to the two thiols used, cysteine and mercaptoethanol. Cysteine inhibited both the enzymes and mercaptoethanol activated GPT and inhibited GOT. Thiols in combination with iodoacetamide showed that the strong inhibitory effect of cysteine on both enzymes was reduced by iodoacetamide, but with mercaptoethanol the inhibitory effect on GOT was greater than when either of them was used alone, while GPT the effect of either counteracted each other. EDTA activated both enzymes and partially protected mercury inhibition of both enzymes and silver inhibition GOT only. It provided no protection against silver inhibition of GPT but complete protection of GPT against total inhibition by cadmium ions.     

Acceleration of metabolism of stress-related substances by L-carnosine]

Liver dysfunction was produced in the rat by injecting CCl4 subcutaneously in the back twice a week, and the effects of L-carnosine (CAR) on the resulting liver injury were examined. When CCl4 was administered to 6-week-old rats for 9 weeks, GOT and GPT values increased, but these changes were suppressed in the group concomitantly treated with CAR, indicating a protective effect of the agent on liver function. No such preventive effects of CAR was observed in 40-week-old rats, but when the CCl4 administration was discontinued after 4 weeks, GOT and GPT decreased to normal levels within 1 week of discontinuation, indicating a therapeutic effect of CAR on hepatopathy. Based on these findings, we determined the cortisone beta-reductase activity in the rat liver. The increase in this enzyme activity in the group treated with CAR indicated acceleration of cortisone metabolism. Changes of blood cortisol level and cerebral and blood noradrenaline (NA) levels were studied by exposing 6-week-old rats to electric shocks at 30 V. Cortisol released into the circulation after the stress was quickly metabolized in the CAR group and the blood level normalized after 3 hours. Following the release of NA from the brain into the circulation, the NA concentration rapidly returned to the normal level both in the brain and the blood. CAR enhanced the liver function and accelerated the metabolism of stress-related substances also in aged animals. CAR, moreover, restored the RNA contents of the mouse spleen and the immunological abilities represented by PFC reaction, which are reduced by stresses such as forced immersion, fasting, and administration of MMC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the toxicity of cypermethrin pesticide on organs weight loss and some biochemical and histological parameters

An increase in global food demand has resulted in a significant increase in the use of pesticides in agriculture. Synthetic pyrethroid pesticides account for over 30% of the global pesticide use; Pyrethroid pesticides were used preferably over organochlorines and organophosphates due to their high effectiveness, low toxicity to non-target organisms and easy biodegrability. It has widespread applications in agriculture through the world and as well in Algeria. Cypermethrin is one of the most insecticidal pyrethroids widely used in agriculture regions of Setif. to control wide range of insect pests in a variety of crops. The aim of this study is to investigate the effects of cypermethrin (Cyper-Ac 271 g/l from the active substance of the cypermethrin) on hematological, biochemical parameters, body weight loss, and histopathological study of some organs. Male mice weighing 30-40g were used, separated in 5 groups, n=6, two groups controls given vehicle (oil vegetable) and three experimental groups (Cypermetherin and vegetable oil). The animals were gavaged by 1/5 LD50 (LD50 = 485 mg/kg b/w) for 2 and 4 weeks respectively, and with 1/20 LD50 for 12 weeks, then the animals sacrificed at the end of the experiment.. Blood was collected. Enzyme activities were assayed in the plasma samples obtained. Glutamate oxaloacetate transaminase (GOT), Glutamate pyruvate transaminase (GPT), Alkaline phosphatase (ALPH) and Glucose. Red blood cells, (RBC), and white blood cells (WBC) were calculated too. The samples of liver and kidney were processed for histology. The results indicated a significant increase in transaminases GOT, GPT, and AlP. The decrease in Hb, RBC and WBC which are related to the immunity, this is probably due to cell lyses explain the effect of Cypermetherin on erythropoeisis. cypermethrin treatment exhibited severe histopathological changes, especially in the liver and kideney accompanied by weight loss of some organs. We conclude that cypermethrin induces oxidative stress and modifies biochemical parameters and histological aspects of liver and kidney.     

Long-term starvation in Xenopus laevis daudin—III. Effects on enzymes in several tissues

• 1.1. Adult, female Xenopus laevis were subjected to 12 months of starvation.
• 2.2. Starvation resulted in a continuous reduction in the activity of both hepatic and renal glucose-6-phosphate dehydroganse.
• 3.3. Fructose-1,6-diphosphatase was significantly reduced at months 10 and 12 in the liver, and at months 4, 10, and 12 in the kidney.
• 4.4. Pyruvate kinase activity of muscle and liver decreased during the experimental period whereas the renal enzyme remained essentially unchanged.
• 5.5. Both hepatic and renal glutamate-pyruvate transaminase (GPT) and hepatic glutamate-oxaloacetate transaminase (GOT) showed a reduction of activity after 2 and 4 months of starvation followed by an increase in GPT but not in GOT.

     

A comparative study of glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) levels in the saliva of diabetic and normal patients

Diabetes has been reported to affect salivary glands adversely in humans and experimental models. Glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT) and lactate dehydrogenase (LDH) are salivary enzymes that also are widely distributed in animal tissues. We determined GOT and GPT levels in saliva samples of 100 type 1 and 30 type 2 diabetic patients using reflectance spectrophotometry and compared them to 30 age and sex matched healthy controls. Statistically significant differences were observed in the mean values of GOT and GPT in type 1 diabetics compared to type 2 and control groups. Significantly higher GOT levels were found in the 1–20 year age group of type 1 diabetics. Our findings suggest that salivary gland damage is due to the same immunological attack that affects pancreatic β cells and results in type 1 diabetes.     

Potential sensitivity of hepatic specific protein regucalcin as a marker of chronic liver injury

A novel calcium-binding protein regucalcin has been shown to be specifically expressed in the liver of various specifies including human. Regucalcin concentration in the serum of patients with chronic liver injury was estimated by enzyme-linked immunoadsorbent assay (ELISA) with rabbit-anti-regucalcin IgG. Serum samples were obtained from 42 persons who were diagnosed as liver disorder. Serum regucalcin concentration in all patients was in the range of 3.7-69.6 ng/ml, although regucalcin was not entirely seen in the serum of normal subjects (10 persons) without hepatitis. Meanwhile, in 18 patients with liver injury, serum glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) activities were normal value (less than 40 I.U./l). Serum GOT and GPT activities from 24 patients showed a comparatively higher level (50-234 I.U./l). The present results demonstrate the potential sensitivity of regucalcin as a marker of chronic liver injury. (Mol Cell Biochem 167: 187-190, 1997)     

Pharmacokinetics of Glutamate–Oxaloacetate Transaminase and Glutamate–Pyruvate Transaminase and Their Blood Glutamate-Lowering Activity in Na?ve Rats

Traumatic brain injury (TBI) and stroke lead to elevated levels of glutamate in the brain that negatively affect the neurological outcomes in both animals and humans. Intravenous administration of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) enzymes can be used to lower the blood glutamate levels and to improve the neurological outcome following TBI and stroke. The objective of this study was to analyze the pharmacokinetics and to determine the glutamate-lowering effects of GOT and GPT enzymes in na?ve rats. We determined the time course of serum GOT, GPT, and glutamate levels following a single intravenous administration of two different doses of each one of the studied enzymes. Forty-six male rats were randomly assigned into one of 5 treatment groups: saline (control), human GOT at dose 0.03 and 0.06?mg/kg and porcine GPT at dose 0.6 and 1.2?mg/kg. Blood samples were collected at baseline, 5?min, and 2, 4, 8, 12, and 24?h after the drug injection and GOT, GPT and glutamate levels were determined. The pharmacokinetics of both GOT and GPT followed one-compartment model, and both enzymes exhibited substantial glutamate-lowering effects following intravenous administration. Analysis of the pharmacokinetic data indicated that both enzymes were distributed predominantly in the blood (central circulation) and did not permeate to the peripheral organs and tissues. Several-hour delay was present between the time course of the enzyme levels and the glutamate-lowering effects (leading to clock-wise hysteresis on concentration-effect curves), apparently due to the time that is required to affect the pool of serum glutamate. We conclude that the interaction between the systemically-administered enzymes (GOT and GPT) and the glutamate takes place in the central circulation. Thus, glutamate-lowering effects of GOT and GPT apparently lead to redistribution of the excess glutamate from the brain's extracellular fluid into the blood and can reduce secondary brain injury due to glutamate neurotoxicity. The outcomes of this study regarding the pharmacokinetic and pharmacodynamic properties of the GOT and GPT enzymes will be subsequently verified in clinical studies that can lead to design of effective neuroprotective treatment strategies in patients with traumatic brain diseases and stroke.     

Blood and liver enzymes in rainbow trout (Salmo gairdneri Rich.) with emphasis on their diagnostic use: Study of CCl4 toxicity and a case of Aeromonas infection

The effect of one intraperitoneal injection of 1.33 ml of CCl₄ per kg of fish was studied. Two experimental series were performed and studied for 10 days (with diluent) and 24 h (pure CCl₄) periods. LDH, GOT, GPT, GR, GDH, CPK, G-6-Pase, and AlkPase were studied. The activity of all enzymes in blood increased: LDH (four times the control), GOT (two times), GPT (three times); they reached a maximal activity 12 h after injection of diluted CCl₄. The levels of some enzymes were also examined in the liver. With pure CCl₄, maximal enzyme activity in blood occurred earlier (6 h). A 6 to 10 times increase was observed for GOT, GPT, LDH, GR, and GDH. Histopathological observations were correlated with these enzymes studies.
An Aeromonas disease characterized by the destruction of the dermis, the exposure of the muscle, and by the presence of numerous petechiae in the liver enabled us to examine the relationships between naturally induced tissue damage and enzyme levels in blood. The levels of seven blood enzymes were determined and the most significant modifications were observed for LDH and CPK. which increased their concentration from 3 to 7 times respectively. A pyruvate saturation test demonstrated that LDH was probably from liver as it was observed after CCl₄ poisoning. The contribution of such biochemical studies in fish research is evaluated.     

Ethacrynic-acid-induced glutathione depletion and oxidative stress in normal and Mrp2-deficient rat liver

Oxidative stress in the liver is sometimes accompanied by cholestasis. We investigated the localization and role of multidrug-resistance-associated protein (Mrp) 2, a biliary transporter involved in bile-salt-independent bile flow, under ethacrynic acid (EA)-induced acute oxidative stress. Normal Sprague-Dawley rat (SDR) and Mrp2-deficient Eisai hyperbilirubinemic rat (EHBR) livers were perfused with 500 microM EA. The release of glutamic pyruvic transaminase (GPT) and thiobarbituric-acid-reactive substances (TBARS) from EHBR liver was markedly delayed compared with that from SDR liver. This is mainly due to the higher basal level of glutathione (GSH) in EHBR liver (59.1 +/- 0.3 nmol/mg protein) compared with SDR liver (39.7 +/- 1.5 nmol/mg protein). EA similarly induced a rapid reduction in GSH followed by mitochondrial permeability transition in the isolated mitochondria from both SDR and EHBR. Internalization of Mrp2 was detected before nonspecific disruption of the canalicular membrane and GPT release in SDR liver perfused with 100 microM EA. SDR liver preperfused with hyperosmolar buffer (405 mosmol/L) for 30 min induced internalization of Mrp2 without changing the basal GSH level, while elimination of hepatic GSH by 300 microM EA perfusion was significantly delayed thereafter. Concomitantly, hepatotoxicity assessed by the release of GPT and TBARS was also significantly attenuated under hyperosmolar conditions. In conclusion, preserved cytosolic and intramitochondrial GSH is the key factor involved in the acute hepatotoxicity induced by EA and its susceptibility could be altered by the presence of Mrp2.     

The effects of thromboxane A2 inhibitors (OKY-046 and ONO-3708) and leukotriene inhibitors (AA-861 and LY-171883) on CCl4-induced chronic liver injury in mice

The effects of OKY-046, a selective thromboxane A2 (TxA2) synthetase inhibitor, ONO-3708, a novel TxA2 receptor antagonist, AA-861, a selective 5-lipoxygenase inhibitor and LY-171883, a peptide leukotrienes (p-LTs) receptor antagonist on the chronic liver injury were investigated in mice. The chronic liver injury was induced by the injection of carbon tetrachloride (CCl4) two times a week for twelve weeks in mice. In chronic liver injury models, significant histopathological changes in the liver and extensive elevation of glutamate transaminase (GOT and GPT) activity were observed. Administration of OKY-046, ONO-3708, AA-861 and LY-171883 for 12 weeks suppressed the elevation of serum GOT and GPT levels and histopathological changes in CCl4-induced chronic liver injury. These results suggest that TxA2 and LTs inhibitors are effective for the onset and development of chronic liver injury in mice.     

Acute exposure to cadmium causes time-dependent liver injury in rats.

1. Serum enzymes activities of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT), after intraperitoneal injection of CdCl2 showed a maximum increase at 12 hours, contrary to the alkaline phosphatase (ALP) that showed a permanent decrease by that time. 2. Cadmium concentration in liver showed an increase at 6 and 12 hours, a decrease at 18, and a re-establishment to the initial values at 24 hours. 3. Liver microsomal membrane fluidity showed an increase at 6 hours followed by a decrease within 24 hours. Free radical generation was decreasing gradually up to 24 hours. 4. Gradually increasing changes were observed from the histological study.     

Post-treatment with N-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious rats

N-acetylcysteine (NAC) is an antioxidant and cytoprotective agent with scavenging action against reactive oxygen species and inhibitory effects on pro-inflammatory cytokines. In a previous study, we found that pretreatment with NAC attenuated organ dysfunction and damage, reduced the production of free radicals, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) following endotoxemia elicited by administration of lipopolysaccharide (LPS). In the present study, we tested the effects of post-treatment with NAC on the sepsis-induced change. Post-treatment imitates clinical therapeutic regimen with administration of drug after endotoxemia. Endotoxin shock was induced by intravenous injection of Klebsiella pneumoniae LPS (10 mg/kg) in conscious rats. Mean arterial pressure (MAP) and heart rate (HR) were continuously monitored for 48 h after LPS administration. NAC was given 20 min after LPS. Measurements of biochemical substances were taken to reflect organ functions. Biochemical factors included blood urea nitrogen (BUN), creatinine (Cre), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), aspartate transferase (GOT), alanine transferase (GPT), TNF-alpha, interleukin-6 (IL-6), and interleukin-10 (IL-10). LPS significantly increased blood BUN, Cre, LDH, CPK, GOT, GPT, TNF-alpha, IL-6, IL-10 levels and HR, and decreased MAP. Post-treatment with NAC diminished the decrease in MAP, increased the HR, and decreased the markers of organ injury (BUN, Cre, LDH, CPK, GOT, GPT) and inflammatory biomarkers (TNF-alpha, IL-6, IL-10) after LPS. We conclude that post-treatment with NAC suppresses the release of plasma TNF-alpha, IL-6, and IL-10 in endotoxin shock, and decreases the markers of organ injury. These beneficial effects protect against LPS-induced kidney, heart and liver damage in conscious rats. The beneficial effects may suggest a potential chemopreventive effect of this compound after sepsis.