Lipid Peroxidation In Liver Tissue Research Articles

Using iron precipitants to remove arsenic from water: Is it safe?

Arsenic-associated health complications are reported worldwide. Arsenic is a documented toxic element in drinking water. Removing arsenic from drinking water is widely dependent on iron-based techniques. Although inorganic arsenic has long been known to be toxic to humans, little is known about the toxic effect of the interaction between arsenic and iron. We investigated the effect of arsenic plus iron on the liver of rats. We gave rats sodium arsenite, iron, or sodium arsenite plus iron. Neither the arsenic-alone nor the iron-alone treatments altered their serum aspartate or alanine transaminase levels. However, a combination of non-toxic doses of arsenite and iron synergistically increased serum aspartate and alanine transaminase levels and lipid peroxidation in liver tissue. Therefore, we hypothesize that arsenic plus iron synergistically induces hepatic damage mediated through oxidative stress in rats. Our study indicates an important public health issue: using iron precipitants to remove arsenic from water may cause oxidative hepatic damage in humans.

Aquilegia vulgaris extract protects against the oxidative stress and the mutagenic effects of cadmium in Balb/c mice

Cadmium (Cd) is a non-essential element and is a widespread environmental pollutant. Exposure to cadmium can result in cytotoxic, carcinogenic and mutagenic effects. The aim of the current work was to evaluate the protective effect of Aquilegia vulgaris extract against the oxidative stress and the genotoxicity induced by Cd using the chromosomal aberrations in somatic and germ cells assay and random amplified polymorphism DNA (RAPD-PCR) analysis. Forty male Balb/c mice were divided into four groups including the control group, Cd-treated group and the groups treated with the extract alone or plus Cd. The results indicated that Cd increased serum ALT, AST, urea, LDH, CK, lipid peroxidation in liver tissue accompanied with a significant decrease in GPX and SOD. Cd also increased the number of chromosomal aberrations in bone marrow and spermatocytes including structural and numerical aberrations. Animals treated with the extract alone were comparable to the control regarding all the tested parameters. The extract succeeded in preventing or diminishing the oxidative stress and the clastogenic effects of Cd. It could be concluded that Aquilegia vulgaris extract is a promising protective agent against oxidative stress and genotoxicity during the exposure to Cd.

Ultrastructural and biochemical changes in the turkeys liver after the chronic cadmium exposure

The aim of our study was to observe the chronic effects of cadmium and cadmium with zinc on the structure and histological changes in turkey liver by means of transmission electron microscopy and to examine whether concentrations of metals influence the activity of superoxide dismutase and lipid peroxidation in liver tissue. The ultrastructural changes were investigated in hepatocytes after 71 days exposure to cadmium (Cd group) and cadmium + zinc (Cd/Zn group). In Cd group, ultrastructural changes included swollen and round mitochondria with injured cristae, dilated rough endoplasmatic reticulum and depletion of glycogen granules. In the Cd/Zn group hepatocytes showed morphological features similar to those from the control group except the mitochondria. They had an oval or elliptical shape similar as in the control group, but the cristae were obviously loose and dissolved. The activity of superoxide dismutase (SOD) and the content of thiobarbituric acid reactive substances (TBARS) were determined. The specific activity of SOD was significantly increased in Cd group. In Cd/Zn group, zinc co-administration shows a protective effect. Alterations in the activitiy of superoxide dismutase showed that the toxic effect of cadmium is not only due to its high affinity for thiol groups, but also in the production of reactive oxygen species. Cadmium induced ultrastructural changes in the hepatocytes were not accompanied by a significant increase in tissue TBARS concentrations.

BCL-2 UPREGULATION AFTER 3-NITROPROPIONIC ACID PRECONDITIONING IN WARM RAT LIVER ISCHEMIA

We aimed to determine whether 3-nitropropionic acid (3-NPA) preconditioning protects rat livers against warm ischemia/reperfusion injury. We hypothesized that 3-NPA mediates its protective effects by Bcl-2 upregulation. Brown-Norway rats (200 g) were injected with 3-NPA (10 mg/kg intraperitoneally) 24 h before 90 min of selective warm in situ ischemia. In additional experiments, 30-day survival was studied after 90 min of warm liver ischemia and resection of nonischemic liver tissue. We demonstrate increased mRNA and protein levels of Bcl-2 by real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis in 3-NPA-pretreated rats. All treated animals survived, whereas all untreated rats died within 3 days after selective ischemia and resection of the nonischemic tissue. This corresponded well with a significant decrease of caspases 3 and 9 activity at 1 h of reperfusion after preconditioning with 3-NPA as compared with untreated rats. The histological sections showed protection of liver tissue after 3-NPA by reduction of apoptotic and oncotic tissue damage. Lipid peroxidation in liver tissue was reduced after 3-NPA preconditioning. We show that subtoxic doses of the mitochondrial toxin 3-NPA induces tolerance to warm liver ischemia in rats associated by synthesis of Bcl-2. Bcl-2 upregulation might protect against the postischemic burst of reactive oxygen species and therefore reduces apoptotic- and oncotic-related cell death.

The effects of exogenous l-carnitine on lipid peroxidation and tissue damage in an experimental warm hepatic ischemia-reperfusion injury model

Background: l-Carnitine is the essential endogenous factor for the transport of long-chain fatty acids from the cytoplasm to within the mitochondrion where the β-oxidation process takes place. l-Carnitine is a superoxide scavenger and an antioxidant that possesses an anti-ischemic action and a stabilizing effect on cell membranes. It may be of help in liver ischemia reperfusion injury. Results regarding the effects of l-carnitine on liver ischemia and reperfusion injury are few and conflicting. Objective: The aim of this study was to investigate the efficacy of exogenous l-carnitine on lipid peroxidation and protecting liver at different stages of experimental total warm hepatic ischemia-reperfusion (TWHIR) procedure in rats. Methods: This experimental study in healthy, weanling, male Wistar rats (weighing 180–200 g) was conducted at the Experimental Animal Research Laboratory of the Faculty of Medicine of Mersin University, Mersin, Turkey. Rats were randomly divided into 5 groups: (A) Control group; (B) TWHIR procedure only; (C) l-carnitine administered 2 hours before the TWHIR procedure; (D) l-carnitine administered just before the TWHIR procedure; and (E) l-carnitine administered after total warm hepatic ischemia but just before the reperfusion procedure. Total warm hepatic ischemia (via the Pringle maneuver) and reperfusion were performed for 45 and 30 minutes, respectively. l-Carnitine (200 mg/kg) was administered intravenously. At the end of each procedure a blood sample was drawn and total hepatectomy was performed following reperfusion. Malondialdehyde (MDA) and myeloperoxidase (MPO) levels of both plasma and liver tissue, total antioxidant capacity (TAOC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma, and histopathologic examination were analyzed to assess lipid peroxidation and damage in liver tissue. Results: Thirty-four rats (mean [SD]age, 59.26 [1.2]days; mean [SD] weight, 194.1 [5.1] g) were used in the study. There was a significant difference observed between groups A (n = 5) and B (n = 5) for all evaluation parameters. The TWHIR procedure performed in group B was associated with significant increases versus baseline in ALT, AST, MDA, and MPO in plasma, and MDA and MPO in liver tissue, but a significant decrease of TAOC in plasma. ALT, AST, serum and liver MDA, and MPO levels of group B were significantly higher than all groups administered l-carnitine. l-Carnitine administration between total warm hepatic ischemia and reperfusion was associated with a significant attenuation in all parameters. The liver MDA levels of groups C (n = 8) and D (n = 8) were significantly lower than that of group E (n = 8) (mean [SD]: C, 16.53 [3.32] and D, 18.28 [1.67] vs E, 23.05 [3.52]; P = 0.001 and P = 0.016, respectively). The mean (SD) liver MPO level of group C (1.09 [0.16]) was significantly lower than that of groups D (2.12 [0.25]) and E (2.11 [0.28]) (both, P = 0.001). The TAOC of group B (0.77 [0.12]) was significantly lower than that of groups C (1.34 [0.19]) and D (1.08 [0.20]) ( P = 0.001 and P = 0.015, respectively). The TAOC of group C was significantly higher than that of the other l-carnitine groups (E, 0.94 [0.13]) ( P = 0.023 vs group D; and P = 0.001 vs group E). Histopathologic scores of groups A, C, and E were significantly lower than that of group B, but the difference between groups B and D was not statistically significant. Conclusions: In this experimental study, administration of exogenous l-carnitine was associated with significantly decreased lipid peroxidation in plasma and liver tissue when administered prior to a TWHIR procedure. In addition, l-carnitine seemed to be more effective with regard to decreasing lipid peroxidation in liver tissue when administered before warm hepatic ischemia. l-Carnitine was associated with significantly decreased leukocyte sequestration in plasma and liver tissue. A significant increase in TAOC was associated with l-carnitine administered prior to ischemia. These observations suggest that l-carnitine might have a protective effect against ischemia-reperfusion injury in rat liver tissue.

Chronic intermittent hypoxia predisposes to liver injury†

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH). OSA is associated with nonalcoholic steatohepatitis (NASH) in obese subjects. The aim of this study was to investigate the effects of CIH on the liver in the absence of obesity. Lean C57BL/6J mice (n = 15) on a regular chow diet were exposed to CIH for 12 weeks and compared with pair-fed mice exposed to intermittent air (IA, n = 15). CIH caused liver injury with an increase in serum ALT (224 +/- 39 U/l versus 118 +/- 22 U/l in the IA group, P < 0.05), whereas AST and alkaline phosphatase were unchanged. CIH also induced hyperglycemia, a decrease in fasting serum insulin levels, and mild elevation of fasting serum total cholesterol and triglycerides (TG). Liver TG content was unchanged, whereas cholesterol content was decreased. Histology showed swelling of hepatocytes, no evidence of hepatic steatosis, and marked accumulation of glycogen in hepatocytes. CIH led to lipid peroxidation of liver tissue with a malondialdehyde (MDA)/free fatty acids (FFA) ratio of 0.54 +/- 0.07 mmol/mol versus 0.30 +/- 0.01 mmol/mol in control animals (P < 0.01), and increased levels of active nuclear factor kappaB (NF-kappaB) in the nuclear fraction of hepatocytes, suggesting that CIH induced oxidative stress in the liver. Finally, CIH greatly exacerbated acetaminophen-induced liver toxicity, causing fulminant hepatocellular injury. In the absence of obesity, CIH leads to mild liver injury via oxidative stress and excessive glycogen accumulation in hepatocytes and sensitizes the liver to a second insult, whereas NASH does not develop.

Lipid peroxidation in liver tissue of ovariectomized and pinealectomized rats: effect of estradiol and progesterone supplementation

The present study aimed to determine the effect of estradiol-progesterone supplementation and pinealectomy on lipid peroxidation of liver tissue in ovariectomized rats. The study was carried out on 36 adult Sprague-Dawley female rats, which weighed 200-250 g. The rats were divided into 6 groups: Group 1: Sham Ovariectomy (Sham-Ovx), Group 2: Ovariectomy (Ovx), Group 3: Ovx + Estradiol-Progesterone supplementation (Ovx + H), Group 4: Sham Pinealectomy and Ovx (Sham Pnx -Ovx), Group 5: Ovx -Pnx, Group 6: Ovx -Pnx + H. Malondialdehyde (MDA), reduced form of glutathione (GSH) and glutathione peroxidase (GSH-Px) levels were determined in liver tissue of rats. The highest MDA levels and the lowest GSH-Px levels were determined in the ovariectomized-pinealectomized group, whereas the lowest MDA was in the Sham-Ovx group, and the highest GSH-Px levels were found in the Sham-Ovx and Ovx + Hormone supplemented group. Furthermore, the highest GSH levels were in group 1 and lowest levels were in group 5. The findings of this study demonstrate that ovariectomy led to lipid peroxidation in liver tissues of rats. Pinealectomy in addition to ovariectomy, increases lipid peroxidation, but, estradiol and progesterone supplementations to the ovariectomized-pinealectomized rats protect against lipid peroxidation to a significant extent.

Antihepatotoxic Nature ofUlva reticulata(Chlorophyceae) on Acetaminophen-Induced Hepatoxicity in Experimental Rats

Ulva reticulata, a marine edible green alga, is a known source of proteins, vitamins, and sulfated polysaccharides. Though there are many reports in the literature regarding the composition and antiviral property of Ulva sp., studies of the antihepatotoxic property of green seaweeds in animal model are scarce. We have studied the antihepatotoxic nature of this marine green edible alga, U. reticulata, in a hot water extract (150 mg/kg of body weight for a period of 15 days) against acetaminophen- induced hepatotoxicity in experimental albino rats. The acetaminophen-induced rats showed significant elevation in levels of the serum marker enzymes aspartate transaminase and alanine transaminase and of lipid peroxides in liver tissue with decreased levels of antioxidant enzymes such as superoxide dismutase and catalase. The levels of reduced glutathione and vitamins (E and C) were also decreased in the liver tissue of acetaminophen-intoxicated rats. The oral pretreatment with a hot water extract of U. reticulata reduced the hepatotoxicity triggered by acetaminophen considerably by improving the antioxidant status in experimental animals with depleted levels of lipid peroxides. These results indicate that the oral pretreatment with a hot water extract of U. reticulata in rats is effective in reducing the hepatic oxidative stress via free radical scavenging properties, suggesting an antihepatotoxic activity.

Effects of dietary vitamin E level on growth and tissue lipid peroxidation of soft-shelled turtle, Pelodiscus sinensis (Wiegmann)

A feeding trial was conducted to determine the effect of dietary vitamin E supplementation on growth, liver lipid peroxidation and liver and muscle vitamin E level of soft-shelled turtle, Pelodiscus sinensis. Eight experimental diets analysed to contain 0–457 IU vitamin E kg−1 were fed to juvenile soft-shelled turtle of 4.8 g initial body weight for 12 weeks. Weight gain (WG) of the turtles fed the diet containing no vitamin E was significantly lower than those fed diets containing 83–457 IU vitamin E kg−1 (P 0.05) was found in whole-body composition among turtles fed the different diets. Dietary vitamin E requirement using WG as the response and estimated using the broken-line regression model is approximately 88 IU kg−1. Liver and muscle vitamin E content increased when dietary vitamin E level increased. Ascorbate-induced lipid peroxidation in liver tissue of turtles fed diets containing 0 and 17 IU vitamin E kg−1 was significantly (P<0.05) greater than those fed diets containing high vitamin E (≥35 IU kg−1).

Protective effects of erdosteine on rotenone-induced oxidant injury in liver tissue

Rotenone, an insecticide of botanical origin, causes toxicity through inhibition of complex I of the respiratory chain in mitochondria. This study was undertaken to determine whether rotenone-induced liver oxidant injury is prevented by erdosteine, a mucolytic agent showing antioxidant properties. There were four groups of Male Wistar Albino rats: group one was untreated as control; the other groups were treated with erdosteine (50 mg/kg per day, orally), rotenone (2.5 mg/mL once and 1 mL/kg per day for 60 days, i.p.) or rotenone plus erdosteine, respectively. Rotenone treatment without erdosteine increased xanthine oxidase (XO) enzyme activity and also increased lipid peroxidation in liver tissue (P < 0.05). The rats treated with rotenone plus erdosteine produced a significant decrease in lipid peroxidation and XO activities in comparison with rotenone group (P < 0.05). Erdosteine treatment with rotenone led to an increase in catalase (CAT) and superoxide dismutase (SOD) activities in comparison with the rotenone group (P < 0.05). There was no significant difference in nitric oxide (NO) level between groups. There were negative correlations between CAT activity and malondialdehyde (MDA) level (r = -0.934, P < 0.05) with between CAT and SOD activities (r = -0.714, P < 0.05), and a positive correlation between SOD activity and MDA level (r = 0.828, P < 0.05) in rotenone group. In the rotenone plus erdosteine group, there was a negative correlation between XO activity and NO level in liver tissue (r = -0.833, P < 0.05). In the light of these findings, erdosteine may be a protective agent for rotenone-induced liver oxidative injury in rats.

5-Aminoisoquinolinone, a novel inhibitor of poly(adenosine disphosphate-ribose) polymerase, reduces microvascular liver injury but not mortality rate after hepatic ischemia-reperfusion.

The aim of this study was to investigate the impact of the novel, potent, water-soluble inhibitor of poly(adenosine diphosphate-ribose) polymerase (PARP) 5-aminoisoquinolinone (5-AIQ) on hepatic microcirculation, hepatocellular injury, and survival in a murine model of hepatic ischemia-reperfusion. Randomized animal study. Research laboratory. C57BL6 mice were subjected to warm either partial (90 mins) or total (75 mins) ischemia of the liver. Either PARP inhibitor 5-AIQ (3 mg/kg) or vehicle was administered to mice intravenously immediately before the start of reperfusion. Sham-operated animals served as controls. As shown by intravital fluorescence microscopy after 30-60 mins of reperfusion, ischemia-reperfusion significantly enhanced platelet- and leukocyte-endothelial cell interactions in hepatic microvessels and impaired sinusoidal perfusion. Hepatocellular injury was characterized by an increase in the number of necrotic and apoptotic cells, dramatic elevation of aspartate aminotransferase/alanine aminotransferase serum activity, and lipid peroxidation in liver tissue. 5-AIQ treatment attenuated ischemia-reperfusion-induced increases in the numbers of adherent platelets and leukocytes as well as of necrotic and apoptotic cells and ameliorated perfusion failure. Furthermore, PARP inhibition prevented the increase in aspartate aminotransferase activity after ischemia-reperfusion but did not affect postischemic alanine aminotransferase release. However, no protective impact of 5-AIQ on postischemic oxidative stress was observed. Although PARP inhibition did not alter the survival percentage after ischemia-reperfusion (22% in both groups), this approach prolonged survival from 1 to 24 hrs (ischemia-reperfusion + vehicle) up to 48-72 hrs in the treated group. PARP inhibition with 5-AIQ during hepatic ischemia-reperfusion attenuates microvascular injury and reduces the extent of necrotic/apoptotic cell damage but does not protect from oxidative injury and does not improve postoperative survival rate.

The effect of N-acetylcysteine (NAC) on liver and renal tissue inducible nitric oxide synthase (iNOS) and tissue lipid peroxidation in obstructive jaundice stimulated by lipopolysaccharide (LPS)

Morbidity and mortality rates are very high in obstructive jaundice when it is associated with sepsis and multiple organ failure. Nitric oxide (NO) formation and increased expression of inducible nitric oxide synthase (iNOS) also take place in obstructive jaundice (OJ). N-Acetylcysteine (NAC) has a beneficial effect by demonstrating anti-inflammatory activity such as inhibits cytokine expression/release, inhibiting the adhesion molecule expression and inhibiting nuclear factor kappa B (NFκB). The aim of this study was to investigate the effects of NAC on liver and renal tissue iNOS, and liver tissue lipid peroxidation in lipopolysaccharide (LPS) induced obstructive jaundice. We randomized 48 rats into six groups. Group A: Sham group; group B: OJ group; group C: OJ+NAC; group D: OJ+LPS ( Escherichia coli LPS serotype L-2630, 100 mg, Sigma) group E: OJ+NAC+LPS; group F: OJ+LPS+NAC. NAC was started subcutaneously 100 mg/kg. LPS was injected intraperitoneally and then at the tenth day we sacrificed the rats. Liver malondialdehyde (MDA) increased and liver ATPase decreased in groups B–D when compared to group A. After the administration of NAC (groups C–E), liver MDA levels decreased, tissue ATPase levels increased as compared to other groups. The liver and renal tissue iNOS expression was increased in groups B, D, and F. After the administration of NAC (groups C–E) the liver and renal tissue iNOS expression were decreased. Our results indicated that NAC prevented the deleterious effects of LPS in OJ by reducing iNOS expression via lipid peroxidation in liver and renal tissue; if it was administrated before LPS. But NAC failed to prevent the iNOS expression and lipid peroxidation if there was established endotoxemia in OJ.

Pharmacological activity of South American plants: effects on spontaneous in vivo lipid peroxidation.

The in vivo protective effects of methanol extracts of eight South American medicinal plants traditionally used as antiinflammatory were determined by means of spontaneous lipid peroxidation of liver tissue in rats. The production of TBARS was reduced in a dose dependent manner for A. macrocarpa (IC50 = 132 mg/kg), A. urundeuva (IC50 = 176 mg/kg), C. reticulata (IC50 = 561mg/kg) and S. obtusifolium (IC50 = 918 mg/kg). The extracts of P. peltata and U. tomentosa were only effective at a high concentration (300 mg/kg), although these values were not significant. The lyophilized latex of C. lechleri decreased the production of TBARS at a 200 mg/kg dose, although pro-oxidant effects were observed at lower doses (50 mg/kg). The extract of H. pallida was pro-oxidant at lower concentrations (50 mg/kg).

Contribution of the antioxidative property of astaxanthin to its protective effect on the promotion of cancer metastasis in mice treated with restraint stress

We investigated the effects of astaxanthin on the antitumor effector activity of natural killer (NK) cells suppressed by stress in mice in order to define the immunological significance of astaxanthin (ASX) when combined with restraint stress treatment. When the mice were treated with restraint stress alone, the total number of spleen cells, and the level NK cell activity per spleen were reduced to a nadir on day 3. The stress also caused a significant increase in the lipid peroxidation of liver tissue. ASX (100 mg/kg/day, p.o., 4 days) improved the immunological dysfunction induced by restraint stress. On the other hand, metastatic nodules were observed in the livers of syngenic DBA/2 mice on day 12 after inoculation of P815 mastocytoma cells. Hepatic metastasis was promoted further by restraint stress when applied on day 3 before the inoculation of P815. Daily oral administration of ASX (1 mg/kg/day, p.o., 14 days) markedly attenuated the promotion of hepatic metastasis induced by restraint stress. These results suggested that astaxanthin improves antitumor immune responses by inhibiting of lipid peroxidation induced by stress.

Dietary effects of conjugated octadecatrienoic fatty acid (9 cis, 11 trans, 13 trans) levels on blood lipids and nonenzymatic in vitro lipid peroxidation in rats.

The present study examined the antioxidant activity of conjugated octadecatrienoic fatty acid (9 cis,11 trans,13 trans-18:3), alpha-eleostearic acid, of karela seed (Momordica charantia), fed to rats for 4 wk. The growth pattern of rats and the effect on plasma cholesterol and high density lipoprotein (HDL) cholesterol and peroxidation of plasma lipid, lipoprotein, eryhrocyte membrane, and liver lipid were measured. Rats were raised on diets containing sunflower oil mixed with three different levels of conjugated trienoic fatty acid (9c,11t,3t-18:3) 0.5, 2, and 10% by weight; the control group was raised with sunflower oil as dietary oil as the source of linoleic acid (9c,12c-18:2). The growth pattern of the three experimental groups of rats showed no significant difference compared to the control group of rats, but the group with 10% 9c,11t,13t-18:3 had slightly higher body weight than the control group of rats. Concentrations of total cholesterol, HDL-cholesterol, and non-HDL-cholesterol in plasma were similar in all four groups. Plasma lipid peroxidation was significantly lower in the case of 0.5% 9c,11t,13t-18:3 group than the control group and the 2 and 10% 9c,11t,13t-18:3 dietary groups as well. Lipoprotein oxidation susceptibility test with 0.5, 2, and 10% 9c,11t,13t-18:3 dietary groups was significantly less susceptible to lipoprotein peroxidation when compared with sunflower oil dietary group, and the dietary group with 0.5% 9c,11t,13t-18:3 showed least susceptibility. There was significant lowering in erythrocyte ghost membrane lipid peroxidation in the 0.5, 2, and 10% 9c,11t,13t-18:3 dietary groups compared to the sunflower oil groups. Nonenzymatic liver tissue lipid peroxidation was significantly lower in the group of rats raised on 0.5% 9c,11t,13t-18:3, but the groups on 2 and 10% 9c,11t,13t-18:3 acid did not show any significant difference compared with the control group of rats.

Age dependent different consequences of bilateral nephrectomy (NX) in rats.

Adult rats survived the removal of both kidneys (NX) for about 48 hours; survival time was distinctly lower in 10- and 20-day-old rats (about 24 hrs). Some of the measured parameters indicate age dependent differences in uremic impairment. In the prefinal period after NX blood urea nitrogen concentrations were distinctly higher in adult than in young rats. After nephrectomy diminution of the concentrations of GSH and GSSG in liver tissue is more distinct in adult than in young rats. Similarly, 24 hrs after NX the content of lipid peroxides in liver tissue was higher in adult than in 10- and 20-day-old rats. Furthermore, the prolongation of bleeding time in uremic rats was more distinct in adult than in young rats. The following parameters indicate uremic impairment clearly, but age dependent differences do not exist: Increase of potassium concentration in plasma, enhanced activities of liver specific enzymes in plasma, reduced concentration of various amino acids in plasma and distinct increase in plasma concentration of taurine.

Protection from CCI 4 toxicity by prestimulation of hepatocellular regeneration in partially hepatectomized gerbils

The present investigation was undertaken to test our hypothesis that the slow responses of hepatocellular regeneration and tissue repair after CCl 4-induced liver injury are responsible for the high sensitivity of gerbils to the hepatotoxic and lethal effects of CCl 4. These studies were conducted in normal and actively regenerating livers using male gerbils 5 or 15 days after partial (2/3) hepatectomy (PH 5 and PH 15, respectively), or those undergoing sham operation (SH). An ld 50 dose of CCl 4 (80 μL/ kg, i.p.) resulted in a mortality (21%) significantly (P < 0.05) less than 50% in PH 5 gerbils 48 hr after CCl 4 administration, whereas the mortality observed in PH 15 or SH gerbils was not significantly different from 50%. The elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly (P < 0.05) less in PH 5 gerbils than in PH 15 or SH groups after the administration of either the ld 50 dose or a low dose (15 μL/kg) of CCl 4. Histopathological and histomorphometric examinations also indicated that CCl 4-induced liver injury was less severe in PH 5 gerbils than in the PH 15 and SH groups. The hepatic microsomal cytochrome P450 content measured before CCl 4 administration in the PH 5 gerbils was decreased (26%) significantly (P < 0.05) as compared with the SH group, but was not significantly different from that of PH 15 gerbils. In vivo metabolism of 14CCl 4 and lipid peroxidation in liver tissue were not significantly different among the various groups. Therefore, the protection against CCl 4 toxicity observed in PH 5 gerbils is unlikely to be due to decreased bioactivation of CCl 4 or lipid peroxidation in that group. [ 3H]Thymidine incorporation into hepatocellular nuclear DNA was 4- to 5-fold higher in PH 5 gerbils than in the PH 15 and SH groups, indicating active hepatocellular proliferation in PH 5 gerbils. [ 3H]Thymidine incorporation was further increased significantly (P < 0.05) 24 hr after challenge with a low dose of CCl 4 in PH 5 gerbils, whereas it remained low until 48 hr after the CCl 4 injection in the PH 15 or SH group. The protection against CCl 4 toxicity afforded by partial hepatectomy was closely associated with active hepatocellular regeneration. The overall results confirm the concept that the high sensitivity of gerbils to CCl 4 is due to very sluggish hepatocellular regeneration and tissue repair response to the CCl 4-induced liver injury.

実験的ラット肝臓の虚血‐再循環モデルにおける肝障害 第１報： 肝障害の生化学的および病理学的検討

Cellular damage of various organs by ischemia following reperfusion is assumed to be at least in part due to lipid peroxidation in biomembranes, and oxygen-derived free radicals play a major role. The level of lipid peroxides in liver tissue increased during 90-min ischemia. When reflow of hepatic blood was allowed, a greater increase in the lipid peroxides was observed. Similar increases were obtained in several serum markers (GOT, GPT and LDH) during the period of ischemia or ischemia-reperfusion. In addition, levels of cytochrome p-450 and NADPH cyt. c reductase activity decreased in proportion to the decrease in microsomal proteins during ischemia or ischemia-reperfusion. On the other hand, superoxide dismutase in blood was significantly increased by ischemia-reperfusion. Rats died within 2 days after liver ischemia of 90 min, while all animals subjected to 30-min ischemia survived. Histopathological examinations indicated that extensive coagulation with erythrocytes occurred and the extent was dependent on the time of ischemia. The liver injury by ischemia-reperfusion could be a useful experimental model for studying liver injury induced by free radicals, for developing hepatoprotective drugs, or for investigating liver transplantation.

Lipid peroxidation in liver tissue stored at subzero temperatures

Lipid peroxidation in liver tissue stored at subzero temperatures

Functional and biochemical correlates of chlordecone exposure and its enhancement of CCl 4 hepatotoxicity

Animals pretreated with chlordecone exhibit a greatly increased hepatotoxic response to CCl 4 challenge. Possible mechanisms underlying this interaction were examined. A single p.o. administration of chlordecone (5 mg/kg) was followed by CCl 4 (200 μl/kg) administered i.p. 48 h later. Twenty-four hours later, animals treated with chlordecone + CCl 4 had decreased hepatic excretory function (20% of controls) and elevated plasma transaminase activities and bilirubin. Hepatic mixed function oxidase activity was assessed as pentobarbital sleeping time and was not affected by chlordecone pretreatment. Irreversible binding of label from 14CCl 4 to hepatic protein or lipid was not different in the chlordecone group compared to vehicle controls. Hepatic and renal glutathione concentrations were not affected by chlordecone alone (at 6 h, 1, 2, 3, 5 and 7 days) or by a combination of chlordecone (48 h) and CCl 4 (24 h). CCl 4-induced lipid peroxidation of liver tissue, measured in vitro or in vivo, was not increased by chlordecone treatment. Thus, while the mechanism for the enhanced toxicity remains to be elucidated, these results suggest that the interaction between chlordecone and CCl 4 is a subtle one, not causally involving increased covalent binding of the toxin, increased susceptibility of tissue lipids to peroxidative damage or decreased hepatic GSH.