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L E Rikans

Publications and source records attributed to L E Rikans.

At least 19 recordsLinked to original sources
PubMed2000

Attenuation of cadmium-induced liver injury in senescent male fischer 344 rats: role of Kupffer cells and inflammatory cytokines.

In the previous study we showed that senescent male Fischer 344 rats were resistant to Cd-induced hepatotoxicity compared with young-adult rats. In the present study we investigated the role of Kupffer cells and inflammatory cytokines in this effect of aging. The phagocytic activity of Kupffer cells, determined as the removal of carbon from blood, was stimulated by the administration of a hepatotoxic dose of Cd (3 mg/kg sc) in young-adult (5 months) rats but not in old (28 months) rats. Hepatic concentrations of interleukin (IL)-1beta and cytokine-induced neutrophil chemoattractant (CINC), but not of tumor necrosis factor-alpha or IL-6, were elevated in young rats treated with Cd. In old rats, however, the increase in IL-1beta produced by Cd was not statistically significant and the increase in CINC was much lower than in young-adult rats. Pretreatment with gadolinium chloride or cyclosporin A inhibited the elevations in hepatic cytokines and attenuated Cd-induced liver damage, assessed on the basis of serum alanine aminotransferase and sorbitol dehydrogenase activities. Cd-induced hepatotoxicity in the different treatment groups correlated well with hepatic levels of CINC (r = 0.98, p < 0.001) but not with those of IL-1beta. The results suggest that (1) Kupffer cell activation is essential for inflammatory liver damage from Cd, (2) IL-1beta and CINC are important mediators of the inflammatory response induced by Cd, and (3) the attenuation of Cd-induced liver injury in senescent rats is caused by an impairment in Kupffer cell activation, leading to a lower production of CINC and less inflammatory liver injury.

Age Factors↗
PubMed2000

Mechanisms of cadmium-mediated acute hepatotoxicity.

The mechanism of cadmium-mediated acute hepatotoxicity has been the subject of numerous investigations and although some uncertainties persist, sufficient evidence has emerged to provide a reasonable account of the toxic process. Acute hepatotoxicity involves two pathways, one for the initial injury produced by direct effects of cadmium and the other for the subsequent injury produced by inflammation. Primary injury appears to be caused by the binding of Cd2+ to sulfhydryl groups on critical molecules in mitochondria. Thiol group inactivation causes oxidative stress, the mitochondrial permeability transition, and mitochondrial dysfunction. Although cadmium may injure hepatocytes directly, there are compelling reasons to believe that hepatocellular injury is produced in vivo as the result of ischemia caused by damage to endothelial cells. Secondary injury from acute cadmium exposure is thought to occur from the activation of Kupffer cells and a cascade of events involving several types of liver cells and a large number of inflammatory and cytotoxic mediators. In this regard, it is clear that Kupffer cell activation and neutrophil infiltration are important events in the toxic process, and the involvement of proinflammatory cytokines and chemokines has also been implicated. The precise roles of the soluble mediators of inflammation warrant further investigation.

Animals↗
PubMed1999

Attenuation of cadmium-induced liver injury in senescent male fischer 344 rats: role of metallothionein and glutathione.

The influence of aging on the sensitivity of the liver to the acute toxicity of cadmium has not been studied previously in adult rats. In this study hepatotoxicity caused by a single sc injection of CdCl(2) was compared in 5-, 18-, and 28-month-old male Fischer 344 rats. Doses of Cd were adjusted on the basis of the mean lean body mass for each age group of rats, and liver injury was evaluated 24 h after treatment. Cd treatment produced substantial increases in serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities in 5- and 18-month-old rats, whereas no significant increases were observed in 28-month-old rats. Histologic examination of representative livers from each age group confirmed the findings for serum enzyme activity; hepatocellular necrosis was observed only in livers from 5- and 18-month-old rats. The attenuation of Cd hepatotoxicity in senescent rats did not appear to be related to pretreatment levels of metallothionein or glutathione. Likewise, resistance to Cd could not be explained on the basis of metallothionein induction, which decreased as a function of aging. Thus, the mechanisms that account for the postmaturational decline in sensitivity to Cd do not appear to be associated with alterations in levels of the major factors that protect against Cd-induced hepatotoxicity.

Aging↗
PubMed1999

Effect of age and carbon tetrachloride on cytokine concentrations in rat liver.

Interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured in livers of young-adult and old rats administered carbon tetrachloride or vehicle. IL-1beta levels were higher and IL-6 levels were lower in old rats than in young-adult rats. Carbon tetrachloride treatment increased IL-1beta and decreased TNF-alpha and IL-6. The elevation in IL-1beta was diminished by aging. These results indicate that the increase in carbon tetrachloride hepatotoxicity that occurs in old age could be related to a dysregulation of inflammatory cytokines.

Aging↗
PubMed1998

Serum and liver concentrations of tumor necrosis factor alpha and interleukin-1beta following administration of carbon tetrachloride to male rats.

Inflammatory cytokines are recognized as early mediators of tissue damage and repair. The purpose of this study was to determine the effects of carbon tetrachloride administration on tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) concentrations in serum and liver of rats. Administration of 0.2 ml/kg, i.p., of CCl4 to male Fischer 344 rats caused modest increases in serum levels of both cytokines; elevations of TNF-alpha were statistically significant at 4 and 12 h, and elevations of IL-1beta were statistically significant at 24 h. Although CCl4 produced substantial increases in liver IL-1beta concentrations (more than 3-fold), levels of TNF-alpha were not affected. Treatment with 0.1, 0.32 or 1.0 ml/kg of CCl4 produced dose-dependent increases in serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities, but serum cytokine concentrations were not dose-dependent and did correspond with serum ALT and SDH activities. The results suggest that IL-1beta production in rat liver is stimulated by hepatotoxic doses of CCl4. Production of TNF-alpha may also be induced, but the source of TNF-alpha in serum could be a tissue or organ other than liver.

Animals↗
PubMed1998

Thiol-disulfide exchange systems in the liver of aging Fischer 344 rats.

The purpose of this study was to determine whether the major thiol-disulfide oxidoreductase activities of the rat liver were altered as a consequence of aging, and whether the alterations had any consequences in terms of hepatic thiol concentrations. Liver fractions were prepared from male and female Fischer 344 rats at ages representing young adulthood (5 months), middle age (15 months) and old age (24-29 months), and the activities of the major thiol-disulfide exchange enzymes, together with protein and nonprotein sulfhydryl contents, were measured using spectrophotometric procedures. Thioltransferase, protein disulfide isomerase and thioredoxin reductase activities in livers of male and female rats were unchanged with aging, while glutathione disulfide (GSSG) reductase activity remained the same (in male livers) or increased (in female livers) as a consequence of aging. Both protein and nonprotein sulfhydryl concentrations were well maintained in old age. The absence of age-dependent alterations in the thiol-protein disulfide exchange enzymes and the lack of compromise in the glutathione GSSG reductase system suggest that aged livers retain their capacity to regulate their thiol-disulfide redox balance under normal physiological conditions.

Age Factors↗
PubMed1997

Lipid peroxidation, antioxidant protection and aging.

The free radical hypothesis of aging proposes that deleterious actions of oxygen-derived radicals are responsible for the functional deterioration associated with aging. Because cellular membranes house the production apparatus of these radicals and because membranes suffer great damage from these radicals, modification of membrane lipids has been proposed to play a major role in the process of aging. Although the relationships between lipid peroxidation and aging have been investigated extensively, the studies have produced conflicting results. Increased lipid peroxidation and decreased antioxidant protection frequently occur, but they are not universal features of aging. Instead, age-dependent changes in these parameters appear to be species-, strain-, sex- and tissue specific. Potential correlations between lipid peroxidation and transition metal concentrations or between lipid peroxidation and declining antioxidant protection have been obscured by the contradictory nature of the findings. Future studies should focus on new approaches for the measurement in vivo lipid peroxidation and on identification of the critical targets of lipid peroxidation.

Aging↗
PubMed1997

Age-associated increase in ferritin content of male rat liver: implication for diquat-mediated oxidative injury.

Our previous studies in rat hepatocytes demonstrated an age-dependent increase in sensitivity to diquat-induced cytotoxicity, possibly as a result of increased iron availability. The present study was conducted to determine whether quantitative or qualitative changes in hepatic ferritin occur as a consequence of aging and whether diquat-mediated oxidation is intensified by elevated ferritin concentrations. Hepatic ferritins were isolated from male Fischer 344 rats ages 5, 15, and 25 months. Age-associated increases were observed in amounts of ferritin protein and ferritin iron per gram of liver, but there were no differences in proportions of H to L subunits or in rates of diquat-mediated iron release. The consequences of a threefold increase in ferritin content for diquat-mediated lipid peroxidation and protein carbonyl formation were examined in microsomal incubation systems. The addition of isolated rat liver ferritin augmented diquat-mediated oxidative damage in a time- and concentration-dependent manner, and the inclusion of deferoxamine completely inhibited the stimulation by ferritin. The results indicate that availability of ferritin iron is an important determinant of diquat-mediated oxidative injury and support the hypothesis that elevated hepatic ferritin content is responsible, at least in part, for the age-associated enhancement of diquat-induced toxicity.

Aging↗
PubMed1996

Oxidation of pyridine nucleotides is an early event in the lethality of allyl alcohol.

The involvement of altered pyridine nucleotide concentrations in the cytolethality of allyl alcohol was studied in isolated rat hepatocytes. NAD+, NADH, NADP+, NADPH and viability loss (leakage of lactate dehydrogenase into the medium) were measured in cells incubated with 0.5 mM allyl alcohol with or without the addition of 2 mM dithiothreitol at 30 min. Exposure to allyl alcohol increased NADH levels in the first 15 min of incubation. A sharp drop in NADH and NADPH with an accumulation of NADP+ occurred between 30 and 60 min of incubation with allyl alcohol, indicating an oxidation and interconversion of pyridine nucleotides. Dithiothreitol prevented the oxidation of pyridine nucleotides, but not their reduction or interconversion, and protected against cell killing by allyl alcohol. The results suggest that pyridine nucleotide oxidation might be important for allyl alcohol-induced cytotoxicity; however, a causal relationship between pyridine nucleotide oxidation and cell killing is yet to be demonstrated.

1-Propanol↗
PubMed1995

Loss of mitochondrial membrane potential is not essential to hepatocyte killing by allyl alcohol.

Allyl alcohol-induced LDH leakage from isolated rat hepatocytes was preceded by a decrease in rhodmine 123 retention, signifying a loss of mitochondrial membrane potential. Addition of dithiothreitol (DTT) prevented the drop in membrane potential and completely prevented cell killing by allyl alcohol. In contrast, cyclosporin A and trifluoperazine delayed the loss of membrane potential without affecting cytolethality. The results indicate that a drop in mitochondrial membrane potential is not essential for allyl alcohol lethality. The mitochondrial dysfunction produced by allyl alcohol appears to be the consequence of an earlier event in the toxicity that is reversible by DTT.

1-Propanol↗
PubMed1995

Allyl alcohol cytotoxicity in isolated rat hepatocytes: effects of azide, fasting, and fructose.

The role of altered energy homeostasis in the lethality of allyl alcohol to isolated rat hepatocytes was studied. ATP, ADP, AMP, and viability loss (leakage of lactate dehydrogenase into the medium) were measured in isolated hepatocytes of fed or fasted rats exposed to 0.5 mM allyl alcohol. Adenine mononucleotides and cytotoxicity were determined also in hepatocytes incubated with allyl alcohol in the presence of 4 mM sodium azide or 15 mM fructose. Allyl alcohol-induced cell death in hepatocytes of fed rats was preceded by slight decreases in ATP content and energy charge (16% and 12%, respectively). More substantial decreases in these parameters occurred in parallel with cell killing, but the effect of allyl alcohol on energy status did not exceed the effect produced by a nonlethal concentration of sodium azide. Neither azide nor fructose affected the development of allyl alcohol cytotoxicity. Moreover, allyl alcohol-induced cytotoxicity was similar in hepatocytes of fed and fasted rats. The results suggest that altered energy homeostasis is a consequence rather than a cause of allyl alcohol-induced hepatocyte lethality.

1-Propanol↗
PubMed1994

Carbon tetrachloride hepatotoxicity as a function of age in female Fischer 344 rats.

Severity of liver damage 24 h after intraperitoneal administration of carbon tetrachloride (0.2 ml/kg) was evaluated in female Fischer 344 rats aged 5, 14 and 28 months, i.e. in young adulthood, middle age and old age. Carbon tetrachloride-induced hepatotoxicity, as judged by the leakage of hepatic enzymes into the bloodstream and the disappearance of hepatic microsomal cytochrome P450, was much less severe in old rats than in young-adult rats. For example, serum sorbitol dehydrogenase (SDH) activity following carbon tetrachloride administration was 680 mumol/min/l in old rats compared with 1710 mumol/min/l in young-adult rats, and the loss of hepatic cytochrome P450 was 25% of the total amount in old rats compared with 50% of the total in young-adult rats. Spin trapping and electron spin resonance (ESR) spectroscopy were utilized to measure the conversion of carbon tetrachloride to trichloromethyl radicals in vivo. This primary bioactivation step occurred at similar rates in female rats aged 5, 14 and 28 months. In addition, the total nonheme iron contents in livers of rats in the three age groups were similar. Thus, the age associated attenuation of carbon tetrachloride-induced hepatotoxicity was not explained on the basis of decreased bioactivation to reactive species or decreased availability of iron for promotion of lipid peroxidation. The results suggest that other factors are important determinants of age-associated changes in sensitivity to toxic chemicals.

Aging↗
PubMed1994

Dithiothreitol reversal of allyl alcohol cytotoxicity in isolated rat hepatocytes.

Reversal by dithiothreitol (DTT) of allyl alcohol cytotoxicity was investigated in isolated rat hepatocytes. Allyl alcohol-induced protein sulfhydryl loss, bleb formation, and cell death were prevented by DTT, when it was added to hepatocytes 30 min after the toxicant. The protective effect of DTT also was demonstrated in cells that were washed after 30 min of exposure to allyl alcohol, indicating that protection was not related to inhibition of allyl alcohol metabolism or inactivation of acrolein. DTT reversed the cell surface protrusions that formed during exposure to allyl alcohol, but reversal of blebbing did not insure that the cells would remain viable. Glutathione disulfide was not formed in allyl alcohol-treated cells, and DTT reversal of cytotoxicity occurred without restoring glutathione levels. Moreover, protection against allyl alcohol toxicity required the continuous presence of DTT. The results suggest that initial events in the toxic process are reversible, and that DTT can prevent cytotoxicity if added to hepatocytes before irreversible damage occurs; however, the mechanism by which DTT exerts its protection is not clear.

1-Propanol↗
PubMed1994

Allyl alcohol cytotoxicity in isolated rat hepatocytes: mechanism of cell death does not involve an early rise in cytosolic free calcium.

We examined the effect of a toxic concentration of allyl alcohol (0.5 mM) on intracellular calcium concentrations in isolated rat hepatocytes. An increase in phosphorylase a activity was evident in the hepatocytes after 30 min of incubation with allyl alcohol, suggesting that the toxicant may produce an early rise in cytosolic free calcium. The increase in phosphorylase a activity was not reversed by the addition of dithiothreitol (DTT), a sulfhydryl compound that reverses the events that initiate cell killing by allyl alcohol. When intracellular calcium concentrations were measured directly, using fura-2 as the calcium indicator, there was no effect of allyl alcohol on cytosolic free calcium during the first 60 min of exposure, a critical period for development of irreversible damage. Incubation with allyl alcohol did not interfere with the measurement of intracellular calcium. The increases in cytosolic free calcium produced by phenylephrine or ATP were similar to those reported by others and not affected by the presence of allyl alcohol. The results from this study demonstrate that increased cytosolic free calcium is not essential for allyl alcohol-induced cytotoxicity to isolated rat hepatocytes.

1-Propanol↗
PubMed1993

Aged mice are resistant to the hepatotoxic effects of endotoxin and galactosamine.

The ability of concurrent intraperitoneal injections of endotoxin (0.1 micrograms/kg) and galactosamine (700 mg/kg) to produce liver damage was determined in fasted C57Bl/6 mice of different ages: 2 months (young), 6 months (mature), and 24 months (aged). Liver damage was assessed after 6 hr by measurement of plasma alanine aminotransferase activity (ALAT, mumole/liter/min) and by histological examination for mature and aged mice. Control mice, those treated with saline, galactosamine, endotoxin, or hydrazine alone, had ALAT activities which ranged from 13 to 72 (n = 21). Plasma ALAT activities were increased to hepatotoxic values in some, but not all, mice injected with both endotoxin and galactosamine. For young mice, 7/11 had increased plasma ALAT activities; for mature mice, 5/8 had increased plasma ALAT activities and substantial centrilobular necrosis, whereas for aged mice, 0/7 had increased ALAT activities and none had centrilobular necrosis. Basophilic staining of the cytoplasm was increased by administration of endotoxin and/or galactosamine in both mature and aged mice whether or not necrosis was present. A 5-hr pretreatment with hydrazine sulfate (80 mg/kg) substantially decreased the ALAT release caused by endotoxin and galactosamine in mature mice. Hydrazine pretreatment prevented centrilobular necrosis in mature mice and decreased basophilic cytoplasmic staining in aged mice. The results demonstrate that aged mice are resistant to the hepatotoxic effects of endotoxin and galactosamine which were observed in both young mice and mature mice. Also, hydrazine sulfate pretreatment will protect against the hepatotoxic effects as well as the lethal actions of endotoxin and galactosamine.

Aging↗
PubMed1993

Diquat-induced oxidative damage in BCNU-pretreated hepatocytes of mature and old rats.

The effects of postmaturational aging on the toxicity of diquat, a redox cycling compound, were investigated in hepatocytes that were isolated from mature (6 months) and old (27 months) male Fischer 344 rats and pretreated with 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU), an inhibitor of glutathione reductase. The hepatocytes were incubated for 2 hr with 0, 0.5, or 2.0 mM diquat dibromide, and samples were taken at various time points for measurements of glutathione, glutathione disulfide, thiobarbituric acid reactive substances, lactate dehydrogenase leakage, protein sulfhydryl groups, and protein carbonyl groups. Diquat cytotoxicity was intensified in hepatocytes of old rats compared with those of mature rats, and the enhanced toxicity was associated with increased lipid peroxidation and protein carbonyl formation. However, the enhanced toxicity in old rat hepatocytes was also accompanied by a decrease in diquat-induced GSH oxidation and there was no difference in protein sulfhydryl loss. Concentrations of total nonheme iron and low-molecular-weight chelatable Fe2+, measured with ferene as the chromogen, were several times higher in freshly isolated hepatocytes of old rats than in those of mature rats. We hypothesize that the age-associated enhancement of diquat toxicity could be due to an increased availability of iron for reaction with diquat-generated hydrogen peroxide and for stimulation of lipid and protein oxidation.

Aging↗