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T F McElligott

Publications and source records attributed to T F McElligott.

At least 19 recordsLinked to original sources
PubMed1987

Furosemide toxicity in isolated mouse hepatocyte suspensions.

Incubation of freshly isolated mouse hepatocytes with 0.5 or 1.0 mM furosemide caused a depletion of cellular acid soluble sulfhydryls to approximately 20-30% of control over the course of 4.5 h. The depletion was accompanied by a reduction in cell viability (indicated by the lactate dehydrogenase latency test) which was significant (P less than 0.05) for 0.5 mM but not for 1.0 mM furosemide at 4.5 h. Ultrastructurally, 0.5 or 1.0 mM furosemide caused cytoplasmic changes including loss of glycogen, disaggregation of polyribosomes, vesiculation of endoplasmic reticulum, and occasional appearance of lamellar bodies consisting of concentric arrays of paired smooth membranes. These concentrations of furosemide also caused cell surface changes, including loss of microvilli, development of an irregular shape compared to the spherical appearance of untreated hepatocytes, and the development of occasional blebs. The appearance of pale staining hydropic cells was indicative of the final stages of cell death. N-Acetylcysteine (6.0 mM) was effective at preventing the depletion of soluble sulfhydryls, the loss of viability, and the ultrastructural effects of 0.5 or 1.0 mM furosemide, suggesting a role for soluble sulfhydryls in the pathogenesis of furosemide hepatotoxicity.

Acetylcysteine↗
PubMed1983

Ultrastructural effects of acetaminophen in isolated mouse hepatocytes.

The ultrastructure of isolated mouse hepatocytes shows good correlation with that of cells from intact liver. Incubation of isolated mouse hepatocytes with 1.0 mM acetaminophen causes a variety of cytoplasmic and cell surface lesions, as well as cell death. The changes are similar or equivalent to those caused by acetaminophen in vivo. The most prominent feature of damage in isolated hepatocytes is bleb formation, which is also seen occasionally in control incubations. The protective compound alpha-mercaptopropionylglycine and the antidote N-acetylcysteine both prevented the acetaminophen-induced changes. It is suggested that the in vivo counterpart to the blebs are endocytic vacuoles which form at cell margins due to the intravascular pressure of the sinusoids. It is suggested that the cell surface changes both in vivo and in isolated hepatocytes are caused by some dysfunction to the microfilament component of the cytoskeleton.

Acetaminophen↗
PubMed1983

Increased acetaminophen-induced hepatotoxicity after chronic ethanol consumption in mice.

The effect of chronic ethanol consumption on acetaminophen (200, 400, and 600 mg/kg) toxicity was determined by maintaining mice for 10 days on diets consisting of chow and one of the following drinking solutions: 10% ethanol + 10% sucrose, 8% sucrose, or tap water. Toxicity as manifested by mortality, liver enlargement, and liver congestion was greatest in the ethanol-treated group. We suggest that the greater mortality was a result of the increased liver congestion and consequent hypovolemia. Despite the increased levels of cytochrome(s) P-450, covalent binding of [3H]acetaminophen reactive metabolite(s) to liver protein was not higher in ethanol-treated animals. This can be explained by the higher initial glutathione concentration and/or ability to replenish glutathione in the ethanol-treated group. We suggest that the enhancement of acetaminophen toxicity by ethanol is the result of an effect of ethanol on hepatocyte membranes which renders the cells more susceptible to toxic injury.

Acetaminophen↗
PubMed1983

Scanning electron microscopic examination of acetaminophen-induced hepatotoxicity and congestion in mice.

Acetaminophen-induced hepatotoxicity and associated hepatic congestion were investigated by scanning and correlative transmission electron microscopy. Acetaminophen (750 mg/kg orally) causes changes in cell surface morphology and the relationship between hepatocytes and sinusoidal lining cells. There is endocytic vacuolation at lateral and sinusoidal margins of centrilobular hepatocytes, loss of microvilli, Disse space enlargement, dilation of bile canaliculi, and disappearance of the studlike projections from hepatocyte lateral surfaces. Erythrocytes enter the enlarged Disse space and endocytic vacuoles via enlarged pores in sinusoidal lining cells, thereby collapsing the sinusoids. Lining cells are not lost, but apparently held in position by preservation of intercellular junctions, cytoplasmic projections from hepatocytes, and anchorage by fat-storing cells within the Disse space. Congestion can abate by 24 hours, indicating that erythrocytes can return to the general circulation from the Disse space.

Acetaminophen↗
PubMed1982

Acetaminophen-induced hypothermia in mice: evidence for a central action of the parent compound.

Pretreatment of mice with phenobarbital, an inducer of oxidative drug metabolism, had no effect on the early hypothermic effect of a toxic dose of acetaminophen, while pretreatment with metyrapone, SKF-525A, or piperonyl butoxide (inhibitors of mixed-function oxidase) enhanced the hypothermia. In mice treated with acetaminophen alone, brain parent drug levels correlated with the degree of hypothermia, while liver drug levels did not. Also, intracerebroventricular injection of acetaminophen resulted in significant hypothermia within 20 min. These results indicate that the early hypothermia caused by acetaminophen in mice is due to the parent drug, not to its toxic reactive metabolite, and that the effect is mediated centrally. The observation that piperonyl butoxide and SKF-525A themselves caused significant hypothermia indicates that the use of these compounds should be avoided when body temperature is being followed in drug metabolism experiments.

Acetaminophen↗
PubMed1982

Acetaminophen toxicity in fed and fasted mice.

Acetaminophen (750 mg/kg) toxicity and its modification by N-acetylcysteine (NAC, 1200 mg/kg) have been compared in fed and fasted mice. There was no significant difference between fed and fasted animals with respect to microsomal protein content, cytochrome(s) P-450 content, and aryl hydrocarbon hydroxylase activity. Glucuronyl transferase activity was significantly higher in fasted mice. Hepatotoxicity, as determined histologically and by liver enlargement was greater in fasted than fed mice. Covalent binding of [3H]acetaminophen metabolite(s) to liver proteins was also greater in fasted animals. NAC administration prevented acetaminophen-induced microscopic changes and liver enlargement and reduced the magnitude of covalent binding of acetaminophen metabolites. Fasting caused a marked fall in liver reduced sulfhydryl concentration. The incidence of acetaminophen-induced hypothermia was greater in fasted than in fed animals. NAC administration reduced hypothermia in fasted mice and abolished it in fed animals. It is concluded that enhanced acetaminophen toxicity in fasted mice compared with fed mice is unlikely to be a consequence of increased reactive metabolite formation, but rather a result of reduced inactivation of reactive metabolite(s) due to reduced hepatic glutathione stores in fasted mice.

Acetaminophen↗
PubMed1981

Furosemide induced hepatotoxicity.

Furosemide-induced (400mg/kg ip) hepatotoxicity progressing to centrilobular necrosis was studied by light and electron microscopy in Swiss white mice. Centrilobular glycogen depletion and cytoplasmic foaminess, usually accompanied by extensive vacuolation, were detectable by light microscopy 1 1/2 hr after furosemide. Centrilobular congestion and hydropic single cell necrosis developed after 3 hr. Electron microscopy revealed disaggregation of polyribosomes, vesiculation of endoplasmic reticulum, an endocytic origin for the vacuolation, and a definite sequence in the development of congestion. Vacuolation coincided with loss of microvilli and resulted in detachment of sinusoidal lining cells from hepatocytes. Small vacuoles apparently formed at the sinusoidal margin of hepatocytes by fusion of microvilli. Congestion and occlusion of sinusoidal lumens developed as a consequence of erythrocytes entering the enlarged Disse space, possibly through pores in the lining cells, and thence entering endocytic vacuoles. The vacuolation, loss of microvilli and terminal hydropic degeneration suggest an important role for the plasma membrane in the development of furosemide-induced hepatotoxicity. Comparisons with known membrane toxins support this concept.

Animals↗
PubMed1979

The ultrastructure of blebs induced in the hamster jejunum by ethanol.

Previous light microscopic studies showed that perfusion of the hamster jejunum with 4.8% ethanol (ethanol period) in vivo produced fluid-filled subepithelial blisters (blebs) on the villi. These blebs had virtually disappeared within 45 min after the discontinuation of the ethanol perfusion (recovery period). The present study examined these ethanol-induced changes in the jejunum by scanning (SEM) and transmission (TEM) electron microscopy. TEM revealed that ethanol did not damage epithelial cells in areas where blebs were not present. In these areas the basal surfaces of the epithelial cells were attached to the basal lamina, and the lateral intercellular spaces (LIS) were open. In the areas where blebs formed, the stretched epithelial cells which covered the blebs lost their basal anchoring and so could not maintain their LIS. Both SEM and TEM indicate that there was a decrease in the quantity of glycocalyx at the surfaces of cells which covered blebs. Our findings indicate that ethanol does not directly damage epithelial cells but that the cellular damage is due to detachment over the blebs. It is likely that ethanol at first traverses the epithelial layer and then produces stasis in the villus core. Continued fluid transport by the epithelial layer in the presence of statis results in accumulation of the fluid and widely dilated LIS. With subsequent enlargement of the LIS the bases of the cells detach from the basal lamina and blebs are formed.

Animals↗
PubMed1978

Effect of ethanol on the morphology of hamster jejunum.

In order to study the morphological effects of exposure of the jejunum to low ethanol concentrations, we perfused hamster jejunum with 2.1-4.8% ethanol. Following 45 min exposure, many of the villi developed fluid-filled blisters. To compare these findings to the effect of an inert solute at similar concentrations, we perfused hamster jejuna with mannitol. This caused necrosis of the villus tips but no blister formation. Therefore the blisters were the result of the action of ethanol. The rat jejunum was less resistant to ethanol than that of the hamster. We suggest that the initial insult of the freely permeant ethanol is deep to the epithelium, resulting in accumulation of edema under the epithelium.

Alcoholic Intoxication↗
PubMed1978

The correlation of ethanol-induced depression of glucose and water transport with morphological changes in the hamster jejunum in vivo.

Glucose and water transport is depressed in the hamster jejunum in vivo by ethanol (4.8%) which also produced fluid-filled blebs at the tips of the villi. The epithelial cells over the blebs appeared stretched and cuboidal, the lateral intercellular spaces (LIS) were no longer recognizable, and the lacteals were closed. Forty-five minutes after discontinuation of the ethanol, water transport returned to normal while glucose transport remained depressed. At this time the villus structure had returned to normal. The blebs had disappeared, the LIS were again recognizable, and their appearance and number were similar to those in the control animals. Thus, the depression of water transport correlated with the obvious structural changes caused by ethanol; however, the depression of glucose absorption is associated with some effect of ethanol not evident by routine light microscopy.

Animals↗
PubMed1975

Effect of ethanol on sodium-dependent glucose transport in the small intestine of the hamster.

The objective of this study was to investigate the mechanism by which ethanol inhibits intestinal absorption of sugars. In vitro experiments on hamster jejunum have shown that the presence of ethanol in the mucosal solution caused an inhibition of the net transport of water and glucose. There was also a decrease in the intracellular water content and an increase in the intracellular sodium and potassium concentration of the gut tissue. In contrast, the intracellular glucose concentration decreased in the presence of ethanol. These ethanol-induced changes were directly related to the ethanol concentration of the mucosal solution. In the presence of 450 mM (2%) ethanol in the mucosal solution, there was also a significant inhibition of transmural potential difference, estimated glucose metabolism, and both unidirectional fluxes of sodium. The net flux of sodium to the serosal side however did not decrease significantly. These effects of ethanol cannot be fully explained by its osmotic action, and it is suggested that the ethanol-induced reduction in glucose transport could be mainly the result of an interference with the carrier-mediated coupled entrance of glucose and sodium across the brush border. A depression of cellular metabolism could also have played a role in this process.

Animals↗