Biomedical subjects

W H Butler

Publications and source records attributed to W H Butler.

At least 19 recordsLinked to original sources

PubMed1992

The histology and development of hepatic nodules and carcinoma in C3H/He and C57BL/6 mice following chronic phenobarbitone administration.

Male C3H/He and C57BL/6 mice were given diets containing sodium phenobarbitone (PB) to allow a daily intake of 85 mg/kg. Control and treated animals were killed at 5, 30, 40, 60, and 80 wk. Other mice were killed in extremis or at the end of the respective experiments: 91 wk for C3H/He and 100 wk for the C57BL/6 animals. A basophilic nodule was found in 1/5 control C3H/He mice at 30 wk; these nodules increased in number with time so that nodules of this type were found in approximately 70% of animals by 91 wk. Nodules were not found in control C57BL/6 mice until 80 wk, when they were found in 4% of mice. PB treatment markedly increased the number of hepatic nodules in both strains of mice. The additional nodule burden was due to the development of a second nodule type formed of large cells with a predominantly eosinophilic cytoplasm. C3H/He animals given PB for 60 wk and then returned to a control diet bore fewer nodules at 91 wk than treated mice killed at 60 or 91 wk. The cumulative incidence of carcinoma in control C3H/He and C57BL/6 mice was 28 and 4%, respectively. The incidence of carcinoma was not increased by PB treatment in either strain. It is concluded that both strains of mice behave in a qualitively similar way to PB administration, although they show considerable quantitative differences in terms of the time and number of nodules that develop. Furthermore, the increased nodule numbers associated with PB treatment were not accompanied by an increase in the number of carcinomas.

Animals↗

PubMed1991

An ultrastructural study of spontaneous and phenobarbitone-induced nodules in the mouse liver.

Male C3H/He mice were given 0 (control) or 85 mg/kg/day phenobarbitone (PB) in the diet. At 40, 60 and 93 weeks, groups of mice were killed and the ultrastructure of spontaneous and PB-induced liver nodules was examined. Treated mice showed typical centrilobular hypertrophy and eosinophilic nodules which may be considered as an end stage lesion. The nodule cells were similar in appearance to those in areas of centrilobular hypertrophy except for the presence of convoluted membranes which are considered to be indicative of proliferation. The incidence of carcinoma was not increased by PB treatment. The carcinomas from control and treated animals differed in their ultrastructure in that increased levels of smooth endoplasmic reticulum (SER) were seen in the carcinomas of the PB animals. The presence of SER proliferation in the carcinomas of PB animals suggests that carcinoma may respond to the enzyme-inducing effects of PB.

Animals↗

PubMed1991

Promutagenic lesions persist in the DNA of target cells for nitrosamine-induced carcinogenesis.

Immunohistochemical procedures for the location of O6-methylguanine (O6-meGua) permit detection of cells proficient for the metabolism of N-nitrosodimethylamine (NDMA) and deficient for the repair of this DNA lesion. Such cells are potentially at high risk for cancer induction and are present in various tissues. In animals maintained on a protein-deficient diet, the distribution and intensity of alkylation of individual cells is altered, particularly in liver where fewer cells apparently retain the capacity to metabolize the nitrosamine, thereby permitting increased levels of alkylation in other tissues. In the renal cortex, specific, O6-meGua-positive target cells for renal cancer induced by a single dose of NDMA in weanling rats persist at least up to the appearance of early lesions. Persistence of alkylated cells in several tissues indicates prospects for the detection of environmental exposure.

Alkylation↗

PubMed1991

Neuropathologic findings in patients receiving long-term vigabatrin therapy for chronic intractable epilepsy.

Vigabatrin is a new antiepileptic drug that acts by the irreversible inhibition of gamma-aminobutyric acid (GABA) aminotransferase. During animal safety testing, vigabatrin was found to cause reversible intramyelinic edema in the brains of rodents and dogs but not in primates. In humans, the drug is well tolerated, and extensive clinical, neurophysiologic, neurochemical, and psychometric testing has failed to demonstrate any evidence of neurotoxicity. Neuropathologic examination has now been carried out on 62 patients with refractory epilepsy, who were on vigabatrin therapy either prior to undergoing neurosurgery for their epilepsy or before death. A further ten similar cases have been included in the study from age-matched patients with refractory epilepsy who had not been treated with vigabatrin prior to surgery or death. None of the neuropathologic changes seen in the preclinical animals studies have been observed in the human cases. In no case was there considered to be any evidence of myelin microvacuolation or myelin sheath splitting that could be attributed to vigabatrin treatment. Demyelination has never been observed in either the animal or human material. These findings support the clinical tolerability seen in long-term treatment.

Adolescent↗

PubMed1990

Chronic toxicity and oncogenicity studies of Macrodantin in Sprague-Dawley rats.

Chronic toxicity and oncogenicity studies of nitrofurantoin formulated as Macrodantin have been undertaken. The doses ranged from 12 to 116 mg/kg body weight/day. At 116 mg/kg/day, female rats showed a decreased weight gain. In the high-dose groups in the chronic toxicity study (males, 81 mg/kg/day; females, 116 mg/kg/day) there was an increase in testicular degeneration, sciatic nerve degeneration and fibrosis in both males and females, and an increase in focal biliary proliferation in females. There was no evidence of renal toxicity. There was no compound-related effect upon neoplasms at any site. In the oncogenicity study, an increase in focal biliary proliferation was observed in females given 31 or 56 mg/kg/day. There was no treatment-related increase in the incidence of neoplasms at any site. In particular there was no increase in the incidence of mammary or renal tumours. The observations in these studies indicate that therapeutic uses of Macrodantin would not present a carcinogenic hazard to man.

Animals↗

PubMed1990

Oncogenicity study of macrodantin in Swiss mice.

A carcinogenicity study of nitrofurantoin formulated as Macrodantin was undertaken. The doses used were 0.0, 50.0, 100.0 and 200.0 mg/kg/day. Increased mortality was observed in male mice given 200 mg/kg/day. Chronic toxicity was observed in the kidneys of male mice: the normally occurring chronic nephropathy was somewhat increased in severity. The gonads of both male and female mice showed evidence of atrophy and degeneration. The ovaries showed an increased incidence of multilobular cysts but no evidence of neoplasia. A significantly higher incidence of malignant lymphoma in the top-dose males was offset by a non-significant difference in the opposite direction in females. Reasons are given for regarding this as a chance finding. The observations in this study indicate that the therapeutic uses of nitrofurantoin would not present a carcinogenic hazard to man.

Animals↗

PubMed1990

Effects of methyl isocyanate on rat brain cells in culture.

Since the disaster in Bhopal, India, people exposed to methyl isocyanate (MIC) have complained of various disorders including neuromuscular dysfunction. In an attempt to get information about such dysfunction we have previously shown that MIC can affect muscle cells in culture. The present communication reports investigations into the effect of MIC on brain cells in culture. MIC was toxic to brain cells and the response was dose related. The observations were supported by light and electron microscopy.

Animals↗

PubMed1990

Ultrastructural features of diethylnitrosamine-induced lesions in the mouse liver.

Mice were given a single dose of diethylnitrosamine (DEN). After 12 and 15 months, the ultrastructural features of simple hepatic nodules and defined hepatocellular carcinomas were compared. The main difference between these two lesions is the presence of highly convoluted membranes in the hepatocytes of the carcinomas. A third population of nodules was also found which could not be easily classified at the light microscope level into either simple hepatic nodules or carcinomas. Ultrastructural examination of these lesions showed them to have areas resembling both simple hepatic nodules and carcinomas. Within both these areas hepatocytes with convoluted plasma membranes were observed. Changes in membrane pattern may be indicative of an altered cell growth pattern and the acquisition of invasive or metastatic properties. This provides further evidence suggesting that a sub-population of cells can be identified which has the potential to develop into overt carcinoma.

Animals↗

PubMed1989

Apoptosis--the mechanism of cell death in dimethylnitrosamine-induced hepatotoxicity.

Dimethylinitrosamine (DMN) induces an acute haemorrhagic centrilobular necrosis when given as a single dose to rats. In this study, the progression of the lesion was studied at the ultrastructural level in order to elucidate the precise mechanisms of hepatic injury. Within 3 h of a single dose of DMN there was disruption of endothelial lining cells. In areas of endothelial cell loss, the exposed hepatocyte sinusoidal membranes became simplified and flattened. In the centrilobular area, hepatocytes became apoptotic and by 16 h apoptotic bodies, formed from degenerate hepatocytes, were engulfed by intact hepatocytes or by circulating macrophages. This progressive degeneration of hepatocytes and endothelial cells gave rise, by 24 h, to the classically recognized centrilobular haemorrhagic necrosis. The damage to the endothelial cells was concurrent with, or in some areas prior to, significant morphological changes in adjacent hepatocytes. This contrasts with other hepatotoxins such as carbon tetrachloride where the primary target is the hepatocyte, giving rise to hydropic degeneration and coagulative necrosis. DMN, however, results in apoptosis, a mechanism of cell death not normally associated with chemically induced injury.

Animals↗

PubMed1989

Chronic toxicity of sodium nitrite in the male F344 rat.

A long-term feeding study was carried out in rats with sodium nitrite. The test substance was administered as part of a reduced-protein diet to groups of 50, 6-wk-old, male F344 rats at dose levels of 0.2 or 0.5% (w/w) sodium nitrite for up to 115 wk. A control group of 20 males received the reduced-protein diet alone. Throughout the study, there was a dose-related decrease in the rates of body-weight gains and a corresponding decrease in body weights among animals fed sodium nitrite in the diet. Food intakes of rats in the low-dose group were slightly raised over most of the study. In the high-dose group, food intakes were reduced during the first month, but thereafter were similar to those of the control group. This reduction in food intake together with the lower body weights in the nitrite-treated animals, may indicate a reduction in food utilization. In the first week of treatment the following haematological parameters were reduced: red blood cell count, haematocrit and haemoglobin concentration. The red blood cell count continued to fall for 8 wk, then slowly returned to normal by wk 52. A dose-related reduction was noted in both the incidence and time of onset of lymphomas, leukaemias and testicular interstitial cell tumours. Leukaemias were only found in animals with lymphoma, indicating an association between the two lesions. Under the conditions described in this study, sodium nitrite was found not to be carcinogenic when fed to rats in the diet for up to 115 wk, but rather that the incidence of tumours was reduced in a dose-related manner, which correlated with a similar trend in body weights.

Animals↗

PubMed1989

Cell and tissue specific localization of O6-methylguanine in the DNA of rats given N-nitrosodimethylamine: effects of protein deficient and normal diets.

An immunohistochemical procedure which is specific for the detection of O6-methylguanine (O6-MeG) in nuclear DNA has been used to examine tissues of rats after treatment with N-nitrosodimethylamine. In liver, the principal cells that are positive for O6-MeG are the centrilobular hepatocytes and the sinusoidal cells. In the kidney cortex the proximal tubules, the mesenchymal elements and the capsules of Bowman are positive, whilst the cells of the glomeruli and the renal medulla are negative. Maintaining the animals on a protein-free diet prior to treatment with the nitrosamine significantly reduces the width of the band of positive cells around the central vein in the liver and increases the number and intensity of positively staining cells in the renal cortex. Subject to subsequent modification by DNA repair and DNA replication, the procedure therefore identifies cells which are potential targets for nitrosamine induced toxicity and carcinogenicity in liver and kidney.

Alkylation↗

PubMed1989

The lectin binding characteristics of spontaneous and phenobarbitone induced hepatic lesions in C3H/He mice.

The surface membrane glycoprotein patterns of spontaneous hepatic nodules, phenobarbitone induced nodules and hepatocellular carcinoma were studied in the C3H mouse using lectin histochemistry. The lectin binding patterns of hepatocellular carcinoma cells were markedly different to those of non-tumour cells and similar to the pattern in chemically induced hepatocellular carcinomas. This supports the hypothesis that changes in surface glycoprotein are a consistent feature associated with malignancy. Similar changes in the distribution of lectin binding sites were also seen in the phenobarbitone induced eosinophilic nodules and in a proportion of spontaneous basophilic nodules. Two populations of early basophilic nodules were identified on the basis of their lectin binding patterns, and this may indicate a link between one nodular type and carcinoma.

Animals↗

PubMed1989

The neuropathology of vigabatrin.

Vigabatrin (gamma vinyl GABA, GVG), an enzyme-activated, irreversible inhibitor of GABA transaminase, was administered orally to rats, dogs, and monkeys to observe toxicologic reactions. Myelin vacuolation of the brain was observed. The vacuolation was limited to myelinated tracts and resulted from separation of the myelin sheath at the interperiod line. There was no evidence of demyelination, axonal degeneration, or damage uolation was histologically similar to that observed in association with other drugs such as triethyltin, isoniazid, or hexachlorophene. However, the distribution is limited to the brain and is reversible upon discontinuation of therapy. Two postmortem and three operative specimens from humans have revealed no evidence of vacuolation of myelin.

Aminocaproates↗

PubMed1988

The lectin-binding characteristics of aflatoxin B1 induced lesions in the rat liver.

Hepatocellular carcinoma was induced in rats by administering aflatoxin B1 (AFB1) for 6 weeks. Malignant tumours were preceded by foci and nodules of altered hepatocytes of three histological types, composed of basophilic, eosinophilic, and vacuolated cells. In addition, there were areas of altered hepatocytes that were considered as hyperplastic. Lectins were used as histochemical markers to compare the expression of membrane glycoproteins in hepatocellular carcinomas and hepatic nodules with non-nodular or control hepatocytes. There were marked changes in the lectin-binding patterns of the hepatocellular carcinoma cells and the eosinophilic nodules. The lectin-binding patterns of basophilic nodules, vacuolated nodules, and hyperplastic areas were similar to non-nodular or untreated hepatocytes. The similarity in the lectin-binding changes of the eosinophilic nodules and hepatocellular carcinomas suggests that the eosinophilic nodules may be an early stage in the development of carcinoma.

Aflatoxin B1↗

PubMed1988

Effects of methyl isocyanate on rat muscle cells in culture.

Since the Bhopal disaster, in which the causal agent was methyl isocyanate (MIC), exposed people have complained of various disorders including neuromuscular dysfunction. In an attempt to gain some information about the response of muscle tissue to MIC its effects were investigated in cells in culture isolated from muscle of 2 day old rats. After treatment with a range of MIC concentrations (0.025-0.5 microliter/5 ml culture) the total number of nuclei of the two main cell types (fibroblasts and myoblasts) and the number of nuclei in muscle fibres (myotubes) were recorded. At lower doses which had little effect on the total number of nuclei, the formation of muscle fibres--that is, fusion of muscle cells--was prevented as the proportion of nuclei in myotubes was decreased. At higher doses both cell types were killed. This would suggest either an effect on muscle differentiation or a selective toxicity towards myoblasts. The observations were supported by light and electron microscopy.

Animals↗

PubMed1988

The ultrastructural features of aflatoxin B1-induced lesions in the rat liver.

Hepatocellular carcinoma was induced in rats by administering aflatoxin B1 (AFB1) for 6 weeks. Malignant tumours were preceded by foci and nodules of altered hepatocytes. The ultrastructural characteristics of the nodular lesions have been studied and compared with those of the hepatocellular carcinoma cells. Alterations in the endoplasmic reticulum, junctional complexes and nuclei were common to both the basophilic and eosinophilic nodular cells and the carcinoma cells. These most likely represent hyperplastic changes rather than malignant alterations. The eosinophilic nodules were distinguished from other lesions by the abundance of concentric, membranous whorls in the cytoplasm of nodular cells. These cytoplasmic structures were also present in some hepatocellular carcinoma cells. The observations provided further evidence suggesting that the eosinophilic nodule, rather than the basophilic nodule, may play a role in the development of malignancy in the rat liver.

Aflatoxin B1↗

PubMed1988

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Curriculum↗

PubMed1987

The assessment of chemically induced liver injury in rats.

The object of this investigation was to study the relationship between acute hepatic injury and blood coagulation. Most of the clotting factors are synthesised by the hepatocytes and therefore it would seem likely that hepatic injury would lead to an impairment of blood clotting. Dimethylnitrosamine (DMN) and carbon tetrachloride (CCl4) were selected as model hepatotoxins to induce an acute hepatic lesion. Single doses of each compound were administered to male rats and groups of animals killed 3, 6, 16 and 24 h later in order to study the morphological development of the lesion and to relate this to changes in the haematological profiles. Both compounds produced a centrilobular necrosis, but with DMN there was a haemorrhagic component due to damage to endothelial cells, which contrasts with the classical coagulative necrosis produced by CCl4. After 6 h apoptosis was commonly seen in the centrilobular areas of the DMN treated rats. This process of cell death has not previously been demonstrated in chemically induced acute hepatic injury and was not seen in the CCl4 treated rats. Significantly prolonged clotting times were seen in both DMN and CCl4 treated rats and occurred in parallel with some of the early morphological changes but prior to the appearance of extensive haemorrhagic or coagulative necrosis. This preliminary data suggests that the measurement of blood coagulation times may provide a relatively specific and sensitive indicator of acute hepatic injury in rats.

Animals↗