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Biomedical subjects

A Brouwer

Publications and source records attributed to A Brouwer.

At least 109 records · Page 6Linked to original sources
PubMed1993

Glucuronidation of thyroid hormone in rat liver: effects of in vivo treatment with microsomal enzyme inducers and in vitro assay conditions.

We investigated the effects of in vivo treatment with different microsomal enzyme inducers, including clofibrate (CLOF), hexachlorobenzene (HCB), 3-methylcholanthrene (MC), 3,3',4,4'-tetrachlorobiphenyl (TCB), and 2,3,7,8-tetrachloro-p-dioxin, as well as of in vitro addition of the detergent Brij 56 on the glucuronidation of T4, T3, and rT3 by UDP-glucuronyltransferase (UGT) activities of rat liver microsomes. The results were compared with measurements of UGT activities for bilirubin, p-nitrophenol (PNP), and androsterone. In general, glucuronidation rates were 5-fold or more higher with rT3 than with T4 or T3 as substrate. In liver microsomes from untreated rats, T4 UGT activity was stimulated by Brij 56 to a maximum of about 2-fold at 0.025% detergent. Treatment of Wistar rats for 4 days with CLOF (200 mg/kg BW.day) resulted in significant increases in UGT activities for T4 (to 154%), rT3 (to 155%), and bilirubin (to 194%), in particular if assayed in the presence of 0.025% Brij 56, but had little effect on the UGT activities for T3, PNP, and androsterone. The CLOF-induced increases in T4 and rT3 UGT activities were not observed in Gunn rats, which have a complete lack of bilirubin UGT activity and greatly impaired PNP UGT activity. Treatment of Wistar rats with a single injection of MC (50 mg/kg BW), TCB (50 mg/kg BW), or 2,3,7,8-tetrachloro-p-dioxin (6.25 micrograms/kg BW) resulted, after 4 days, in 6.3- to 7.3-fold increases in T4 UGT activity and 15.1- to 16.7-fold increases in rT3 UGT activity if determined in the absence of Brij 56, whereas T4 UGT activity was only increased by 33-68% when assayed in the presence of Brij 56. T3 glucuronidation was not affected (with Brij 56) or was increased by only 33-68% (without Brij 56) after treatment with these MC-type inducers. PNP UGT activity was induced 3.6- to 4.3-fold, whereas bilirubin and androsterone UGT activities were changed little by these treatments. Similar findings regarding T4, rT3, PNP, and bilirubin UGT activities were obtained after chronic treatment of WAG rats with HCB, another MC-type inducer. However, WAG rats lack androsterone UGT and show low T3 UGT activity, which was increased about 2.3-fold by HCB treatment. On the basis of these and previous findings it is concluded that at least three UGT isoenzymes are involved in the glucuronidation of thyroid hormone.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Visualization of the uptake and processing of oxidized low-density lipoproteins in human and rat liver.

The interaction of oxidized human low-density lipoproteins with human and rat liver was analyzed by light and electron microscopy. At the light microscopic level oxidized low-density lipoprotein was visualized by the fluorescent dye 1,1' dioctadecyl 3,3,3',3' tetramethyl indocarbocyanine perchlorate, whereas at the electron microscopic level, an indirect immunolabeling procedure was used that detected the apoprotein B of the oxidized low-density lipoprotein. In rats, oxidized low-density lipoprotein was administered intravenously, and uptake by human liver was studied by perfusion of tissue blocks. Both in human and in rat liver, fluorescently labeled oxidized low-density lipoprotein was mainly found to become concentrated in Kupffer cells and, to a lesser extent, in endothelial cells. In both species the cell association of fluorescently labeled oxidized low-density lipoprotein could be inhibited by preadministration of polyinosinic acid, indicating a scavenger receptor-mediated process. At the electron microscopic level, oxidized low-density lipoprotein was found to bind mainly to areas of the plasma membrane of the Kupffer cells without clathrin coating, although binding to coated regions was also noticed. Internalization of the ligand occurred through coated vesicle formation and through membrane folding of interacting lamellipodia and wormlike structures. No indication for phagocytosis of aggregated oxidized low-density lipoprotein particles was noticed. After internalization, the immunoreactive oxidized low-density lipoprotein was detected in relatively electron-lucent endosomes and, subsequently, in lysosomes. Endothelial cells internalized oxidized low-density lipoprotein solely through coated pits, after which the particles were transferred through endosomes into lysosomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Impact of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls on human and environmental health, with special emphasis on application of the toxic equivalency factor concept.

A scientific evaluation was made of the mechanisms of action of polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls. Distinction is made between the aryl-hydrocarbon (Ah) receptor-mediated and non-Ah receptor-mediated toxic responses. Special attention is paid to the applicability of the toxic equivalency factor (TEF) concept.

Animals↗
PubMed1992

On the fibrinolytic system in aged rats, and its reactivity to endotoxin and cytokines.

Aged rats are more susceptible to endotoxin-induced effects, including microthrombosis and platelet aggregation, than are young rats. To investigate whether changes in the fibrinolytic system might be involved, we investigated the fibrinolytic activity in plasma euglobulin fractions and tissues (lung and heart) of young (6-months old) and aged (24-months old) rats under baseline conditions and after challenge with endotoxin. Aged rats had lower plasma levels of tissue-type plasminogen activator (t-PA) and of urokinase-type PA (u-PA) activity. PA inhibitor (PAI) activity was higher in the plasma of aged rats, as was t-PA activity in lung and heart. Rats were treated with either a low dose (1 microgram/kg) or a high dose (10 mg/kg) of endotoxin. Both treatments induced a transient phase of increased blood fibrinolytic activity, as evidenced by higher levels of tissue-type plasminogen activator (t-PA) activity and decreased levels of PA inhibitor (PAI) activity. Over time, the fibrinolytic activity decreased, probably due to increased levels of PA inhibitor. Both the early increase in t-PA activity, and the subsequent increase in PAI activity, were more pronounced in the aged rats, as compared with the younger rats, after the high dose of endotoxin. The aged rats also responded to an injection of interleukin-1 beta or tumor necrosis factor-alpha with a larger increase of PAI activity than did the younger rats. Together the data suggest that, compared to young rats, aged rats have a decreased base-line plasma fibrinolytic activity, while their fibrinolytic system is more responsive to challenge by endotoxin and cytokines.

Aging↗
PubMed1992

Subchronic toxicity and reproduction effects of tri-n-butyltin oxide in Japanese quail.

A subchronic toxicity/reproduction study was performed in Japanese quails that were fed a diet containing 0, 24, 60, and 150 mg tri-n-butyltin oxide (TBTO) per kg basal diet for 6 weeks. Eggs produced during the 6 weeks of treatment were incubated and hatched, and chicks hatched from eggs collected in weeks 5 and 6 of exposure were reared for 2 weeks. In parent quail, neither diminished food consumption nor any overt toxic or histopathologic signs were observed following exposure to TBTO. A statistically significant decrease in hatch-ability and increase in percent of chicks found dead in the shell were observed following TBTO exposure at concentrations of 60 and 150 mg/kg food. However, no significant, adverse effects were recorded on total egg production, eggshell thickness and cracked eggs. Blood chemistry parameters of birds measured at the last day of TBTO treatment revealed a statistically significant decrease in serum aspartate aminotransferase (ASAT) enzyme activity among both sexes in all treatment groups. In addition, a statistically significant dose-related decrease in serum calcium level was observed in females only, while serum follicle stimulating hormone (FSH) levels were statistically significantly reduced in male birds in all treatment groups (approximately 50% of the controls). Moreover, a significant decrease in hepatic microsomal 7-ethoxyresorufin (EROD) activity was recorded in females fed 24 and 60 mg TBTO/kg diet and males fed 60 and 150 mg TBTO/kg diet, whereas pentoxyresorufin-o-deetylase (PROD) activity was only significantly decreased in males fed 150 mg TBTO/kg diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Inhibition of binding of thyroxin to transthyretin by outdoor and indoor airborne particulate matter and effects on thyroid hormone and vitamin A metabolism in rats.

Previous studies have indicated that chemicals, e.g., hydroxylated polychlorinated biphenyls (PCBs) decrease plasma thyroxin levels through interaction with transthyretin. As a consequence, plasma vitamin A and thyroxin are depleted. Both thyroxin and vitamin A are important regulators of normal epithelial differentiation and proliferation and might act in the promotion phase of carcinogenesis. In the present report, extracts of indoor and outdoor airborne particulate matter (APM), originating from different pollution sources, were tested for a possible interaction in vitro and in vivo with thyroxin and vitamin A. Results indicated that all APM extracts significantly interfered with thyroxin binding to transthyretin. In all cases, the more polluted samples inhibited binding more than the corresponding control samples. Exposure of rats to a cigarette smoke extract induced clear changes in plasma thyroxin and triiodothyronin hormone levels. Triiodothyronin levels were reduced most. Effects on plasma vitamin A levels were also found, but these were less clear. In addition a decrease in lung vitamin A levels was found, but this decrease was not statistically significant. Exposure of rats to an outdoor APM extract induced significant changes in plasma triiodothyronin levels. Effects on thyroxin levels were not significant, although the same trend was seen as for the cigarette smoke APM extract. No changes in plasma or liver vitamin A concentrations were induced by the outdoor APM extract. Lung vitamin A levels were decreased, but again this decrease was not statistically significant. Taken together, the present report shows that APM extracts have the potency to interfere with thyroid hormone metabolism both in vitro and in vivo and probably with vitamin A metabolism as well.(ABSTRACT TRUNCATED AT 250 WORDS)

Air Pollutants↗
PubMed1991

Selective uptake of cholesteryl esters from apolipoprotein-E-free high-density lipoproteins by rat parenchymal cells in vivo is efficiently coupled to bile acid synthesis.

[3H]Cholesteryl ester-labelled human high-density lipoprotein (HDL) was injected into rats and its decay, intrahepatic cellular distribution and the kinetics of biliary secretion were determined. At 10 min after injection the hepatic uptake of cholesteryl esters from HDL was 3-fold higher as compared with the apolipoprotein. Selective uptake was exerted only by parenchymal cells (5.6-fold more cholesteryl esters than apolipoprotein) and not by liver endothelial or Kupffer cells. The kinetics of biliary secretion of processed cholesteryl esters initially associated with HDL or low-density lipoprotein (LDL) were compared in unrestrained rats, equipped with permanent catheters in bile duct, duodenum and heart. At 72 h after injection of [3H]cholesteryl oleate-labelled HDL, 51.0 +/- 2.5% of the injected dose was recovered as bile acids, which is about twice as high as the secretion of biliary radioactivity after injection of [3H]cholesteryl oleate-labelled LDL. Oestradiol treatment stimulated only liver uptake of LDL cholesteryl esters, and resulted in a 2-fold higher liver uptake than with HDL. However, the rate of radioactive bile acid formation from [3H]cholesteryl oleate-labelled HDL was still more rapid than for LDL. It is concluded that the selective uptake pathway for cholesteryl esters from HDL in parenchymal cells is more efficiently coupled to the formation of bile acids than is the cholesteryl ester uptake from LDL. This efficient coupling may facilitate the role of HDL in reverse cholesterol transport.

Animals↗
PubMed1991

Visualization of the interaction of native and modified lipoproteins with parenchymal, endothelial and Kupffer cells from human liver.

The interaction of low density lipoprotein, acetylated low density lipoprotein and apolipoprotein E-free high density lipoprotein with parenchymal, endothelial and Kupffer cells of human liver was visualized. For this purpose, the fluorescent phospholipid analog 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate was used to label the lipoproteins. The involvement of both parenchymal and nonparenchymal cells in the uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate-labeled low density lipoprotein and acetylated low density lipoprotein was studied using in vitro perfusion of human liver tissue blocks. In addition, primary hepatocyte cultures were used to visualize the interaction with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate-labeled apolipoprotein E-free high density lipoprotein and (modified) low density lipoprotein. 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate-low density lipoprotein showed a time-dependent and concentration-dependent interaction with both hepatocytes and Kupffer cells, although the intensity of the interaction with parenchymal cells varied strongly among the liver donors. Uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate-low density lipoprotein by both cell types was strongly inhibited by the presence of excess unlabeled low density lipoprotein in the (perfusion) medium. Methylation and hydroxyacetaldehyde treatment of low density lipoprotein prevented the uptake of low density lipoprotein. This indicated that the uptake of low density lipoprotein by Kupffer and parenchymal cells was mediated by the low density lipoprotein receptor. 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate-acetylated low density lipoprotein was mainly taken up in situ by liver endothelial cells and by a minor population of Kupffer cells. Polyinosinic acid, a known inhibitor of the scavenger receptor, prevented the uptake by liver endothelial cells. Therefore human liver endothelial cells express active scavenger receptors on their surface. Apolipoprotein E-free 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indocarbocyanine perchlorate-high density lipoprotein was found to be associated with the membrane of cultured liver parenchymal cells but was not taken up intracellularly, indicating a cholesterol exchange process occurring extracellularly at the plasma membrane. The cellular localization of lipoprotein receptors and uptake of the various classes of lipoproteins are comparable with the situation in rats.

Cells, Cultured↗
PubMed1991

Changes in endotoxin sensitivity in ageing. Absorption, elimination and mortality.

In this paper we describe the influence of ageing on responses to intravenously-injected endotoxin in two rat strains. Old age had no apparent effect on the absorption of 51Cr-labelled endotoxin from either jejunum or colon. Notwithstanding, aged animals appeared much more sensitive than their young counterparts to the lethal effects of intravenously injected endotoxin. Old animals exhibited virtually 100% mortality over the dose range 1-4 mg/100 g body weight while only sporadic deaths were seen in young animals. One consistent feature of dying animals was a profound and progressive hypothermia. At post mortem examination, the major findings were in the liver (leukocyte infiltrates and hepatocellular necrosis) and kidneys (acute tubular necrosis). Ageing was associated with slower removal of endotoxin from the circulation but not to an extent that could reasonably account for the enhanced sensitivity to endotoxin toxicity.

Aging↗
PubMed1991

Chronic administration of ethanol with high vitamin A supplementation in a liquid diet to rats does not cause liver fibrosis. 1. Morphological observations.

Rats of two strains (BN/BiRij and WAG/Rij) were fed the ethanol-containing Lieber-De Carli liquid diet supplemented with high amounts of vitamin A for 16 months. In contrast to Lieber and co-workers, who showed liver fibrosis developing within 9 months on the same diet in Sprague-Dawley rats, we were unable to demonstrate a histological and biochemical increase in liver collagen in either strain. Steatosis was present to a varying degree in both strains in ethanol-treated rats, but also in control animals. Considerable liver inflammation with focal necrosis accompanied by severe systemic inflammation was observed in 60% of the ethanol-treated WAG rats. This suggests that, at least in rats, the main effects of chronic ethanol consumption on the liver may be secondary to interference with host resistance to infections. The ethanol-high vitamin A Lieber-De Carli liquid diet does not necessarily elicit fibrosis or other characteristic histological abnormalities of human alcoholic liver disease.

Animals↗
PubMed1991

Chronic administration of ethanol with high vitamin A supplementation in a liquid diet to rats does not cause liver fibrosis. 2. Biochemical observations.

The inability of the 'ethanol/high vitamin A Lieber-DeCarli diet' to induce liver fibrosis in two different rat strains was further evaluated by determining changes in parameters of liver cell damage and of retinoid and lipid metabolism. In the ethanol/vitamin A-treated group, slight but constant hepatic cell damage, as indicated by elevated alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase activities in blood, was already observed at 6 months and maintained until the time of death at 16 months. Serum gamma-glutamyl transaminase activities were not raised. Moderate parenchymal liver cell damage was not accompanied by fibrosis. Hypertriglyceridemia or hypercholesterolemia were observed at 6-16 months of chronic alcohol administration. This response was strain dependent. In ethanol-treated rats of both strains, total liver retinoids and serum retinol concentrations were not altered. Therefore, the hypothesis that interaction between alcohol and retinoids is a major factor in the pathogenesis of alcoholic liver disease, needs to be reconsidered.

Animals↗
PubMed1991

The toxicity of tetrachlorobenzyltoluenes (Ugilec 141) and polychlorobiphenyls (Aroclor 1254 and PCB-77) compared in Ah-responsive and Ah-nonresponsive mice.

The toxicity of the PCB substitute Ugilec 141, a mixture of tetrachlorobenzyltoluenes (TCBTs), is compared with the toxicity of a commercial mixture of polychlorobiphenyls (Aroclor 1254) and with the model toxic PCB-congener 3,3',4,4',-tetrachlorobiphenyl (PCB-77) as a positive control. Alterations in liver weight, hepatic cytochrome P450 content and EROD and PROD activity, plasma thyroxin and retinol level, hepatic retinoid level and liver and thyroid pathology, have been studied in Ah-responsive and Ah-nonresponsive mice. Ugilec 141 proved to induce similar toxicological changes, qualitatively and quantitatively, to Aroclor 1254. Therefore Ugilec may pose a similar environmental and health risk as PCBs. The criteria for acceptance of new substances, like Ugilec 141, on the European market are discussed.

Journal Article↗
PubMed1991

Mitogen response of B cells, but not T cells, is impaired in adult vitamin A-deficient rats.

The effect of vitamin A deficiency on the mitogen response of splenic B and T lymphocytes was determined in adult vitamin A-deficient rats. Female weanling Brown Norway/Billingham-Rijswijk (BN/BiRij) and Sprague-Dawley rats were fed a semipurified, essentially vitamin A-free diet, which resulted in clinical symptoms of vitamin A deficiency and severely decreased plasma retinol contents at the age of about 17 and 41 wk for BN/BiRij and Sprague-Dawley rats, respectively. A lower B cell proliferative response after stimulation with lipopolysaccharide in combination with dextran sulfate was observed in vitamin A-deficient rats of both strains, but the T cell proliferative response after concanavalin A stimulation was unchanged. The lower B cell mitogen response was not associated with changes in the cellular composition of the spleen (as analyzed with monoclonal antibodies specific for the various subsets of T and B cells and of macrophages). We suggest that the age at which clinical symptoms of vitamin A deficiency are induced may be an important determinant for the immunological variables affected.

Animals↗
PubMed1991

Copper uptake and retention in liver parenchymal cells isolated from nutritionally copper-deficient rats.

Copper uptake and retention were studied in primary cultures of liver parenchymal cells isolated from copper-deficient rats. Male Sprague-Dawley rats were fed a copper-deficient diet (less than 1 mg Cu/kg) for 10 wk. Copper-deficient rats were characterized by low copper concentrations in plasma and liver, anemia, low plasma ceruloplasmin oxidase activity and increased 64Cu whole-body retention. Freshly isolated liver parenchymal cells from copper-deficient rats showed a higher 64Cu influx, which was associated with a higher apparent Vmax of 45 +/- 4 pmol Cu.mg protein-1.min-1 as compared with 30 +/- 3 pmol Cu.mg protein-1.min-1 for cells isolated from copper-sufficient rats. No significant difference in the apparent Km (approximately 30 mumol/L) was observed. Relative 64Cu efflux from cells from copper-deficient rats was significantly smaller than the efflux from cells from copper-sufficient rats after prelabeling as determined by 2-h efflux experiments. Analysis of the medium after efflux from cells from copper-deficient rats showed elevated protein-associated 64Cu, suggesting a higher incorporation of radioactive copper during metalloprotein synthesis. Effects of copper deficiency persist in primary cultures of parenchymal cells derived from copper-deficient rats, and short-term cultures of these cells offer a prospect for the study of cell biological aspects of the metabolic adaptation of the liver to copper deficiency.

Animals↗