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Biomedical subjects

A Brouwer

Publications and source records attributed to A Brouwer.

At least 91 records · Page 5Linked to original sources
PubMed1994

Toxic potency of 3,3',4,4',5-pentachlorobiphenyl relative to and in combination with 2,3,7,8-tetrachlorodibenzo-p-dioxin in a subchronic feeding study in the rat.

Toxic and biochemical potencies of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) were studied relative to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a 13-week feeding study in female Sprague-Dawley rats. To study possible interactive effects the combinations of both compounds were administered. The diets were supplemented with PCB 126 (7, 50, or 180 micrograms/kg diet), with TCDD (0.4 or 5 micrograms/kg diet), or with combinations of both compounds. An estimated daily intake of 0.47 micrograms PCB 126/kg body weight/day caused thymic atrophy, a dramatic loss in hepatic retinoids, and a marked induction in CYP1A1 and CYP1A2 activities. At a daily intake of 3.18 micrograms PCB 126/kg body weight/day a decrease in body weight gain, liver enlargement, and plasma thyroid hormone concentrations occurred. Based on a simultaneous subchronic feeding study with TCDD, a toxic equivalency factor range between 0.01 and 0.1 was estimated for PCB 126 for the mentioned effects. Antagonism was found between TCDD and PCB 126 for hepatic retinol levels and CYP1A2 activity. At the same time, TCDD and PCB 126 liver residue levels were slightly decreased by coadministration. However, these antagonistic effects occurred at maximum induction levels of CYP1A1 and CYP1A2, which are not likely to occur at levels relevant for humans.

Acetanilides↗
PubMed1994

Inhibition of intercellular communication by 2,3,7,8-tetrachlorodibenzo-p-dioxin and dioxin-like PCBs in mouse hepatoma cells (Hepa1c1c7): involvement of the Ah receptor.

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and the coplanar 3,3',4,4'-tetrachlorobiphenyl (3,3',4,4'-TCB) and 3,3',4,4',5,5'-hexachlorobiphenyl (3,3',4,4',5,5'-HCB) on intercellular communication (IC) were determined in order to investigate the in vitro tumor promoting potency of these compounds. 2,3,7,8-TCDD and the two coplanar PCBs tested caused a rapid (2 hr) and a sustained inhibition (48 hr) of IC in the mouse hepatoma cell line (Hepa1c1c7) to 20 and 50% of the unexposed control, respectively. Inhibition of IC was dose dependent with an EC50 range of about 50-100 pM for 2,3,7,8-TCDD, 2-5 nM for 3,3',4,4'-TCB, and 10-15 nM for 3,3',4,4',5,5'-HCB, respectively. A comparison of the IC inhibitory effects of 2,3,7,8-TCDD and PCBs with a well-known aryl hydrocarbon receptor (AhR)-mediated response, the induction of ethoxyresorufin O-deethylase (EROD) activity, in the same cells revealed EROD induction by 2,3,7,8-TCDD, 3,3',4,4'-TCB, and 3,3',4,4',5,5'-HCB with EC50 ranges of 100-200 pM, 20-70 nM, and 5-10 nM, respectively. The time course of IC inhibition was paralleled by EROD induction, although the time of onset of the response was earlier for IC (1 hr) than for EROD (2.5 hr). A role of the AhR in the inhibition of IC by 2,3,7,8-TCDD and PCBs was demonstrated by the lack of inhibition in AhR-defective Hepa1c1c7 cells. Transient inhibition of IC was observed in the mutant cells only at early time points (within 2 hr of exposure). These results and the observation that alpha-naphtoflavone (an AhR antagonist) greatly reduced the 2,3,7,8-TCDD-dependent sustained inhibition of IC strongly support a role of the AhR in the sustained inhibition of IC by these compounds. Furthermore, these data suggest that the mouse Hepa1c1c7 cells may be a good model in which to study in vitro tumor promoting capacity of dioxins, PCBs, and related compounds.

Animals↗
PubMed1994

Toxic and biochemical effects of 3,3',4,4'-tetrachlorobiphenyl (CB-77) and clophen A50 on eider duckling (Somateria mollissima) in a semi-field experiment.

In this study the possible toxic and biochemical effects of one intraperitoneal dose of 5 or 50 mg kg(-1) of 3,3',4,4'-tetrachlorobiphenyl (CB-77) or 50 or 200 mg kg(-1) of Clophen A50 (CloA50) on 28-day-old eider ducklings (Somateria mollissima) were investigated. After ten days, no significant differences could be observed in any of the toxic and biochemical parameters studied, apart from ethoxyresorufin (EROD) activity, when comparing group average values of the dosed and control animals. However, significant correlations were observed at day 10 after exposure between the individual internal PCB concentration and body weight gain and beak length growth (negative correlations in the CloA50 groups); relative liver weight and cytochrome P4501A activity (positive correlations in CB-77 and CloA50 groups); plasma thyroid-hormone and hepatic retinoid levels (negative correlations in CB-77 groups); and plasma retinol levels and the ratio plasma retin/hepatic retinyl palmitate (positive correlations in CB-77 groups only). Animal activity was significantly reduced in the group that received 50 mg CB-77 kg(-1). These observations indicate that eider ducks are a sensitive species to PCB toxicity and may be at risk for development of adverse health effects in relatively highly contaminated areas such as the Waddenzee.

Journal Article↗
PubMed1994

Effects of outdoor and indoor airborne particulate matter on thyroid hormone and vitamin A metabolism.

Vitamin A is an important regulator of normal epithelial differentiation and proliferation and might act in the promotion phase of carcinogenesis. Vitamin A and thyroid hormone metabolism are linked by a common plasma carrier protein transthyretin (TTR). Results indicated that extracts of outdoor and indoor airborne particulate matter (APM), originating from different pollution sources, significantly interfered with thyroxine (T4) binding to TTR. The neutral fraction accounted for most of the inhibitory activity. Polycyclic aromatic hydrocarbons and nitrated derivatives were not responsible for the activity of the neural fraction. A single treatment of rats with an outdoor and cigarette smoke APM extract depleted plasma T4 and triiodothyronine levels and increased plasma retinol levels, while liver and lung retinol levels were depleted. The studies show that APM extracts have the potency to interfere with thyroid hormone metabolism both in vitro and in vivo and to deplete lung vitamin A in vivo.

Air Pollutants↗
PubMed1994

Alcohol in combination with malnutrition causes increased liver fibrosis in rats.

Rats were malnourished for 12 months with a highly inadequate fat-rich, calorie-sufficient but otherwise poly-deficient liquid diet composed of mashed potatoes with mayonnaise, comparable with the nutritional intake of many chronic alcoholics. When alcohol was incorporated into this diet, administered as whisky in drinking water available ad libitum, the livers of all eight rats showed increased fibrosis and cirrhosis as compared to the livers of the eight non-alcohol-treated, isocalorically fed, paired control rats. Alcohol-treated rats developed fibrosis and cirrhosis on a dietary fat content of 38% of total caloric intake and low blood alcohol levels, ranging from 50 to 126 mg/dl, due to gradual intake over the day and to low absolute intake (mean 11.9 +/- 0.6 g/kg per day). None of the rats died spontaneously. Malnutrition is likely to be an important factor in the development of the fibrosis of alcoholic liver disease, and this rat model may be used to study aspects of the pathogenesis.

Alanine Transaminase↗
PubMed1994

Biotransformation and toxicity of halogenated benzenes.

1. Multiple potentially harmful metabolites can be distinguished in the metabolic activation of halogenated benzenes: epoxides, phenols, benzoquinones and benzoquinone-derived glutathione conjugates. 2. The role of these (re-) active metabolites in the toxic effects induced by halogenated benzenes such as hepatotoxicity, nephrotoxicity, porphyria and thyroid toxicity is discussed. 3. Evidence is presented suggesting that the formation of reactive benzoquinone metabolites rather than the traditional epoxides is linked to halogenated benzene-induced hepatotoxicity. 4. A crucial role for the benzoquinone-derived glutathione adducts in halogenated benzene-induced nephrotoxicity is clearly established. 5. Although metabolic activation appears to be involved in porphyria, the nature of the ultimate porphyrinogenic metabolite has not been elucidated yet. 6. Disturbances in thyroid hormone (and retinoid) homeostasis can be (at least partially) explained by the formation of halogenated phenol metabolites. 7. In conclusion, for a relevant prediction of the ultimate fate of a compound in a living organism, one should know the chemical characteristics and reactivity of the parent compound and its metabolites, together with insight into the formation mechanism of each of the suspected metabolites, and an understanding of the interaction between a specific chemical (reactive) structure and its target molecule.

Animals↗
PubMed1994

Effects of dioxins and polychlorinated biphenyls on thyroid hormone status of pregnant women and their infants.

Dioxins [polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF)] and polychlorinated biphenyls (PCB) are potentially hazardous compounds. Animal studies have demonstrated that PCDD, PCDF, and PCB can alter thyroid hormone homeostasis. We investigated thyroid hormone levels in 105 mother-infant pairs. To estimate maternal and infant exposure, four nonplanar PCB congeners were measured in maternal plasma during the last month of pregnancy and in umbilical cord plasma. Seventeen PCDD and PCDF congeners, three planar PCB congeners, and 23 nonplanar PCB congeners were measured in human milk. Higher PCDD, PCDF, and PCB levels in human milk, expressed as toxic equivalents, correlated significantly with lower plasma levels of maternal total triiodothyronine and total thyroxine, and with higher plasma-levels of TSH in the infants in the 2nd wk and 3rd mo after birth. Infants exposed to higher toxic equivalents levels had also lower plasma free thyroxine and total thyroxine levels in the 2nd wk after birth. We conclude that elevated levels of dioxins and PCB can alter the human thyroid hormone status.

Breast Feeding↗
PubMed1994

Chloracne. Some recent issues.

Chloracne is an acneiform skin eruption that is still the most sensitive indicator of systemic poisoning caused by chemicals belonging to the group of chlorinated polycyclic aromatic hydrocarbons. Generally these chemicals are known as dioxins, dibenzofuranes, and PCBs. The cause of chloracne is probably interference of these chemicals with vitamin A metabolism in the skin, resulting in disturbances of the epithelial tissues of the pilosebaceous duct. A study of workers in a factory where chloracne is endemic is described. The product manufactured, pentachlorophenol, a wood preservative, was found to be contaminated with dioxins (congeners of TCDD) and dibenzofuranes. Blood levels of these chemicals in affected workers are given, along with supporting evidence of disturbances in vitamin A (retinoid) metabolism as demonstrated in skin biopsies.

Acne Vulgaris↗
PubMed1994

Cholesteryl esters from oxidized low-density lipoproteins are in vivo rapidly hydrolyzed in rat Kupffer cells and transported to liver parenchymal cells and bile.

Human low-density lipoprotein was labeled in its cholesteryl ester moiety with [3H]cholesteryl oleate or [3H]cholesteryl oleoyl ether and oxidized by exposure to 10 mumol/L of cupric sulfate. The in vivo metabolism of cholesteryl esters of oxidized low-density lipoprotein was determined after injection into rats. When oxidized low-density lipoprotein was labeled with [3H]cholesteryl oleoyl ether, a nonhydrolyzable analog of cholesteryl oleate, Kupffer cells contributed to 55.1% +/- 4.1% of the total liver uptake 10 min after injection. When [3H]cholesteryl oleate-labeled oxidized low-density lipoprotein was injected, the radiolabeled cholesterol esters were nearly completely hydrolyzed within 1 hr of injection. Within this time, the Kupffer cell-associated radioactivity declined to 32% of the maximal uptake value. In serum, the highest specific resecreted [3H]cholesteryl (esters) were associated with the serum high-density lipoprotein fraction, suggesting a role for high-density lipoprotein as an in vivo cholesterol acceptor. The kinetics of biliary secretion were studied in rats equipped with catheters in the bile duct, duodenum and heart. One hour after injection of [3H]cholesteryl oleate-labeled oxidized low-density lipoprotein, 4.15% +/- 0.67% of the injected dose was secreted in the bile, mainly as bile acids. Six hours after injection, this value was 19.2% +/- 1.2%. These values are three times higher than those for injected [3H]cholesteryl oleate-labeled acetylated low-density lipoprotein, which is initially mainly taken up by liver endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Energy restriction, a useful intervention to retard human ageing? Results of a feasibility study.

OBJECTIVE: Energy restriction (ER) retards the ageing process in animal models. It is possible that ER has a similar effect in humans. As a first approach to look after the potential application of ER in man the feasibility of a moderately energy-restricted diet was studied. DESIGN: A controlled intervention study. SETTING: TNO Toxicology and Nutrition Institute. SUBJECTS: 24 middle-aged non-obese men, selected from men responding to advertisements in regional newspapers. INTERVENTIONS: After a run-in period subjects were divided into two groups, a control group (n = 8) and an ER group (n = 16). Groups were matched on age and body mass index. The effects of 10 weeks of moderate ER (80% of habitual energy intake) on body composition, general health (blood pressure, lipid profile, routine clinical chemistry and haematology), physical and mental performance, and feelings of hunger, satiety and state of mind were measured. RESULTS: Subjects in the ER group lost about 7.4 +/- 2.6 kg weight (P < 0.001). This weight loss concerned mainly loss of fat mass. Diastolic and systolic blood pressure decreased significantly within the ER group (P < 0.05 and P < 0.01 respectively). The increase in HDL-cholesterol level was significantly related to weight loss (P < 0.05). CONCLUSIONS: The results show beneficial effects of 10 weeks of moderate ER on blood pressure and lipid profile without adverse effects on physical and mental performance and feelings of hunger, satiety and mood.

Adult↗
PubMed1994

Fat-storing cells and myofibroblasts are involved in the initial phase of carbon tetrachloride-induced hepatic fibrosis in BN/BiRij rats.

This study on the appearance, distribution and kinetics of fibroblast-like cells (fat-storing cells, transitional cells, myofibroblasts and fibroblasts) after CCl4-treatment was undertaken to delineate further the respective roles of these cell types in liver fibrogenesis. The different cell types were distinguished on the basis of their immunophenotypic pattern with a combination of marker antibodies and on the basis of ultrastructural characteristics. Combined staining for alpha-smooth muscle actin (sma) and desmin (Des) revealed perisinusoidal fat-storing cells (FSC) as d+ sma- and myofibroblasts around the central veins of the normal rat liver as d+ sma+. During the initial phase of CCl4-induced hepatic fibrosis (week 1 and 2), the number of d+ sma+ cells increased in the degenerating area around the central veins and d+ sma+ cells appeared in the very thin fibrotic septa at week 2. Ultrastructural examination of the affected central areas showed the presence of myofibroblasts. These sma+ cells proliferated, as shown by double staining for bromodeoxyuridine (BrdU) and sma. In degenerating parenchymal areas, d+ sma- FSC were present. The FSC in the perisinusoidal space of areas which were not affected by CCl4 intoxification, remained d+ sma-. These immunostaining findings support the electron microscopical results, which show the presence of cells with the typical ultrastructural characteristics of FSC in both the degenerating areas and the perisinusoidal space of unaffected areas. After one week of CCl4-treatment, enhanced deposition of procollagen type III was observed around the central veins. Enhanced deposition of collagen type IV was seen subendothelially along the sinusoids, notably in degenerating parenchymal areas where the septa were later formed. FSC appear to be the principal source of collagen type IV during fibrogenesis. These observations further support and specify the role of FSC in early fibrogenesis. With the progression of the CCl4-induced fibrosis, d+ sma+ myofibroblasts remained localized in the fibrotic septa, but now along their outer edge. The majority of the cells in the septa were formed by d- sma- cells indicating a prominent role of fibroblasts in the septal formation. Septal fibroblasts are not only likely to produce matrix components, but also were shown to degrade collagen, as evidenced by the increased number of collagen-containing vacuoles during the course of fibrosis. In conclusion, myofibroblasts and FSC appear to be the main cell types involved in the initial phase of liver fibrogenesis induced by CCl4. Both myofibroblasts and FSC divide and transform.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Vitamin A deficiency potentiates carbon tetrachloride-induced liver fibrosis in rats.

Earlier studies have shown that retinoid administration suppresses the generation of hepatic fibrosis and stimulates its regression in normal (i.e., vitamin A-sufficient) carbon tetrachloride-treated rats. This study focuses on the possible role of a marginal or deficient vitamin A status on carbon tetrachloride-induced fibrosis. This experimental study in rats shows that vitamin A status, reflected by hepatic retinoid content (retinol and retinyl esters), modulates the development of hepatic fibrosis induced by carbon tetrachloride. In rats with low hepatic retinoid levels (12 +/- 0.9 micrograms/gm liver), carbon tetrachloride-induced liver fibrosis was more pronounced than in rats with sufficient hepatic retinoid levels (1,065 +/- 327 micrograms/gm liver). Enhanced liver fibrogenesis was confirmed both morphologically and by a higher hydroxyproline content of the liver. It was associated with a reduced liver weight and the development of parenchymal regeneration nodules. Furthermore, carbon tetrachloride treatment itself reduced the hepatic retinoid content in rats independently of the liver vitamin A status before treatment and increased serum retinol levels in vitamin A-sufficient rats. The results show that the vitamin A status of the liver plays an important role in hepatic fibrogenesis. Low hepatic vitamin A levels, which can be the result not only of low dietary intake but also of interference with vitamin A metabolism by agents such as ethanol and carbon tetrachloride, may be a risk factor for the development of liver fibrosis. We suggest that retinoids modulate collagen synthesis and deposition irrespective of the degree of hepatocellular necrosis induced by carbon tetrachloride.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Retinol uptake from retinol-binding protein (RBP) by liver parenchymal cells in vitro does not specifically depend on its binding to RBP.

The uptake characteristics of both the retinol and retinol-binding protein (RBP) moieties of the retinol-RBP complex by liver parenchymal cells (PC) in vitro were studied to assess whether retinol uptake is mediated by a cell-surface receptor for RBP. At 37 degrees C as well as 4 degrees C, [3H]retinol uptake from [3H]retinol-RBP showed a time-dependent increase, and was not saturable at concentrations exceeding the physiological concentration by more than a factor of 2 (3 microM). Uptake of [3H]retinol was not inhibited by a 10-fold molar excess of unlabeled retinol-RBP. Cell association of 125I-RBP at 37 and 4 degrees C was low and showed no time dependence. In addition, the association of 125I-RBP was not saturable at concentrations up to 3 microM. These data do not support the existence of a cell-surface receptor for RBP on rat liver PC. The uptake of [3H]retinol from RBP was also compared to the uptake of retinol from cellular retinol-binding protein (CRBP) and lactoglobulin. Uptake characteristics of [3H]retinol from CRBP and lactoglobulin were similar to that of [3H]retinol from RBP. Furthermore, a similar percentage of the [3H]retinol taken up by PC was metabolized into retinyl esters, irrespective of its carrier. These data suggest that the uptake of retinol and its subsequent metabolic processing do not depend on binding to RBP. The low level of cell association of 125I-binding proteins was not due to uptake, degradation, and secretion of ligand by PC. This suggests that retinol is dissociated from its binding protein before uptake by PC.

Animals↗
PubMed1993

The role of oxidative metabolism in hexachlorobenzene-induced porphyria and thyroid hormone homeostasis: a comparison with pentachlorobenzene in a 13-week feeding study.

Hexachlorobenzene (HCB) induces a broad spectrum of effects including disturbances in the heme synthesis (porphyria) and in thyroid hormone homeostasis. For most of its effects, biotransformation of the parent compound seems to be a prerequisite. The present study was designed to assess the relevance of the oxidative metabolites in HCB-induced toxicity, with special attention to the role of the reactive tetrachlorobenzoquinone (TCBQ). To this end, toxicity and biotransformation of HCB were compared with those of pentachlorobenzene (PCB), since this chemical is oxidized to the same products as HCB, i.e., pentachlorophenol (PCP) and TCBQ. Female Wistar rats received diets containing different dose levels of HCB or PCB for 13 weeks, with or without cotreatment with triacetyloleandomycin (TAO), a selective inhibitor of cytochrome P450IIIA1/2. Rats treated with HCB (high dose) had significantly elevated levels of urinary porphyrins from the 4th week on and had a significant hepatic accumulation of porphyrins at the end of the study. Both urinary porphyrin excretion and hepatic porphyrin accumulation were greatly inhibited in rats receiving cotreatment with HCB and TAO. However, the inhibition of HCB-induced porphyria by TAO cannot be explained by a diminished formation of the highly reactive TCBQ, since rats treated with a high dose of PCB, which had a several fold higher urinary excretion of PCP and TCHQ compared to a high dose of HCB, did not develop porphyria. Instead, the present study points to the involvement of a putative reactive intermediate in the primary oxidative step in HCB-induced porphyria, since based on paired observations of individual rats, the degree of porphyria was correlated to a high degree with excretion of PCP, whereas correlation of porphyria with early excretion of TCHQ was much weaker. This finding fits well with the fact that the mechanisms of oxidation of HCB to PCP and PCB to PCP are different. Both HCB and PCB were oxidized to PCP and tetrachlorohydroquinone (TCHQ), the reduced analog of TCBQ. Cytochrome P450IIIA1/2 appears to be involved in the conversion of HCB and PCB, since cotreatment of TAO resulted in a strongly diminished urinary excretion of PCP and TCHQ. Treatment with HCB as well as PCB results in disturbances of retinoid and thyroid hormone homeostasis. These effects, which have also been reported after exposure to polychlorinated biphenyls, originate from interference of hydroxylated metabolites (notably PCP) with the plasma thyroxine transport protein, transthyretine, and since this metabolite is formed from both HCB and PCB, this results in the same toxicity for both compounds.

Animals↗
PubMed1993

Interference of polychlorinated biphenyls in hepatic and brain thyroid hormone metabolism in fetal and neonatal rats.

The effects of prenatal oral administration of 0.2, 0.6, and 1.8 mg/kg body wt of 3,3',4,4'5,5'-hexachlorobiphenyl (HCB) on Day 1 of gestation and a combination of 1 mg/kg 3,3',4,4'-tetrachlorobiphenyl (TCB) from Day 2 to Day 18 with 0.6 mg HCB/kg body wt on Day 1 of gestation on thyroid hormone status and peripheral thyroid metabolism were studied in pregnant Wistar rats and their fetuses and offspring. Plasma total thyroxine and free thyroxine levels were reduced by HCB in a dose-dependent fashion in pregnant rats (Days 12 and 20 of gestation) and neonates (Day 21 postpartum), while only a combined dose of HCB and TCB was effective in decreasing fetal thyroid hormone levels by 65% on Day 20 of gestation. The activity of type II thyroxine 5'-deiodinase (5'D-II), the enzyme responsible for the deiodination of thyroxine (T4) to biologically active triiodothyronine in the brain, was examined in whole brain homogenates in fetuses and neonates. Decreases in plasma thyroid hormones were accompanied by significant increases, up to 100%, in 5'D-II activity in brain homogenates from fetuses (Day 20 of gestation) and neonates (Days 7 and 21 postpartum). The glucuronidation of 125I-T4 by hepatic microsomes was increased by at least 100% relative to control levels by all treatments in fetuses (Day 20 of gestation) and increased at least 40% in neonates (Days 7 and 21 postpartum) by a dose of 0.6 and 1.8 mg HCB/kg and the combined dose. These data indicate that prenatal HCB and/or TCB administration result in increased peripheral T4 metabolism. The increase in 5'D-II activity suggests that local hypothyroidism occurs in the brains of fetal and neonatal rats exposed to HCB and/or TCB. Since these effects occur during a period in which thyroid hormones play an important role in brain maturation, they may help explain the mechanism of developmental neurotoxicity induced by polychlorinated biphenyls.

Administration, Oral↗
PubMed1993

Structure-dependent, competitive interaction of hydroxy-polychlorobiphenyls, -dibenzo-p-dioxins and -dibenzofurans with human transthyretin.

Previous results from our laboratory indicated specific and competitive interactions of hydroxylated metabolites of 3,3', 4,4'-tetrachlorobiphenyl with the plasma thyroid hormone transport protein, transthyretin (TTR), in rats in vivo and with human TTR in vitro. In the present study the structural requirements for competition with thyroxine (T4) for TTR-binding were investigated in more detail. Several hydroxylated polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) were tested in an in vitro competitive binding assay, using purified human TTR and [125I]T4 as a displaceable radioligand. All hydroxylated PCBs, but not the single PCB tested, competitively displaced [125I]T4 from TTR with differential potency. The highest competitive binding potency was observed for hydroxylated PCB congeners with the hydroxygroup substituted on meta or para positions and one or more chlorine atoms substituted adjacent to the hydroxy group on either or both aromatic rings (IC50 range 6.5-25 nM; Ka range: 0.78-3.95 x 10(8) M-1). The relative potency of all meta or para hydroxylated PCBs was higher than that of the physiological ligand, T4 (relative potency range: 3.5-13.6 compared to T4). There were no marked distinctions in TTR-T4 competitive binding potencies between the ortho- and non-ortho-chlorine substituted hydroxy-PCB congeners tested. Marked differences in TTR-T4 binding competition potency were observed between the limited number of hydroxylated PCDDs and PCDFs tested. The hydroxy-PCDD/Fs, with chlorine substitution adjacent to the hydroxy-group, i.e. 7-OH-2,3,8-trichlorodibenzo-p-dioxin, 2-OH-1,3,7,8-tetrachlorodibenzo-p-dioxin and 3-OH-2,6,7,8-tetrachlorodibenzofuran, all showed a similar or higher relative binding potency, i.e. 1, 4.4 and 4.5 times higher, respectively, than T4. No detectable [125I]T4 displacement was observed with 2-OH-7,8-dichlorodibenzofuran, 8-OH-2,3,4-trichlorodibenzofuran and 8-OH-2,3-dichlorodibenzo-p-dioxin, which did not contain chlorine substitution adjacent to the OH-group. These results indicate a profound similarity in structural requirements for TTR binding between hydroxy-PCB, -PCDD and -PCDF metabolites and the physiological ligand, T4, e.g. halogen substitution adjacent to the para hydroxy group, while planarity does not seem to influence the ligand-binding potency.

Benzofurans↗
PubMed1993

Effects on thyroid hormone metabolism and depletion of lung vitamin A in rats by airborne particulate matter.

Thyroxine (T4) and vitamin A are important regulators of normal epithelial differentiation and proliferation and might act in the promotion phase of carcinogenesis. Thyroid hormone and vitamin A metabolism are linked by a common plasma carrier protein, transthyretin (TTR). Polychlorinated biphenyls (PCBs) and related organochlorine compounds deplete vitamin A and thyroxine by interaction with TTR and alteration of their metabolism in hepatic and other organs. In the present report an outdoor airborne particulate matter (APM) extract was tested for both interaction with thyroid hormone and vitamin A metabolism, in order to address the question of whether APM has the potency to deplete vitamin A and thyroid hormones. Furthermore, studies were performed to characterize compounds present in APM that interact with TTR. A third aim was to compare the interaction of APM extracts with TTR and thyroxine-binding globulin (TBG), the major carrier protein for thyroxine in humans. Results showed that a single treatment of rats with an outdoor APM extract depleted plasma thyroxine and triiodothyronine levels and increased plasma retinol levels gradually over the time period studied, while liver retinol, lung retinol, and retinyl palmitate levels were depleted by 30-50%. As outdoor APM was able to inhibit T4-TTR binding in vitro, this suggests that the reduction in thyroxine levels in vivo is caused by the same phenomenon. Experiments showed that the neutral fraction of the APM extract accounted for most of the inhibitory activity on T4-TTR binding. Polycyclic aromatic hydrocarbons and nitrated derivatives are not likely to be responsible for the activity of the neutral fraction, because several representatives of these compounds showed no or very little interaction with TTR. Pentachlorophenol, a compound with known inhibitory activity on T4-TTR binding, was detected in the organic acid fraction of both a cigarette smoke sample and an outdoor APM sample. Finally, it was shown that several indoor and outdoor APM extracts only interact with TTR, but not with TBG. As APM has the potency to deplete lung vitamin A in vivo and vitamin A might have a protective effect in the process of lung carcinogenesis, APM might increase the susceptibility for the development of lung cancer.

Aerosols↗