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Biomedical subjects

A Brouwer

Publications and source records attributed to A Brouwer.

At least 19 recordsLinked to original sources
PubMed1996

Binding of a 3,3', 4,4'-tetrachlorobiphenyl (CB-77) metabolite to fetal transthyretin and effects on fetal thyroid hormone levels in mice.

The present study was conducted in order to study the effect of the PCB congener 3,3', 4,4'-tetrachlorobiphenyl (CB-77) on fetal thyroxin homeostasis in the mouse, and to examine a possible underlying mechanism behind the effect. C57BL mice were treated with 14C-labelled or unlabelled CB-77 (1 or 10 mg/kg body wt.) on day 13 of gestation, and control animals were treated with corn oil. The experiment was terminated at 4 days after exposure. Maternal and fetal plasma and livers, and whole fetuses for homogenate preparation, were collected and analysed for total radioactivity, in vitro binding of 125I-thyroxin to plasma transthyretin (TTR; a thyroxin-transporting protein), and free and total thyroxin (FT4, TT4) levels. Maternal plasma, fetal plasma and homogenates were also analyzed for presence of CB-77 and metabolites. Results showed a dose-dependent uptake of radioactivity in plasma and liver, fetal plasma 14C-levels being about five-times higher in 10 mg/kg dosed animals as after 1 mg/kg. Fetal; plasma levels of total radioactivity were four- to nine-times above maternal levels and corresponded to only one compound, the metabolite 4-OH-3,3', 4',5-tetrachlorobiphenyl (4-OH-tCB). 4-OH-tCB was the major metabolite also in whole fetuses, with only small amounts of the parent compound (approximately 15% of the 4-OH-tCB) and traces (approximately 6%) of two other metabolites, 2-OH-3,3, 4,4'-tetrachlorobiphenyl and 5-OH-3,3', 4,4'-tetrachlorobiphenyl. Polyacrylamide gel electrophoresis confirmed that the 14C-radioactivity in fetal plasma was bound to TTR, and revealed that in vitro binding of 125I-T4 to fetal TTR was reduced to 50% of control values in treated animals (10 mg/kg body wt.). Fetal plasma FT4 and TT4 levels were significantly decreased (64 and 55% of control fetuses) after 10 mg/kg treatment. In conclusion, exposure of pregnant mice to CB-77 results in the accumulation of the metabolite 4-OH-tCB in fetal mouse plasma. The metabolite binds to TTR and is accompanied by a significant decrease in fetal plasma T4 levels. A causative correlation between TTR binding and effects on T4 levels is suggested.

Animals↗
PubMed1996

Alterations in rat brain thyroid hormone status following pre- and postnatal exposure to polychlorinated biphenyls (Aroclor 1254).

The effect of daily oral maternal exposure to 0, 5, or 25 mg/kg body wt of a polychlorinated biphenyl (PCB) mixture (Aroclor 1254) on Days 10 to 16 of gestation on plasma and brain thyroid hormone concentrations and peripheral thyroid hormone concentrations and peripheral thyroid hormone metabolism were examined in fetal and weanling rats. Plasma thyroid hormone levels and hepatic microsomal thyroid hormone glucuronidation were also examined in pregnant rats and the adult offspring. Plasma and brain levels of PCBs and hydroxylated PCB metabolites were analyzed in fetal, weanling, and adult offspring. Maternal exposure to Aroclor 1254 significantly decreased fetal (Gestation Day 20) and neonatal (Postnatal Day 4) plasma total thyroxine (T4) and free T4 levels in a dose-dependent manner. Effects of maternal Aroclor 1254 exposure on plasma total and free T4 concentrations were less pronounced in offspring at 21 days of age and absent 90 days after birth. Plasma concentrations of thyroid-stimulating hormone were unaltered in fetuses, neonates, weanling rats, and adult offspring following maternal treatment with Aroclor 1254. the concentration of T4 was severely depressed in the forebrain and cerebellum of fetal rats on Day 20 of gestation following maternal Aroclor 1254 exposure. Brain triiodothyronine (T3) concentrations in the Aroclor-exposed fetuses were significantly decreased relative to control values only in the low-dose group. On Day 21 postpartum T4 concentrations were significantly decreased in the forebrains of female weanling rats from the 25 mg Aroclor 1254/kg dose group, and no reductions were observed in forebrain T3 concentrations in male or female neonates. The deiodination of T4 to T3 was significantly increased in fetal forebrain homogenates by both PCB treatments. In female weanling brain homogenates the deiodination of T4 to T3 was significantly decreased in the low-dose group and unaltered in the high-dose group. No alterations in brain thyroid hormone metabolism were observed in forebrain homogenates from adult offspring exposed pre- and postnatally to Aroclor 1254. Hepatic microsomal T4 glucuronidation was significantly decreased in fetal microsomes following perinatal PCB exposure and significantly increased in weanling hepatic microsomes in a dose-dependent manner. An accumulation of mainly one PCB metabolite, 2,3,3',4',5-pentachloro-4-biphenylol was observed in fetal plasma and forebrain on Gestation Day 20 and in neonatal and weanling rat plasma on Postnatal Days 4, 21, and 90. The plasma level of 2,3,3',4',5-pentachloro-4-biphenylol was higher than that of the persistent PCB congener 2,2',4,4',5,5'-hexachlorobiphenyl in the control and PCB-exposed offspring up to Postnatal Day 21, and even after 90 days, the 2,3,3',4',5-pentachloro-4-biphenylol was present in amounts approximately equal to those of CB 153. Although PCB levels were relatively high in the weanling rat forebrain, no hydroxylated PCB metabolites were detected. On Day 90 postpartum, plasma levels of PCBs and 2,3,3',4',5-pentachloro-4-biphenylol were still elevated in the offspring of PCB-treated dams relative to controls. These results suggest that the accumulation of hydroxylated PCB metabolites in fetal plasma can reduce fetal plasma T4 levels and accordingly fetal brain T4 levels. However, in late gestational fetuses, the induction of brain type II thyroxine 5'-deiodinase activity compensates for decreases in brain T4 levels, so that brain T3 levels are maintained.

Animals↗
PubMed1996

Comparison of Ah receptor-mediated luciferase and ethoxyresorufin-O-deethylase induction in H4IIE cells: implications for their use as bioanalytical tools for the detection of polyhalogenated aromatic hydrocarbons.

A recombinant H4IIE rat hepatoma cell line (H4L1.1c4, H4IIE-luc), containing a luciferase reporter gene under control of dioxin-responsive enhancers, was examined for responsiveness to several polyhalogenated aromatic hydrocarbons (PHAHs). The recombinant cell system was compared with the widely used wild-type cell line (H4IIE-wt), which expresses Ah receptor-mediated cytochrome P450 1A induction. We also report an improved and down-scaled method for the H4IIE-wt bioassay which allows for the rapid screening of environmental samples for Ah-active PhAHs. This method employs 96-well plates, a plate-reading spectrofluorometer, and a fluorescence-based protein assay that enables the simultaneous measurement of resorufin and protein. Both cell lines demonstrated a dose-dependent increase in Ah receptor-mediated response upon exposure to a number of known Ah receptor agonists, including Halowax 1014. H4IIE-luc cells were 3-fold more sensitive than H4IIE-wt cells to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The detection limit and ED50 for EROD induction by TCDD were 0.6 and 4.9 fmol/well (2,4 and 20 pM), respectively; for luciferase induction they were 0.2 and 1.4 fmol/well (0.8 and 5.6 pM). The detection limit for EROD induction in H4IIE-wt cells was a 50-fold improvement over that reported previously (Tillitt et al., Environ. Sci. Technol. 25, 87-92, 1991) and comparable to that of a chicken embryo primary hepatocyte bioassay (Kennedy et al., Anal. Biochem. 211, 102-112, 1993). The tested PHAHs exhibited a similar structure-activity relationship in H4IIE-luc as in H4IIE-wt cells. Binary mixtures of TCDD, PCB-126, and PCB-77 showed no departure from additivity in their combined responses when tested in H4IIE-wt cells. PCB-153 at the highest tested dose of 14 nmol/well (56 microM) significantly reduced the potency of TCDD and PCB-126 without affecting their efficacy in both H4IIE-wt and H4IIE-luc cells. These findings support the use of H4IIE-luc cells as an alternative bioanalytical tool to the wild-type cells for the detection of Ah agonists in environmental samples.

Animals↗
PubMed1996

Prevalence of the eaeA gene in verotoxigenic Escherichia coli strains from dairy cattle in Southwest Ontario.

This study determined the prevalence of the eaeA gene and its relationship to serotype and type of verotoxin produced in a collection of 432 verotoxigenic Escherichia coli (VTEC) obtained from the faeces of healthy cows and calves in a systematic random survey involving 80 dairy farms in Southwest Ontario. A PCR amplification procedure involving primer pairs which target the conserved central region of the O157:H7 eaeA gene showed that 151 (35.2%) strains were positive for the eaeA gene. All isolates (9-21 for each O group) of O groups 5, 26, 69, 84, 103, 111, 145 and 157 were positive, whereas all isolates (7-34 for each O group) of O groups 113, 132, and 153 and serotype O156:NM (38 isolates) were negative for eaeA. Seventy-three percent of 130 isolates of eaeA-positive serotypes produced VT1 only compared with 20% of 253 isolates of eaeA-negative serotypes. We conclude that there is a strong association between certain O groups and the eaeA gene, that serotypes of eaeA-positive and eaeA-negative VTEC implicated in human and cattle disease are present at high frequency in the faeces of healthy cattle, that VT1 is more frequently associated with eaeA-positive than with eaeA-negative serogroups, and that the eaeA gene is more frequently found in VTEC from calves compared with VTEC from adult cattle.

Animals↗
PubMed1995

Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants.

A scientific evaluation was made of functional aspects of developmental toxicity of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in experimental animals and in human infants. Persistent neurobehavioral, reproductive and endocrine alterations were observed in experimental animals, following in utero and lactational exposure to PCBs, PCDDs and PCDFs. The lowest observable adverse effect levels (LOAELs) for developmental neurobehavioral and reproduction endpoints, based on body burden of TCDD-toxic equivalents (TEQs) in animals, are within the range of current background human body burdens. Relatively subtle adverse effects on neurobehavioral development and thyroid hormone alterations have also been observed in infants and children exposed to background levels. Exclusive use of the toxic equivalency factor (TEF) approach may underestimate the risk of neurodevelopmental effects, because both Ah receptor dependent and independent mechanisms may be involved in these effects. The use of marker congeners and/or bioassays based on Ah receptor mediated mechanisms are rapid, low cost pre-screening alternatives for expensive and time consuming gas chromatographic-mass spectrometric analysis.

Animals↗
PubMed1995

Subchronic effects of 2,3,7,8-TCDD or PCBs on thyroid hormone metabolism: use in risk assessment.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), or 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156) on thyroid hormone metabolism were studied in 13-week feeding studies in female Sprague-Dawley rats. The diets were supplemented with the compounds tested at concentrations ranging from 0.2 to 20 micrograms/kg diet for TCDD, 7 to 180 micrograms/kg diet for PCB 126, or 1.2 to 12 mg/kg diet for PCB 156, respectively. Significant correlations were found for all three compounds between reductions in plasma total thyroxine (TT4) levels and inductions of the microsomal phase II enzyme UDP-glucuronosyltransferase by using T4 as a substrate (T4UGT). Furthermore, the coinduction of certain phase I and II isozymes, i.c., cytochrome P450 1A1 (CYP1A1) and UGT1A1, by these compounds, clearly suggests the involvement of an Ah receptor-mediated mechanism in the disturbance of thyroid hormone metabolism by these polyhalogenated aromatic compounds. These results provide a mechanistic base for the use of certain effects on thyroid hormone metabolism by polyhalogenated aromatic compounds in risk assessment. By using these effects, potencies of PCB 126 and PCB 156 relative to TCDD ranged from 0.008 to 0.1 for PCB 126, and from 0.00007 to 0.004 for PCB 156, respectively. These values correspond very well with relative potencies of PCB 126 and PCB 156 by using some other well-known Ah receptor-mediated toxic and biochemical parameters.

Animals↗
PubMed1995

Metabolism and biochemical effects of 3,3',4,4'-tetrachlorobiphenyl in pregnant and fetal rats.

The metabolism and distribution of a single oral dose of 25 mumol 14C-labelled 3,3',4,4'-tetrachlorobiphenyl (14C-TCB) were investigated in pregnant female Wistar rats and their fetuses. TCB was administered on day 13 of gestation and the elimination was followed for 7 days. Non-pregnant rats were treated similarly for comparison. Fecal elimination of 14C-TCB derived radioactivity was significantly lower in pregnant rats than in non-pregnant rats. The major metabolite found in adult liver and plasma, placental tissue, whole fetuses and fetal plasma was 3,3',4',5-tetrachloro-4-biphenylol (4-OH-TCB). Tissue levels (liver, abdominal fat, skin, skeletal muscle, kidney and plasma) of 14C-TCB-derived radioactivity declined by 65-85% over a 7-day period following administration in the adult animals. However, 14C-TCB-derived radioactivity accumulated more than 100-fold in the fetuses over the same time period, and GC/MS analysis revealed that the fetal accumulation in radioactivity was due primarily to 4-OH-TCB, and not the parent compound. On day 20 of gestation, concentrations of 4-OH-TCB were 14 times greater in fetal plasma than maternal plasma. Treatment with 14C-TCB significantly reduced plasma thyroxine levels by at least 28% up to 7 days after administration in non-pregnant animals and up to 4 days after administration in pregnant rats (31% decrease). By 7 days after administration plasma thyroxine levels had returned to control levels in the TCB-treated pregnant rats. However, fetal plasma thyroxine levels were significantly decreased by 35% in fetuses from 14C-TCB-treated dams 7 days after TCB administration. Hepatic microsomal ethoxyresorufin-O-deethylase (EROD) activity was significantly induced in TCB-treated dams relative to controls at 4 and 7 days after administration, while no EROD activity was detected in hepatic microsomes from control or TCB treated fetal rats at day 20 of gestation. These data suggest that hydroxylated metabolites of polychlorinated biphenyls may play a role in the development toxicity of these compounds.

Animals↗
PubMed1995

Fetal, neonatal, and long-term alterations in hepatic retinoid levels following maternal polychlorinated biphenyl exposure in rats.

This study was undertaken to investigate the effects of perinatal polychlorinated biphenyl (PCB; Aroclor 1254) exposure on hepatic and plasma retinoid levels in fetal rats, their dams, and neonatal and adult offspring. Pregnant Wistar rats were treated with 0, 5, or 25 mg Aroclor 1254/kg body wt from Days 10 to 16 of gestation. Hepatic retinoid (retinol, retinyl palmitate, and retinyl stearate) levels were determined in fetuses and dams from Day 20 of gestation, in male and female neonates 21 days postpartum, and in young adult offspring 90 days after birth. Retinol levels were determined in fetal and maternal plasma (Gestation Day 20) and plasma from the offspring 21 and 90 days after birth. Maternal and fetal plasma retinol levels were decreased by 35 and 38% on Day 20 of gestation following exposure to the highest dose of Aroclor 1254. Male, but not female, neonatal plasma retinol levels were significantly decreased (23%) in the high-dose group. No effects of PCB treatment were seen on plasma retinol levels in the offspring 90 days after birth. Only slight reductions in fetal and maternal hepatic retinol and retinyl palmitate concentrations were observed after prenatal PCB exposure. Male neonatal hepatic retinyl palmitate levels were reduced by 25 and 50% in the 5 and 25-mg Aroclor 1254/kg dose groups, respectively, while female neonatal hepatic retinyl palmitate levels were significantly reduced only in the high-dose group. Ninety days after birth, male hepatic retinyl palmitate levels were only slightly reduced in the highest dose group; however, hepatic retinol concentrations were significantly reduced by 50% in both PCB treatment groups. Female adult offspring exhibited significant reductions in hepatic retinyl palmitate levels (25%) in both PCB treatment groups, while hepatic retinol levels exhibited an unusual increase of more than 100% of controls in the low-dose group, while levels in the high-dose group were similar to controls. This study demonstrates that even a relatively low maternal dose of Aroclor 1254 results in long-term alterations in retinoid status of the offspring in the rat.

Animals↗
PubMed1995

Subchronic dose-response study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats.

Toxic and biochemical potencies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied in a 13-week feeding study in female Sprague-Dawley rats. The diets were supplemented with 0, 0.2, 0.4, 0.7, 5, or 20 micrograms TCDD/kg diet. The estimated daily intakes were calculated to be 0, 14, 26, 47, 320, or 1024 ng TCDD/kg body wt/day. At the end of the study, TCDD concentrations were measured in liver and adipose tissue. The lowest estimated daily intake that caused an increase in liver weight was 320 ng TCDD/kg/day, while an intake of 47 ng TCDD/kg/day resulted in a decrease in plasma thyroid hormone concentrations and a decrease in body weight gain. Decreases in relative thymus weights, loss of hepatic retinoids, and induction of CYP1A1 and CYP1A2 activities were already found at 14 ng/kg/day, the lowest dose used. Therefore, 95% confidence limits for the no-effect levels (CNELs) were calculated from the corresponding dose-response relationships by using sigmoidal curve fittings (Hill, Weibull, and a Logistic model) and a probability level of p < 0.05. For increases in CYP1A1 and CYP1A2 activities, the right critical values for the CNELs ranged from 0.7 to 4 ng TCDD/kg/day (Hill and Weibull). Based on hepatic TCDD residue levels, these right critical values for the CNELs ranged from 0.06 to 0.4 ng TCDD/g liver (wet weight) (Hill and Weibull). The CNELs in this study agree very well with the no-observed-adverse-effects levels as reported before in chronic, carcinogenicity, and reproductive studies with rats and TCDD, i.e., 1 ng/kg/day.

Animals↗
PubMed1995

Interactive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and retinoids on proliferation and differentiation in cultured human keratinocytes: quantification of cross-linked envelope formation.

Dioxins are potent inducers of chloracne in humans. This skin aberration can be interpreted as an altered differentiation pattern of acinar sebaceous base cells and a change in the rate of terminal differentiation of the keratinocytes. We measured this rate induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in primary cultures of human keratinocytes. As parameters for differentiation, we quantified the 35S-methionine incorporation into cross-linked envelopes (revealing the total CLE biomass), as well as the number of microscopically visible CLEs. It was shown that TCDD is a very potent inducer of both CLE biomass and number with a half-maximal effect concentration (EC50) of 1.4 nM. CLE biomass was maximally increased 10-fold and the number of cells in culture producing a CLE was increased from 15% in control cultures to maximally 75% of the cells in TCDD-treated cultures. Both effects were Ca(2+)-dependent and increased with elevated cell density, being optimal in post-confluent cultures. Retinoic acid dose-dependently decreased the effect of 10(-8) M TCDD, 10(-6) M having a nearly complete antagonistic action. This interaction of retinoic acid with TCDD-induced differentiation was non-competitive. Retinol was equally potent as an antagonist of the TCDD-induced elevation of CLE formation as compared with retinoic acid. Retinyl palmitate and etretinate were not very effective as TCDD antagonists. Supplementation of hydrocortisone suppressed the TCDD-induced keratinocyte differentiation. It was concluded that CLE biomass quantification provides a reliable and sensitive parameter for keratinocyte differentiation. In this in vitro system it is shown that TCDD strongly induces a switch from proliferation to terminal differentiation and that this effect can be antagonized effectively by retinoic acid and retinol.

Adult↗
PubMed1995

Short term fasting does not aggravate immunosuppression in harbour seals (Phoca vitulina) with high body burdens of organochlorines.

Two groups of 11 harbour seals (Phoca vitulina) with different body burdens of organochlorines were subjected to an experimental 15-day fasting period, during which they lost an average 16.5% of their body weights. Blood levels of the most persistent organochlorines showed an approximate twofold increase, while levels of aryl hydrocarbon receptor-binding organochlorines remained largely unaffected. Few differences in immunological parameters were observed between the two dietary groups. Numbers of circulating lymphocytes dropped to about 65% of the initial values and NK cell activity showed a slight increase in both groups. Mitogen- and antigen-induced lymphoproliferative responses of the Baltic group of seals remained within normal ranges. These results suggest that relatively short-term fasting periods do not present an additional immunotoxicological risk to seals with high body burdens of organochlorines.

Adipose Tissue↗
PubMed1995

Expression patterns of the paired-related homeobox genes MHox/Prx1 and S8/Prx2 suggest roles in development of the heart and the forebrain.

Prx1 and Prx2 (previously called MHox and S8, respectively) are the members of a small subfamily of vertebrate homeobox genes expressed during embryogenesis from gastrulation onwards. We directly compared the expression domains of the Prx genes in detail in mouse and in addition some aspects of these patterns in chicken. In addition to the superficially similar expression patterns of Prx1 and Prx2 in cranial mesenchyme, limb buds, axial mesoderm, and branchial arches and their derivatives, we detect major differences at many sites particularly in heart and brain. Our analysis indicated in several cases a correlation with regions developing into connective tissues. From at least day 8.5, Prx-1 expression was observed in the heart, initially in the endocardial cushions and later in the developing semilunar and atrioventricular valves. Prx2 develops early on a diffuse myocardial expression pattern and is later higher expressed in the ventricular septum and in particular in the ductus arteriosus. Prx2 is never expressed in the brain, whereas Prx1 is expressed, from at least day 9.5 onwards, in a unique distinct domain in the ventral part of the hypothalamus, as well as in a broader region of the telencephalon.

Amino Acid Sequence↗
PubMed1995

Production of eicosanoids and cytokines by Kupffer cells from young and old rats stimulated by endotoxin.

1. The clinicopathological features of endotoxaemia have been ascribed to cytotoxic mediators such as tumour necrosis factor, interleukins and eicosanoids. Macrophages, particularly Kupffer cells, are an important source of these mediators. Mortality from endotoxaemia is highly age related. 2. These studies focus on the role of hepatic Kupffer cells in the increased sensitivity of old rats to bacterial endotoxins. Possible age-related changes in the production of eicosanoids and induction of gene expression and secretion of interleukin 1, tumour necrosis factor and interleukin 6 were investigated in Kupffer cells derived from both young and old animals. 3. Basal production of biological response modifiers was low in cells of both young and old rats. Lipopolysaccharide stimulated production of the same types of monokines as described for other types of macrophages, although the pattern was specific for Kupffer cells. 4. Eicosanoids, predominantly prostaglandin D2 and prostaglandin F2 alpha, were produced mainly during the first hour after exposure to lipopolysaccharide. Endotoxin stimulated synthesis of mRNAs of interleukin 1, interleukin 6 and tumour necrosis factor alpha resulting in increased secretion of these cytokines into the medium. 5. Kupffer cells from both young and aged animals appear to be exquisitely sensitive to endotoxin in respect of expression of mRNA for both interleukin 1 alpha and interleukin 1 beta and less sensitive with respect to interleukin 6 and tumour necrosis factor alpha gene expression. At relatively high lipopolysaccharide concentrations interleukin 6 was secreted in particularly large amounts. 6. The effects of ageing on any of these responses of Kupffer cells were minimal.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1995

Beta-carotene (provitamin A) decreases the severity of CCl4-induced hepatic inflammation and fibrosis in rats.

Earlier data from experiments in rats have shown that administration of retinyl esters (vitamin A) strongly influences the effects of CCl4 on the liver. The accumulation of collagen was inhibited, but an increase in CCl4-toxicity with high mortality was observed. The present study was conducted to examine the effects of beta-carotene (provitamin A) on CCl4-related general and hepatic toxicity in rats. Oral administration of beta-carotene during CCl4-treatment resulted, biochemically, in a significantly lower increase in the hydroxyproline liver content and, histopathologically, in less severe liver fibrosis as compared with the liver of rats not treated with beta-carotene. The study also showed that beta-carotene administration could prevent the long-term loss of retinoids from the CCl4-injured liver. No significant toxic effects of beta-carotene, as previously found with retinyl esters (vitamin A), were observed. This experimental study suggests that beta-carotene has the therapeutic potential to decrease the severity of liver fibrosis without marked toxicity.

Animals↗
PubMed1995

beta-Naphthoflavone- and self-induced metabolism of 3,3',4,4'-tetrachlorobiphenyl in hepatic microsomes of the male, pregnant female and foetal rat.

1. The in vitro metabolism of 3,3',4,4'-tetrachloro-[14C]-biphenyl ([14C]-TCB) by hepatic microsomes from the Wistar rat was investigated with liver microsomes from the male, pregnant female and foetus. 2. Three hydroxylated metabolites (4-OH-3,3',4,5'-tetrachlorobiphenyl, 5-OH-3,3',4,4'-tetrachlorobiphenyl, and 6-OH-3,3',4,4'-tetrachlorobiphenyl) were identified by hplc and gc-ms after incubations of liver microsomes from the beta-naphthoflavone-pretreated male rat and TCB-treated pregnant rat. No metabolites of [14C]-TCB were found after incubation with foetal liver microsomes from dams pretreated with [14C]-TCB. The results indicate that the in vivo accumulation of 4-OH-tetraCB in the foetal compartment is probably due to transplacental transport rather than the formation of this metabolite in the foetus. 3. Pretreatment of the male rat with beta-naphthoflavone substantially induced the formation of hydroxylated metabolites, but pretreatment with phenobarbital and dexamethasone was without effect. Based on in vitro incubations of liver microsomes from the beta-naphthoflavone pretreated male rat, an apparent Km and Vmax of 4.5 microM and 240 pmol/mg protein/min respectively was determined for the metabolism of [14C]-TCB. The formation of phenolic metabolites of [14C]-TCB was most likely dependent on P4501A induction.

Animals↗
PubMed1995

The influence of dietary restriction on the metabolism of theophylline and antipyrine in the ageing female BN/BiRij rat.

The influence of ageing and dietary restriction (DR) on the in vivo activities of different P450 enzymes was studied longitudinally in female BN/BiRij rats. For this purpose, antipyrine (AP) and theophylline (TH) were used as substrates. The metabolic clearances of AP (CIm AP) and TH (CIm TH) were used as indicators for P450 enzyme activities in vivo. Therefore, we also included the assessment of the clearances of formation of three AP metabolites, i.e., 3-hydroxymethylantipyrine (CI-->HMA), 4-hydroxyantipyrine (CI-->OHA) and norantipyrine (CI-->NORA). Ninety, 50 and 10% survival times were prolonged significantly in DR rats. In control animals, the contribution to the metabolism of AP in the formation of HMA, OHA and NORA, expressed as percentage of the dose, decreased with ageing, indicating that other pathways compensate for this decrease. Only a significant decrease in the metabolism to OHA was observed in DR animals. CI-->HMA, CI-->OHA and CI-->NORA showed an age-related decrease in the control rats, whereas in the DR rats an age-related decrease was observed for CI-->HMA and CI-->OHA. The results of the present study suggest that the decrease in the activities of the P450 enzymes involved in the formation of HMA, OHA and NORA have a later onset in the DR rats. In conclusion, DR not only has a strong positive influence on the health and life span of the rats, but also results in a delayed onset of the decrease in activity of certain P450 enzymes.

Aging↗
PubMed1994

Different competition of thyroxine binding to transthyretin and thyroxine-binding globulin by hydroxy-PCBs, PCDDs and PCDFs.

In an earlier study several hydroxylated polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) competitively displaced [125I]thyroxine (T4) from transthyretin with different potencies. Transthyretin is the major T4 transport protein in plasma of rodents. In man, however, thyroxine-binding globulin transports most of the T4 in blood. In this study, hydroxylated PCBs, PCDDs and PCDFs were tested in an in vitro competitive binding assay, using purified human thyroxine-binding globulin and [125I]T4 as the displaceable radioligand. None of the tested hydroxylated PCBs, PCDDs and PCDFs inhibited [125I]T4 binding to thyroxine-binding globulin. In addition, some T4 derived compounds, e.g., tyrosine, mono-iodotyrosine, di-iodotyrosine and tri-iodophenol were tested on both transthyretin and thyroxine-binding globulin to investigate possible differences in structural characteristics determining T4 binding to thyroxine-binding globulin and transthyretin. The T4 derived compounds also did not inhibit [125I]T4 binding to thyroxine-binding globulin as tested in the in vitro assay. However, tri-iodophenol and to a lesser extent di-iodotyrosine inhibited [125I]T4-transthyretin binding. These results indicate a marked difference in T4 binding to thyroxine-binding globulin or transthyretin. The hydroxylated PCBs, PCDDs and PCDFs can inhibit T4 binding to transthyretin, but not to thyroxine-binding globulin, and thus may cause different effects in rodents and man.

Benzofurans↗