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I Brandt

Publications and source records attributed to I Brandt.

At least 55 records · Page 3Linked to original sources
PubMed1990

Effect of o,p'-DDD on the in vivo incorporation of 3H-thymidine into DNA: evidence for induced cell proliferation in the mouse lung.

The effects of o,p'-DDD on the DNA synthesis in the C57Bl mouse lung and liver were studied. As determined by 3H-thymidine incorporation into DNA, a selective increase in the lung DNA synthesis (+59%) was observed 2 days after a single intraperitoneal injection of 100 mg/kg o,p'-DDD. Microautoradiography showed that the incorporated 3H-thymidine was confined to a restricted number of heavily labelled cells, presumably proliferating type II cells. At the most, a 9 times higher rate of cell proliferation was observed in the lung 4 days after an intraperitoneal injection of 500 mg/kg o,p'-DDD. Using mouse lung or liver S-9 as activating system, no mutagenic activity of o,p'-DDD was detected in the Ames test. The induced cell proliferation may indicate a tissue-selective promoter activity of o,p'-DDD in the mouse lung.

Animals↗
PubMed1990

[Growth in head circumference: parent-child correlation and secular trend].

Head circumference is an important growth parameter; it is closely related to brain development in normal infants. Therefore regular meticulous measurements of head circumference can give diagnostic hints of abnormal brain growth, i. e., reduced growth as in severe malnutrition or accelerated as in hydrocephalus, for example. The results presented here are based on the Bonn Longitudinal Study on growth and development; 150 infants (65 preterm and 85 full-term) were measured regularly from birth. Head circumference of the parents was also measured. For the full term infants the highest correlation was found between mother and daughter (r = 0.75), in the preterm infants the highest correlation was seen between mother and son (r = 0.65). In the Bonn Longitudinal Study and in a recent additional Bonn Study no positive secular trend of head circumference was observed which agrees with results of others. Interestingly enough, growth of head circumference behaves completely differently from that of height in the Bonn Study, where a positive secular trend was observed.

Cephalometry↗
PubMed1989

Epithelial binding of 1,2-dichloroethane in mice.

The metabolism and binding of 14C-labelled 1,2-dichloroethane (DCE) in female C57BL-mice were studied. As shown by whole-body autoradiography with heated and organic solvent-extracted tissue sections of i.v. injected mice, a selective localization of non-volatile and bound DCE-metabolites occurred in the nasal olfactory mucosa and the tracheo-bronchial epithelium. Low levels of metabolites were also present in the epithelia of the upper alimentary tract, vagina and eyelid, and in the liver and kidney. A decreased mucosal and epithelial binding was observed after pretreatment with metyrapone, indicating that the binding might be due to an oxidative metabolism of DCE. The quantitated levels of in vivo binding were considerably lower in mice injected i.p. with DCE, as compared to mice given equimolar doses of 14C-labelled 1,2-dibromoethane. In vitro experiments with 1000 g supernatants from various tissues showed that the nasal mucosa has a marked ability to activate DCE into products that become irreversibly bound to the tissue. It is proposed that the nasal olfactory mucosa is a target tissue for toxicity of DCE.

Animals↗
PubMed1989

Dichlorovinyl cysteine (DCVC) in the mouse kidney: tissue-binding and toxicity after glutathione depletion and probenecid treatment.

The kidney binding of dichloro[14C]vinyl cysteine (14C-DCVC, 8 mg/kg body wt) and the kidney histopathology of DCVC (5 mg/kg body wt) were examined and compared in female C57BL mice subjected to various treatments. To evaluate the roles of organic anion transport and glutathione (GSH) status, mice were pretreated with probenecid (inhibitor of organic anion transport), L-buthionine-S,R-sulfoximine (BSO; inhibitor of GSH synthesis) or with diethyl maleate (DEM; GSH-depleting agent). In addition, the sites of 14C-DCVC binding in BSO-treated and control mice were monitored by microautoradiography. Probenecid was found to inhibit both kidney binding and toxicity of DCVC. In BSO-treated mice, DCVC binding remained roughly unchanged, whereas nephrotoxicity was severely increased and topographically extended to the subcapsular region. Microautoradiography showed that the site of DCVC binding in the straight portion of the proximal tubule was not changed by BSO. In DEM-treated mice, a clearly decreased DCVC binding was observed, while the effect on nephrotoxicity was minute. The effects of probenecid on DCVC binding and toxicity support a role for carrier-mediated transport of DCVC equivalents into the target cells. The BSO result suggests a protective function of GSH towards the nephrotoxicity of DCVC. Moreover, they support our previous contention that a primary lesion occurs at the site of DCVC binding, followed by a secondary, dose-dependent lesion localized outside the DCVC-binding region. In the case of DEM it is proposed that a DEM-GSH conjugate might compete for the uptake and/or activation of DCVC in the target cells.

Animals↗
PubMed1989

In vitro macromolecular binding of 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethane (o,p'-DDD) in the mouse lung and liver.

The activation and covalent binding of 14C-labelled 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethane (o,p'-DDD) in mouse lung and liver S-9 preparations were examined in vitro. These results showed an oxidative cytochrome P-450 mediated transformation of o,p'-DDD to metabolite(s) that bind covalently to proteins, phospholipids and to added naked DNA in both lung and liver. The apparent Km-values for the covalent binding of o,p'-DDD to protein were 0.25 microM and 3.30 microM in lung and liver, respectively. Addition of glutathione to the incubation medium decreased the binding of o,p'-DDD more efficiently in the liver than in the lung. Thus, the selective lung binding of o,p'-DDD previously observed in vivo seems to result from an in situ activation. The tissue selectivity in vivo is suggested to be due to the low apparent Km in the lung favouring bioactivation at low, ecotoxicologically relevant doses, as well as to a less pronounced protection by glutathione in the lung.

Animals↗
PubMed1989

1,2-Dibromoethane and chloroform in the rainbow trout (Salmo gairdneri): studies on the distribution of nonvolatile and irreversibly bound metabolites.

The disposition of metabolites from 14C-labeled 1,2-dibromoethane (DBE) and chloroform (CF) in juvenile rainbow trout was studied by autoradiography and quantitation of tissue radioactivity. Whole-body autoradiography of heated tissue sections showed a considerable level of nonvolatile metabolites of DBE and CF in the liver and certain areas of the body kidney. A lower level of metabolites appeared in the gills, intestinal mucosa, and olfactory rosettes in trouts exposed to DBE- or CF-containing water. Unlike previous studies in rodents, no specific uptake or binding of DBE or CF occurred in the surface epithelia of the upper alimentary tract. Microautoradiography and exhaustive tissue extraction confirmed a high irreversible binding of DBE metabolites in the liver and in a proximal tubular segment of the body kidney in fish exposed to DBE-containing water. A high level of radioactivity in the bile indicated fecal excretion of metabolites from both compounds. The results suggest that there is marked metabolism of DBE and CF in the liver and kidney, whereas the metabolism in the surface epithelia is low. The liver and kidney are proposed to be target organs of toxicity in fish.

Animals↗
PubMed1989

Tissue localization of the carcinogenic glutamic acid pyrolysis product Glu-P-1 in control and beta-naphthoflavone-treated mice and rats.

Autoradiograms obtained after i.v. injection of the 14C-labelled carcinogenic glutamic acid pyrolysis product Glu-P-1 to mice and rats showed a pronounced uptake of radioactivity in the liver, kidney, thyroid and nasal mucosa. High concentrations of radioactivity were present in the bile and intestinal contents at short post-injection times. In the male rat, the Zymbal's gland and the preputial gland were identified as sites of high and specific binding at all post-injection times examined. The liver and nasal mucosa were identified as sites of retention of non-extractable radioactivity. In the pigmented mouse, Glu-P-1 and/or its metabolites were accumulated in melanin. Glu-P-1 is known to be activated by cytochrome P-448. Pretreatment with beta-naphthoflavone (a cytochrome P-448 inducer) did not change the tissue localization of radioactivity in either species except for the liver where the overall labelling was decreased. Neither did pretreatment of mice with the glutathione-depleting agent phorone change the distribution pattern significantly. However, combined pretreatments of mice with either phorone or beta-naphthoflavone and the cytochrome P-448 inhibitor 9-hydroxyellipticine resulted in an increased overall retention of radioactivity in the body.

Animals↗
PubMed1989

Covalent binding of four DDD isomers in the mouse lung: lack of structure specificity.

Previous studies have shown that o,p'-DDD is activated and covalently bound in the mouse lung. In order to examine the structure dependency of the selective lung binding, the 14C-labelled DDD isomers p,p'-DDD, m,p'-DDD and o,m'-DDD were injected intravenously into female C57B1 mice and covalent binding was measured. Autoradiography of solvent-extracted tape-sections showed that all isomers were selectively and covalently bound in the lung alveolar region. As determined by exhaustive extraction of homogenized tissue, maximal binding was observed 4 hr after injection, although the lung/liver concentration ratio increased for 12 days. Covalent protein binding was also observed in vitro, implying that the activation of DDD to a reactive metabolite takes place in the target organ. Since the aryl-chlorine substitution pattern did not change the selective lung binding, bioactivation of DDD may take place at the ethane side-chain.

Animals↗
PubMed1989

Metabolic activation of carbon tetrachloride by the cervico-vaginal epithelium in rodents.

The metabolism and binding of 14C-labelled carbon tetrachloride (CCl4) in the genital tract of female adult or juvenile NMRI-mice and Sprague-Dawley rats (mainly in the pro-oestrous/oestrous stage) and an adult New Zealand rabbit were studied. A marked irreversible binding of radioactivity in the squamous cervico-vaginal epithelium of mice given intravenous injections of 14C-CCl4 was revealed by autoradiography of solvent-extracted tissue. The localization of binding in the mouse genital tract incubated with 14C-CCl4 under air was similar to that observed in vivo. Bound radioactivity was also present in the cylindrical epithelium of the rabbit vagina incubated with 14C-CCl4 in vitro. For a comparison, no preferential binding of radiolabelled diethylstilbestrol or ethinylestradiol was observed in the mouse cervico-vaginal epithelium. The level of irreversible binding to PMSG-primed (pregnant mare's serum gonadotrophin) vaginal epithelial 100 x g supernatants of mice and rats incubated with 14C-CCl4 under air was low. Addition of the reducing agent dithionite to the incubations increased the binding in the vaginal epithelium 20-fold. In juvenile mice and rats injected with 14C-CCl4, the levels of metabolites in the epithelium were low, whereas PMSG-primed juvenile rats contained a higher level of metabolites. The results show that the cervico-vaginal epithelium can metabolically activate CCl4 to reactive metabolites and suggest that the metabolism is under endocrine control.

Animals↗
PubMed1988

S-(1,2-dichloro-[14C]vinyl)-L-cysteine (DCVC) in the mouse kidney: correlation between tissue-binding and toxicity.

Uniformly 14C-labeled DCVC and unlabeled DCVC were synthesized and used for autoradiographical and histopathological studies. Four hours after administration of [14C]DCVC (25 mg/kg body wt), a strong binding of radioactivity was observed in the straight proximal tubular cells. Later, the radioactivity was redistributed from the proximal tubules to scattered foci in the kidney medulla, suggesting desquamation and tubular transport of labeled epithelial cells. The redistribution was less pronounced at a lower [14C]DCVC dose (5 mg/kg body wt). Localization of [14C]DCVC was also observed in the liver, exocrine pancreas, and stomach (fundal part), although at a lower level than in the kidney. While the low dose (5 mg/kg body wt) produced a moderate lesion in the straight proximal tubules 24 hr after DCVC, the high dose (25 mg/kg body wt) not only induced a more pronounced lesion in this tubular segment but also extended the lesion to other tubular segments, including the subcapsular region. The results indicate binding of (a) vinyl-containing metabolite(s) to the straight portion of the proximal tubules, where a primary lesion is subsequently developed. Depending on dose, a "secondary" lesion appears in the subcapsular region, topographically different from the DCVC-binding region.

Animals↗
PubMed1988

Distribution of nicotinic receptors in human thalamus as visualized by 3H-nicotine and 3H-acetylcholine receptor autoradiography.

Nicotinic cholinergic receptors in human thalamus were measured using (-)3H-nicotine (20 nM) and 3H-acetylcholine (3H-ACh) (20 nM) as radioligands. The specific binding for 3H-nicotine to homogenates of thalamus was 51.6 +/- 8.3 pmol/g protein and for 3H-ACh 18.6 +/- 1.9 pmol/g protein. Receptor autoradiography indicated a high labelling of both 3H-Nicotine and 3H-ACh in the antero-ventral nucleus of thalamus and dorso-medial nucleus of thalamus, while the labelling was lower in the postero-lateral nucleus of thalamus and in the postero-lateral ventral nucleus of thalamus. Quantitative measurement of the 3H-nicotine autoradiograms showed highest labelling in the anteroventral nucleus of thalamus (17.34 +/- 0.76 pmol/g tissue). This study indicates a heterogeneous distribution of high-affinity nicotinic receptors in the human thalamus.

Acetylcholine↗
PubMed1988

Metabolic activation and toxicity of a DDT-metabolite, 3-methylsulphonyl-DDE, in the adrenal zona fasciculata in mice.

Whole-body autoradiography of 14C-labelled 3-methylsulphonyl-DDE (3-MeSO2-DDE) in female C57BL mice revealed a heavy accumulation in the adrenal cortex. Fairly high radioactivity appeared in the nasal mucosa and fat, while the labelling of the liver was intermediate. The adrenal radioactivity remained largely unextracted in tissue-sections treated with organic solvents. In the liver and intestinal contents the radioactivity was partly extracted, whereas in all other tissues almost completely extracted. According to light microscopic autoradiography, the tissue-bound adrenal radioactivity was confined to the zona fasciculata, leaving the other adrenal zones devoid of bound material. Incubation of 3-MeSO2-DDE with adrenal tissue (300 X g supernatant) revealed a dose- and time-dependent covalent binding to protein and formation of water-soluble metabolites. The cytochrome P-450 inhibitors metyrapone and carbon monoxide inhibited both covalent binding and polar metabolite formation. Addition of reduced glutathione decreased binding, while polar metabolite formation was increased. Histopathological examination of adrenals from 3-MeSO2-DDE-treated mice revealed extensive vacuolation and necrosis of the zona fasciculata 1-12 days after single doses down to 25 mg/kg. Degenerative changes were observed at 12.5 mg/kg. In contrast to 3-MeSO2-DDE, 14C-labelled 3,3'-bis(methylsulphonyl)-DDE was not accumulated in the adrenal cortex. 3-MeSO2-DDE is thus a persistent environmental pollutant with a unique ability to produce acute toxicity subsequent to metabolic activation in a mammalian tissue.

Adrenal Cortex↗
PubMed1988

Tissue and subcellular localizations of 3H-cyclosporine A in mice.

The tissue and subcellular localizations of 3H-cyclosporine A after administration to mice were determined with whole-body autoradiography and scintillation counting of lipid extracts of tissues and subcellular fractions. The radioactivity was widely distributed in the body and the pattern of distribution after oral or parenteral administration was the same, except that tissue levels were generally lower after oral administration. Pretreatment of the animals with a diet containing cyclosporine A for 30 days before the injection of radioactive cyclosporine A did not change the pattern of distribution substantially. No significant radioactivity was found in the central nervous system, except for the choroidal plexus and the area postrema region of the brain. In pregnant mice no passage of radioactivity from the placentas to fetuses was observed after a single injection. 3H-cyclosporine A and/or its metabolites showed a high affinity for the lympho-myeloid tissues, with a marked long-term retention in bone marrow and lymph nodes. There was massive excretion in the intestinal tract after parenteral administration, and the liver, bile, pancreas and salivary glands contained high levels of radioactivity. In the kidney radioactivity was confined to the outer zone of the outer kidney medulla. In liver homogenates no quantitatively significant binding of 3H-cyclosporine A and/or its metabolites to cellular molecules such as proteins, DNA, phospho- or neutral lipids was found. After lipid extraction with organic solvents, almost all radioactivity was recovered in the organic phase.

Animals↗
PubMed1988

Metabolism of 2,6-dichlorobenzamide in rats and mice.

1. Oral doses of 2,6-dichlorobenzamide (DCB) were excreted by rats as DCB, two monohydroxy-DCBs, 2-chloro-5-hydroxy-6-(methylthio)benzamide and 2-chloro-5-hydroxy-6-[S-(N-acetyl)cysteinyl]benzamide (mercapturic acid). 2. Biliary excretion (33% of the dose), enterohepatic circulation and intestinal micro-floral metabolism were involved in formation of 2-chloro-5-hydroxy-6-(methylthio)benzamide, and the mercapturic acid served as a precursor. 3. Whole body autoradiography and microautoradiography showed the accumulation of non-extractable residues from DCB in the nasal mucosa and contents of the large intestines of rats and mice dosed with 14C-labelled DCB.

Animals↗
PubMed1988

Metabolism of 2,6-dichlorobenzonitrile, 2,6-dichlorothiobenzamide in rodents and goats.

1. Twelve 14C-labelled metabolites were isolated from either urine or bile from either rats (11 metabolites) or goats (7 metabolites) given single oral doses of 2,6-dichlorobenzo[14C]nitrile (DCBN). Five of these metabolites were also excreted in urine from rats dosed orally with 2,6-dichlorothiobenz[14C]-amide (DCTBA). 2. All metabolites from either DCBN or DCTBA were benzonitriles with the following ring substituents: Cl2, OH (three isomers); Cl2, (OH)2; Cl, (OH)2; Cl, OH, SH; Cl, OH, SCH3; SCH3, SOCH3, OH; Cl2, S-(N-acetyl)cysteine; Cl, S-(N-acetyl)cysteine; Cl, OH, S-(N-acetyl)cysteine. 3. The thiobenzamide moiety of DCTBA was converted to the nitrile in all the excreted urinary metabolites. No hydrolysis of the nitrile in DCBN to either an amide or an acid was detected. 4. Urine was the major route for excretion; however, enterohepatic circulation occurred. 5. Whole-body autoradiography of 14C-DCBN and 14C-DCTBA in mice showed the presence of bound residues in the mucosa of the nasal cavity, trachea, tongue, oesophagus, the kidney, liver and the intestinal contents.

Amides↗
PubMed1987

Uptake and specific binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the olfactory mucosa of mice and rats.

Whole-body autoradiography of mice and rats after i.v. administration of 2,3,7,8-[14C]tetrachlorodibenzo-p-dioxin ([14C]TCDD) showed a selective localization of radioactivity in the liver and nasal olfactory mucosa. In microautoradiograms of solvent extracted sections of the skulls of mice given injections of [3H]TCDD, no radioactivity was observed in the olfactory mucosa, suggesting that TCDD is not covalently bound in this tissue. The amount of specific [3H]TCDD binding sites in cytosol from the ethmoturbinates of rats (33 fmol/mg cytosolic protein) was comparable to that of the liver cytosol as estimated by electrophoresis in polyacrylamide concentration gradient gel, and therefore probably too low to explain the retention of radioactivity in the olfactory mucosa. The specific TCDD binding species in the mucosa of the ethmoturbinates exhibited a similar binding affinity for [3H]TCDD, ligand specificity, and molecular weight as the TCDD receptor from rat liver. The 7-ethoxyresorufin O-deethylase activity of the mucosa of the ethmoturbinates was induced less than twice by administration of the TCDD receptor ligand beta-naphthoflavone (5,6-benzoflavone) 40 h before killing. By administration of beta-naphthoflavone (5,6-benzoflavone) 16 h before killing, mRNA coding for cytochrome P-450d but not for cytochrome P-450c was induced to detectable levels in the mucosa of the ethmoturbinal tissue of the rat. The basal activity of 7-ethoxyresorufin O-deethylation of the mucosa of the ethmoturbinates of the rat was comparable to the corresponding activity of the liver. This basal metabolic activity of the ethmoturbinal tissue was only marginally inhibited by antibodies raised against beta-naphthoflavone (5,6-benzoflavone) induced hepatic cytochrome P-450s. Thus, enzymes other than cytochrome P-450c may possibly account for a part of the basal 7-ethoxyresorufin O-deethylase activity in the rodent olfactory mucosa.

Animals↗