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Biomedical subjects

H G Neumann

Publications and source records attributed to H G Neumann.

At least 109 records · Page 6Linked to original sources
PubMed1980

Peroxidase activity in the rat Zymbal gland and its possible role in the metabolic activation of aminostilbenes in the target tissue.

Peroxidase (EC 1.11.1.7) activity is detected in the rat Zymbal gland, which is the target organ of trans-4-dimethylaminostilbene (trans-DAS) carcinogenicity. Measurements of peroxidase activity in ovariectomized rats show that the enzyme activity is lowered in the uterus and Zymbal gland by trans-DAS treatment and in the lungs by diethylstilboestrol (DES) treatment. In an in vitro system containing horseradish peroxidase (HRP), hydrogen peroxide and calf-thymus DNA, irreversible binding of the 3H-labelled trans-DAS metabolites 3-hydroxy-, 4'-hydroxy-, and N-hydroxy-4-acetylaminostilbene to DNA is observed. The peroxidase activity in the Zymbal gland together with the HRP-catalyzed oxidation of trans-DAS metabolites suggest a possible role for peroxidase in the organ-specific metabolic activation of trans-DAS.

Animals↗
PubMed1980

Correlation of nucleic acid binding by metabolites of trans-4-aminostilbene derivatives with tissue specific acute toxicity and carcinogenicity in rats.

The reaction with macromolecules was determined in various tissues of female Wistar rats 24 h following a single oral administration of [3H]-trans-4-dimethylamino- and [3H]-trans-4-acetylaminostilbene. Total binding to proteins was 4-9 times greater than to nucleic acids in most tissues. Binding to RNA and DNA was very similar and greatest in liver, about 1/4 in kidney and 1/8 - 1/10 in lung, glandular stomach (target tissue for acute toxicity), bladder, mammary glands and Zymbal glands (target tissue for carcinogenicity). The target tissues, therefore, appear not to be notably exposed to reactive metabolites. The pattern of adducts was analyzed by Sephadex LH20 chromatography of RNA and DNA hydrolysates from liver, glandular stomach, lung and kidney. It was found to be very similar qualitatively. DNA-bound metabolites were very persistent in the non-target tissues liver and kidney, t 1/2 being 34 and 60 days, respectively. Some of the major adducts in liver were not eliminated at all within 4 weeks. It thus appears that aminostilbene derivatives represent examples of strong and genotoxic carcinogens for which the extent and persistence of primary DNA lesions are not correlated with the biological effect.

Animals↗
PubMed1980

Biochemical effects and early lesions in regard to dose-response studies.

Trans-4-dimethylaminostilbene is metabolically activated independent of dose after single doses ranging from 5 x 10(-10) up to the LD50 = 2.5 x 10(-4) mol/kg. This is based on the dose related increase of covalent binding to macromolecules in liver, blood and kidney 24 h after oral administration to female Wistar rats. Deviations from proportionality at high doses are related to the rate rather than to the extent of formation of altered cell constituents. It is concluded that the early biochemical lesions critical to tumor formation are also independent of dose. A pharmacokinetic threshold with subcarcinogenic doses cannot be demonstrated down to exposures equivalent to 25 ng per animal or 2 microgram/kg diet.

Administration, Oral↗
PubMed1980

The role of lipophilicity in the extrahepatic disposition of aminostilbene derivatives following administration to rat.

1. Carcinogenic trans-4-dimethylaminostilbene and its unbound metabolites in rat tissues are highly lipophilic with partition coefficients of 10 000 to 80 000. The values for bibenzyl derivatives are somewhat lower. 2. Sulphates and glucuronic acid conjugates are present in liver, kidney, blood and bile, but not to any extent in other extrahepatic tissues. 3. The patterns of unbound metabolites in lung, spleen, adrenals, brain and fat after oral administration of 3H-labelled trans-4-dimethylaminostilbene, cis-4-dimethylaminostilbene and 4-dimethylaminobibenzyl have been determined. The concn. of tissue metabolites do not parallel plasma concn. of metabolites and do not correlate with lipophilicity. 4. Binding of trans-4-aminostilbene metabolites to tissue proteins is 3--5 times greater than that of cis-4-aminostilbene metabolites and more than 10 times higher than that of aminobibenzyl metabolites. In Zymbal gland, the target tissue for trans-4-dimethylaminostilbene carcinogenicity, the tissue concn. of reactive metabolites is insufficiently high to account for the specific effect. 5. The analysis of fat tissue provided circumstantial evidence that reactive metabolites bind covalently to fatty acids.

Animals↗
PubMed1979

Pharmacokinetic parameters influencing tissue specificity in chemical carcinogenesis.

Highly and specifically (3H)-labeled trans-4-dimethylaminostilbene was orally administered to female Wistar rats in doses ranging from 5 X 10(-10) to 2.5 X 10(-4) mol/kg. The following parameters were determined: tissue index in several tissues, binding index of liver proteins, rRNA, DNA, plasma proteins and haemoglobin and stomach proteins. Up to a dose of 2.5 X 10(-6) mol/kg all parameters remained constant, i.e. binding increased proportionately with the dose. It is concluded that simple and linear kinetics prevail and that a pharmacokinetic threshold does not exist in this dose range. At higher doses deviations from linearity were observed, however, the binding index decreased rather than increased with the dose. The results indicate that reactive metabolities are involved in the acute toxic effects observed in the rat stomach and that proximate or ultimate activation products are distributed in the circulation. Their concentration in the target tissue appears not be be specifically high to account for the tissue susceptibility.

Animals↗
PubMed1979

The binding of metabolites formed from aminostilbene derivatives to nucleic acids in the liver of rats.

Carcinogenic trans-4-dimethylaminostilbene (trans-DAS) and trans-4-acetylaminostilbene (trans-AAS) as well as inactive cis-DAS and DABB were highly and specifically labeled with tritium and administered orally to female Wistar rats. Covalent binding to liver rRNA and DNA was measured and found to be higher for the carcinogenic compounds. Digests from these nucleic acids were chromatographed on Sephadex LH-20 and 16 different nucleoside adducts were characterised by their retention volumes. Labeled trans-DAS was administered in doses ranging from 0.025--250 mumol/kg. Binding to nucleic acids was directly proportional to the dose at low doses (0.025--2.5 mumol/kg) and less than proportional at higher doses (25--250 mumol/kg). The pattern of nucleoside adducts remained practically constant over the wide range of doses. A pharmacokinetically determined threshold of metabolic activation thus could not be demonstrated for this compound. A modified procedure is described to simultaneously isolate pure liver rRNA and DNA from nonfasted rats in high yields.

Animals↗
PubMed1979

Identification of some products from the reaction of trans-4-aminostilbene metabolites and nucleic acids in vivo.

Esters of N-hydroxy-N-acetylaminostilbene react with guanosine, adenosine and cytidine in vitro and yield a number of different reaction products, some of which have been recently identified. We have now demonstrated that Urd-N3,alpha-beta,OH-AABB, Guo-N1,alpha-beta,OH-AABB, AdoN1,alpha-N6,beta-AABB and a Guo-O6 derivative are also formed in vivo, when the precarcinogen trans-4-dimethylaminostilbene is orally administered to female Wistar rats. However, these reaction products constitute only a small fraction of the adducts formed with liver rRNA. N-Acetylaminobibenzyl-alpha,beta-threo-diol is released from liver RNA upon hydrolysis. Comparison of the adduct pattern resulting from the reaction of N-acetoxy-N-acetylaminostilbene with yeast RNA in vitro and that obtained from in vivo rat liver RNA reveals not only quantitative but also qualitative differences. This indicates that reactive metabolites other than hydroxamic acidesters may contribute to the in vivo binding.

Adenosine↗
PubMed1978

Methemoglobin formation and binding to blood constituents as indicators for the formation, availability and reactivity of activated metabolites derived from trans-4-aminostilbene and related aromatic amines.

trans-4-Aminostilbene derivatives exhibit higher acute and chronic toxicity than 4-aminobibenzyl derivatives. Yet, trans-4-aminostilbene produced less methemoglobin in female Wistar rats than 4-aminobibenzyl. This cannot be explained by differences in N-oxidation since trans-4-nitrosostilbene was also less efficient than 4-nitrosobibenzyl. The fate of intravenously injected, highly and specifically 3H-labeled trans-4-aminostilbene, cis-4-aminostilbene, 4-aminobibenzyl, trans-4-nitrosostilbene and 4-nitrosobibenzyl was investigated. The results indicate that trans-4-aminostilbene and 4-aminobibenzyl are N-oxidized to a similar extent and primary activation products of trans-4-aminostilbene appear even faster in the blood. However, intermediates originating during methemoglobin formation are more reactive and covalently bind to hemoglobin 2--3 times as much with trans-stilbene as compared to bibenzyl derivatives. As a consequence the availability of these intermediates in the cyclic process and thus methemoglobin formation is reduced. Therefore, binding to hemoglobin rather than levels of methemoglobin appears to be an indicator for the availability and reactivity of some activated aromatic amine metabolites.

Animals↗
PubMed1978

The major metabolite of aflatoxin B1 in the rat is a glutathione conjugate.

[14C]aflatoxin B1 (AFB1) was injected i.p. into female Wistar rats. Half of the dose was eliminated into the bile mostly as polar non-extractable metabolites. Among these a glutathione conjugate was the main component. The same conjugate was formed when rat liver postmitochondrial supernatant was incubated with AFB1 and [3H]glutathione. The conjugate was purified by ion exchange chromatography, gel-filtration and thin layer chromatography (TLC). It was tentatively identified as 2,3-dihydro-2-(S-glutathionyl)-3-hydroxy aflatoxin B1 (AFB1-GSH-conjugate). This structure was derived mainly from amino acid analysis, ultraviolet spectra and the enzymatic requirements for its formation in in vitro experiments. In the rat this detoxification product of the potentially ultimate reactive AFB1-epoxide constitutes about 10% of the administered dose and thus underlines the quantitative importance of this activating pathway.

Aflatoxins↗
PubMed1977

Metabolic activation of diethylstilbestrol and aminostilbene-derivatives.

Diethylstilbestrol and trans-4-dimethylaminostilbene are metabolically activated and several of their metabolites are able to react with cellular macromolecules. Some of the problems are discussed which are encountered in linking a particular metabolite with the mutagenic and carcinogenic properties of these compounds.

Animals↗
PubMed1977

Epoxidation of the stilbene double bond, a major pathway in aminostilbene metabolism.

1. The vicinal diol 1-(4-acetylamino)-phenyl-2-phenyl-1,2-ethanediol is shown to be a major metabolite of cis- and trans-4-dimethylaminostilbene in the rat. 2. The threo-diastereomeric diols were identified in urine with both the cis- and trans-aminostilbene. This is consistent with enzymic trans-opening of an epoxide intermediate only for the cis-stilbene. For the hydrolysis of the trans-stilbene epoxide alternative mechanisms are discussed. 3. A mercapturic acid isolated from urine is identical with the reaction product of 4-acetylaminostilbene epoxide and N-acetylcysteine. This provides additional evidence for an epoxide intermediate. 4. Oxidation of the intercyclic linkage occurs also in 4-dimethylaminobibenzyl, leading to 1-phenyl-2-(4-acetylamino)-phenyl-1-ethanol as a major urinary metabolite. 5. The syntheses of several reference compounds, including the epoxides and dihydrodiols of cis- and trans-4-acetylaminostilbene are described.

Animals↗
PubMed1977

[Cytological finding in the pre- and early stages of cervix carcinoma--a contribution to the evaluation of Papanicolau III].

Cytologic findings and the histologic diagnosis are compared in 326 cervical cones. We have found following ratio of the groups Papanicolaou (Pap) III: Pap IV--in dysplasia 1: 1: 1, in "more dysplasia than carcinoma in situ (CIS)" 1:2:2. The Pap IV dominates in "pure" CIS and in cones with "more CIS than dysplasia". We take out of the Pap III ("with cytologic control") cases named "Pap III with necessity for histologic diagnosis". We have found in this subgroup of Pap III prestages or early stages of cervical carcinoma.

Carcinoma in Situ↗
PubMed1976

Metabolic epoxidation of trans-4-acetylaminostilbene: a protective mechanism against its activation to a mutagen.

Trans-4-acetylaminostilbene is activated by liver preparations to mutagens for Salmonella typhimurium. Since this compound is metabolized to the trans-alpha,beta-epoxide and since many epoxides are ultimate mutagens, this epoxide was tested for direct mutagenicity. It was, however, found to be non-mutagenic, and, in contrast to the parent compound, the epoxide was no longer activated by liver preparations to mutagens. The same was found for the beta-ketone and for the threo-alpha,beta-dihydrodiol, which are formed metabolically from trans-4-acetylaminostilbene and from its alpha,beta-epoxide. 4-Acetylaminobibenzyl showed a very weak mutagenic activity in the presence of the liver preparation. Thus, it is important to realize that where epoxides are formed from compounds which are known to be metabolized to mutagens, they are not necessarily responsible for the mutagenicity. Epoxidation may even prevent the possibility of bioactivation to mutagens.

Animals↗
PubMed1976

[2-year analysis of the results of a screening program on computer basis for the detection of pre- and early stages of cervix carcinoma (model Rostock) (II)].

Two years experiences with a computer-assisted program for early detection of prestages and early cervical cancer in Rostock-city are reported. 65% = 27028 women finally cooperated. Pathological papsmears were found in 0,52%. 9 cases of severe dysplasia, 30 carcinomata in situ, 3 cases of early invasion, 3 micro- and 5 macrocarcinomas were observed. Accessory findings were seen in 10,2%.

Adult↗