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H G Neumann

Publications and source records attributed to H G Neumann.

At least 73 records · Page 4Linked to original sources
PubMed1988

Reaction of trans-4-N-acetoxy-N-acetylaminostilbene with guanosine and deoxyguanosine in vitro: the primary reaction product at N2 of guanine yields different final adducts.

The model ultimate carcinogen, trans-4-N-acetoxy-N-acetylaminostilbene (N-acetoxy-AAS), was reacted with guanosine (Guo) and deoxyguanosine (d-Guo) and the resulting adducts were purified by Sephadex LH-20 chromatography and HPLC for structure identification. A number of new adducts was identified by mass and 1H-NMR spectroscopy. The generation of all known adducts can now be explained by a common mechanism. The electrophile formed from the hydroxamic acid ester at C-beta reacts in a first step predominantly with N2 of guanine (Gua). The resulting quinone-imide intermediate reacts in a second step with either one of three nucleophiles: (1) predominantly with N3 of Gua to yield the previously described angular cyclic adducts ((5R,6R)/(5S,6S)-9-oxo-5,6,7,9-tetrahydro-imidazo(2,1-b)purines); (2) with N1 of Gua to yield linear cyclic adducts ((6R,7R)/(6S,7S)-9-oxo-5,6,7,9-tetrahydro-imidazo(1,2-a)purines); (3) with water to yield the open ring (1R,2R)/(1S,2S)-2-(N2'-guanyl)-1-hydroxyethanes. To some minor extent (1:8-1:9) the electrophile reacts first with N1 or N3 of guanine which leads to the formation of two pairs of the corresponding regioisomeric cyclic adducts. This reaction mechanism may also explain the formation of cross-links between different bases.

Carcinogens↗
PubMed1988

Synergistic effects on the initiation of rat liver tumors by trans-4-acetylaminostilbene and 2-acetylaminofluorene, studied at the level of DNA adduct formation.

Both trans-4-acetylaminostilbene (AAS) and 2-acetylaminofluorene (AAF) exert tumor-initiating activity in rat liver when administered in the initiation phase of an initiation-promotion experiment. The effects are more than additive when the compounds are sequentially combined in the initiation phase of such an experiment, and this synergism is more pronounced when AAS is given first, followed by AAF, than vice versa. In order to determine the role of target DNA dose, [3H]AAS and [14C]AAF were administered to female Wistar rats adhering to the protocol of the initiation phase of the above-mentioned experiment and the following parameters measured at the end of this phase: total radioactivity in tissues, binding to DNA, RNA and proteins in liver, adduct pattern in liver DNA and RNA. In neither combination were these parameters significantly different from those in the appropriate controls in which only one of the compounds was administered. This result indicates that combining the substances did not alter the pharmacokinetics of the individual compounds and that the target dose is additive. This suggests that effects unrelated to DNA binding, possibly promoting effects, may cause the more than additive generation of preneoplastic lesions in rat liver.

2-Acetylaminofluorene↗
PubMed1988

[Sexuality in the aged].

Sexuality in older age group persons, important for human self reliance, is often underestimated or ignored. But the possibility to be orgastic can maintain up to the postmenopausal lifetime of a woman, depending on a fulfilled partnership. Somatic troubles, connected with the estrogen deficiency-syndrome, can be treated with oral or local estrogens.

Adult↗
PubMed1988

Haemoglobin binding in control of exposure to and risk assessment of aromatic amines.

Haemoglobin is proposed as a dose monitor for aromatic amines. Metabolically formed nitrosoarenes react with sulphydryl groups of haemoglobin and, after intramolecular rearrangement, yield sulphinic acid amides. This type of adduct is stable in vivo but can readily be hydrolysed after haemoglobin is isolated from blood samples, usually yielding the parent amine, which is quantified by gas chromatography or high-performance liquid chromatography. The haemoglobin binding index was determined in rats for a series of monocyclic aromatic amines, benzidine and some benzidine congeners. The following relationships are discussed: between binding of metabolites to DNA and to proteins; between haemoglobin binding and biological endpoints such as carcinogenesis and methaemoglobin formation; and between haemoglobin binding and molecular endpoints such as DNA binding and protein binding in liver and kidney. Haemoglobin binding correlates with a biologically active dose of aromatic amines and is thus well suited for monitoring exposure. The relationship between haemoglobin binding and the dose at critical targets is more complex, and, at present, carcinogenic risk cannot be assessed from biological monitoring data.

Amines↗
PubMed1987

Variables influencing DNA-binding in mouse liver.

The suitability of certain mouse strains for carcinogenicity testing has been questioned. Some chemicals increase the incidence of liver tumors above a relatively high background, an effect not seen in rats. This raises the question whether species and tissue specific effects are involved which are reflected in the DNA binding of metabolites. DNA binding indices in mouse liver have been determined in only a few instances. They are comparable to those found for rat liver DNA with aniline, benzo(a)-pyrene, butadiene, dimethylnitrosamine, methylnitrosourea and they are lower in the mouse with aflatoxin B1, trans-4-acetylaminostilbene and 2-aminofluorene derivatives. The available data on DNA binding in mouse liver suggest that the same adducts are formed as in rats but that metabolism and repair are variables which can modify the extent of DNA damage. However, the extent of DNA binding does not always correlate with the susceptibility of this tissue to carcinogenesis. But mouse liver is no exception in this respect. It is concluded that the formation of mouse liver tumors in long term studies with genotoxic chemicals indicates tumor initiating potential. In contrast, there are other chemicals such as chlorinated hydrocarbon insecticides which do not bind to DNA to any extent and which are not genotoxic in common short term tests and yet give rise to liver tumors in mice but not in rats. Positive results in long term studies are suggested to indicate promoting properties of such compounds.

Aflatoxin B1↗
PubMed1987

Reaction of trans-4-N-acetoxy-N-acetylaminostilbene with guanosine, deoxyguanosine, RNA and DNA in vitro: predominant product is a cyclic N2,N3-guanine adduct.

The model ultimate carcinogen trans-4-N-acetoxy-N-acetylaminostilbene was reacted with guanosine, deoxyguanosine, RNA and DNA using differently labeled reactants. The nucleoside as well as the deoxynucleoside yielded predominantly four cyclic guanine adducts: (S,S)- and (R,R)-guanine-N2,beta-N3,alpha-N-acetyl-aminobibenzyl and the regioisomers with the N2,alpha-N3,beta-attachment in a ratio of 9:9:1:1. The same adducts predominate in RNA and DNA which demonstrates that guanine reacts most avidly among the bases. The stability of the N-glycosidic bond is quite different between ribosides and deoxyribosides. Under neutral conditions, the riboside derivatives are stable, whereas deoxyribose is cleaved off rather readily. As a consequence DNA depurinizes to some extent during the in vitro reaction and during enzymatic digestion. On the other hand, N2,N3-attachment of the acetylaminostilbene moiety to guanine appears to impair the activity of nucleases for steric reasons. This could explain the incomplete enzymatic hydrolysis of modified nucleic acids. The results provide an important basis for further investigations to identify the nucleic acid adducts generated in vivo.

Animals↗
PubMed1987

[Computer-assisted screening for cervical carcinoma--the results for a 10-year period].

A report is given of 10 years experiences with a computer assisted mass-screening-programme to detect pre-stages and early stages of cervical carcinoma in Rostock city. The participation in the age-groups up to 40 years was over 75%. With this programme it is possible to make statistical analysis, to control the quality of Pap-smears and colposcopical results and to identify the risk-group of unscreened women for special examinations. As a result of the programme a decrease of cervical carcinomas since 1980 of about 25% was noticed. The same situation was found in pre-stages. Inert of all registered cervical carcinomas the number of stage one-cases increased.

Carcinoma↗
PubMed1986

Identification of nucleic acid adducts from trans-4-acetylaminostilbene.

It has been proposed that trans-4-acetylaminostilbene (AAS) is an initiator for tumor formation in rat liver and that the metabolically formed hydroxamic acid ester ultimately reacts with nucleic acids in vivo. We have now studied the generation of a major adduct in vitro. trans-4-N-Acetoxy-N-acetylaminostilbene (N-acetoxy-AAS) was reacted with guanosine at pH 7.5 and reaction products were separated by chromatography on Sephadex LH-20 and RP18 HPLC. The major adduct isolated consists of four isomers which have been tentatively identified by mass- and 1H-NMR spectroscopy as (S,S)- and (R,R)-guanosine-N2,beta-N3,alpha-N-acetylaminobibenzyl and the respective regio isomers guanosine-N2,alpha-N3,beta-N-acetylaminobibenzyl. These adducts are formed in a ratio of 9:9:1:1. Under acidic conditions (pH 2) the ribose moiety is removed and two regio isomeric base adducts are formed in the ratio 9:1. Results to be published indicate that the adducts are also formed in vivo in rat liver RNA and DNA.

Animals↗
PubMed1986

V79 Chinese hamster cells deacetylate trans-N-acetoxy-4-acetylaminostilbene and trans-N-hydroxy-4-acetylaminostilbene to mutagenic and cytotoxic metabolites.

The N-acetoxy and N-hydroxy derivatives of trans-4-acetylaminostilbene (AAS) were demonstrated to induce gene mutations at the hgprt locus and to be cytotoxic in V79 cells. These cells deacetylated AAS. Paraoxon inhibited the deacetylation of AAS by more than 99% and reduced the mutagenicity and cytotoxicity of N-hydroxy-AAS and N-acetoxy-AAS to about one-tenth. Hence, deacetylated metabolites, formed by the target cells, were important for the observed biological effects.

Animals↗
PubMed1986

The role of DNA damage in chemical carcinogenesis of aromatic amines.

Many findings support the notion that the generation of DNA adducts by aromatic amines is causally related to carcinogenesis. Adducts have been identified in most cases and representative examples are reviewed. However, extent and persistence of DNA adducts (DNA dose) does not correlate satisfactorily with the tumor response of different tissues. Distribution of DNA damage, repair, indirect and secondary DNA damage are discussed as possible explanations for the observed noncorrelations. In addition, however, it is proposed to pay attention to specific mechanisms such as receptor mediated cellular effects which are not related to the generation of electrophiles. The effects of trans-4-aminostilbene and 2-amino-fluorene derivatives on rat liver are compared. It is concluded that trans-4-acetylamino-stilbene is a strong liver tumor initiator but an incomplete liver carcinogen lacking tumor promoting properties, and that 2-acetylaminofluorene is a complete liver carcinogen with initiating and promoting properties.

2-Acetylaminofluorene↗
PubMed1986

Organ specific acute toxicity of the carcinogen trans-4-acetylaminostilbene is not correlated with macromolecular binding.

trans-4-Acetylaminostilbene (trans-AAS) is acutely toxic in rats and lesions are produced specifically in the glandular stomach. Toxicity is slightly increased by pretreating the animals with phenobarbital (PB) and is completely prevented by pretreatment with methylcholanthrene (MC). The prostaglandin inhibitors, indomethacin and acetyl salicylic acid, do not reduce toxicity. The high efficiency of MC suggested that toxicity is caused by reactive metabolites. trans-[3H]-AAS was administered orally to untreated and to PB- or MC-pretreated female Wistar rats and target doses in different tissues were measured by means of covalent binding to proteins, RNA and DNA. Macromolecular binding in the target tissue of poisoned animals was significantly lower than in liver and kidney and comparable to other non-target tissues. Pretreatment with MC lowered macromolecular binding in all extrahepatic tissues but not in liver. These findings are not in line with tissue specific metabolic activation. The only unique property of the target tissue, glandular stomach, that we observed was a particular affinity for the systemically available parent compound. In the early phase of poisoning, tissue concentrations were exceedingly high and the stomach function was impaired.

Animals↗
PubMed1986

The reduction of aromatic nitro compounds with Zn/Cu. A new synthesis of N-acetoxy-N-acetyl-arylamines.

A new and simple synthesis is described for N-acetoxy-N-acetyl-derivatives of trans-4-aminostilbene, 2-aminofluorene and 2-aminophenanthrene using a Zn/Cu-couple for the reduction of the nitro-aromatics. This method produces good yields and should also be applicable for other N-aryl-compounds. It can also be used for the reduction of nitro-aromatics to the respective arylamines and arylamides.

Copper↗
PubMed1985

Biomonitoring of aniline and nitrobenzene. Hemoglobin binding in rats and analysis of adducts.

Covalent binding to hemoglobin was studied to further substantiate the proposal that it may be used for biomonitoring N-substituted aryl compounds. (14C)-Labeled acetanilide and nitrobenzene were orally administered to female Wistar rats and binding indices [Binding(mmol/mol Hb)/Dose(mmol/kg)] determined; these were 12 +/- 1 and 73 +/- 10, respectively. After mild acidic or alkaline hydrolysis, 90% of the bound material was released and identified as aniline by radio thin layer chromatography. This supports the hypothesis that nitroso aryl derivatives, common intermediates in the metabolism of N-substituted aryl compounds, react with SH-groups of hemoglobin to yield sulfinic acid amides. Aniline was furthermore identified and quantified by capillary gas chromatography, using hemoglobin from animals treated with unlabeled aniline and nitrobenzene. Binding indices in this case were 30 +/- 3 and 85 +/- 19, respectively. With this method human blood samples may also be analysed. Although nitrobenzene is known to produce less methemoglobin than aniline, hemoglobin binding is higher. This indicates that hemoglobin binding may be a better index of body burden than methemoglobin levels in biomonitoring N-substituted aryl compounds.

Acetanilides↗
PubMed1985

Tissue specific, acute toxic effects of the carcinogen trans-4-dimethylaminostilbene.

The acute toxicity of the carcinogen trans-4-dimethylaminostilbene was studied in Wistar rats. The animals die after oral administration of 50 mg/kg (LD50) with a latency period of 11 days. Specific lesions of the stomach epithelium together with acute bone marrow incapacity and toxic effects on peripheral blood cells lead to acute anemia, which is considered to be the cause of death. Histological observations indicate that the stomach lesions develop in three phases. Firstly, necroses appear in the proliferative area predominantly in the antrum. This leads, secondly, to cystic transformation of the antrum, cardia, and Brunner's glands and further to peptic erosions and ulcerations. Thirdly, mitotic activity increases. With lethal doses, cell replacement remains incomplete. There ist a correlation between the proliferation rate of different cell types and their susceptibility; but this cannot entirely account for the tissue-specific, systemic effects of trans-4-dimethylaminostilbene. Metabolic activation is also involved, since enzyme induction with methylcholanthrene inhibits toxicity. The study disclosed a new target tissue which may now be used to investigate the mechanism of action of reactive metabolites of an aromatic amine in acute experiments. The same stomach lesions were also observed with adriamycin. With this compound, however, the intestine is also involved.

Acute Disease↗