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Biomedical subjects

H G Neumann

Publications and source records attributed to H G Neumann.

At least 91 records · Page 5Linked to original sources
PubMed1985

Accumulation and elimination of macromolecular lesions in susceptible and non-susceptible rat tissues after repeated administration of trans-4-acetylaminostilbene.

Trans-4-acetylaminostilbene (trans-AAS) is a potent carcinogen and quite specifically produces sebaceous gland tumors, predominantly in the Zymbal's gland of rats. It is also acutely toxic to the rat glandular stomach. Recent results have shown that these target tissues are not notably exposed to reactive metabolites after single administration of the compound. Therefore, experiments were designed to test whether multiple exposures cause changes in metabolic activation or repair of DNA-bound metabolites to the effect that target and non-target tissues accumulate macromolecular damage differently. Trans-[3H]AAS was orally administered to female Wistar rats in 12 doses over 6 weeks and binding of metabolites to proteins, RNA and DNA in several tissues as well as the pattern of adducts in liver nucleic acids were measured. In addition, the elimination of macromolecular-bound metabolites was determined at various intervals during the treatment. Metabolism and clearance of bound metabolites remained unaltered. As a consequence, DNA-bound metabolites accumulated in all tissues measured; to the greatest extent in the non-target tissues liver and kidney. Tissue exposure, as estimated by protein-binding, differed by a factor of 10 and decreased in the following order: liver, kidney, lung, Zymbal's gland, glandular stomach, mammary tissue. The results support the notion that neither the extent nor the persistence of DNA-binding correlate with the biological effects of trans-AAS.

Animals↗
PubMed1985

Syncarcinogenic effects on the initiation of rat liver tumors by trans-4-acetylaminostilbene and 2-acetylaminofluorene.

Two carcinogenic aromatic amines with different organotropism were tested for syncarcinogenic effects in rat liver in an initiation-promotion experiment. Trans-4-acetylaminostilbene (AAS) and 2-acetylaminofluorene (AAF) were administered as initiators in four doses each either alone or sequentially combined in both orders. The promotion phase was started by partial hepatectomy and continued by adding phenobarbital (250 p.p.m.) to the drinking water for 26 weeks. The number/cm2 of tissue section and average size of hyperplastic foci, glucose-6-phosphatase-deficient and gamma-glutamyl-transpeptidase-positive foci were determined and a total area of lesions calculated during the promotion phase after 18 and 31 weeks, and in the post-promotion phase after 42 and 47 weeks. The synergistic effects of AAS and AAF were clearly more than additive if compared with the sum of the effects exerted by each compound individually. The sequence in which both initiators were administered remarkably influenced the development of lesions. They developed more rapidly and persisted longer in the post-promotion phase when AAS was administered first and AAF second. In the final stage, enzyme altered foci increased in the livers of both combination groups, but to a greater extent in the AAS-AAF group. It is concluded that the two arylamides damage DNA independently. In addition, however, the results suggest that AAS acts predominantly as an initiator, and AAF as a weak initiator and a strong promoter in what is considered the initiation phase of this experiment.

2-Acetylaminofluorene↗
PubMed1984

Analysis of hemoglobin as a dose monitor for alkylating and arylating agents.

Genotoxic xenobiotics bind covalently to hemoglobin in vivo. The major reaction product of aromatic amines is a sulfinic acid amide resulting from the reaction of arylnitroso derivatives with SH-groups. Alkylating compounds react with cysteine, histidine and the terminal valine. The adducts are formed proportional to dose down to extremely small doses, they are stable throughout the life-span of the erythrocytes and accumulate upon repeated exposure. Methods for their determination in blood samples from experimental animals and humans are becoming available. Moreover, it has been demonstrated that for a given agent, a constant ratio exists between the reaction with tissue DNA and hemoglobin over a wide range of doses, which indicates that the reactions follow apparent first order kinetics. The extent of hemoglobin binding is therefore considered to be a relative measure of tissue dose, and should correlate much better with risk than exposure levels calculated from concentrations in the environment. Not only can the actual uptake be monitored more reliably, but also the individual's capacity to metabolically activate the absorbed agent. Biomonitoring of hemoglobin-bound metabolites represents a novel approach to control exposure to potential carcinogens, to correlate environmental exposure with tissue dose and eventually also with human risk.

Alkylating Agents↗
PubMed1983

Role of extent and persistence of DNA modifications in chemical carcinogenesis by aromatic amines.

The initial step in tumor formation with aromatic amines is assumed to involve the modification of nucleic acids. Reactive metabolites bind covalently to purine and pyrimidine bases. The extent of formation of DNA adducts and their persistence is therefore expected to correlate with the biological effect. Using [3H]trans-4-amino-stilbene derivatives as model compounds, several parameters have been measured in susceptible and nonsusceptible rat tissues: total initial DNA binding, initial pattern of adducts, persistence of DNA adducts, accumulation of DNA binding after repeated doses, and persistence of DNA adducts after repeated doses. They did not correlate with tissue susceptibility. The tissue burden decreased in the order: liver greater than kidney greater than lung greater than glandular stomach greater than Zymbal gland. The latter tissue is the primary target for tumor formation. Comparison with other aromatic amines shows that aminostilbene derivatives are no exceptions. The role of specific nucleic acid modifications for mutagenic and carcinogenic effects is also difficult to evaluate in these cases. It is therefore emphasized that modulation of secondary steps in the multistage process may largely influence the final outcome. The role of cell proliferation and its stimulation as well as tumor promoting effects are discussed. Aminostilbene derivatives appear to produce primary lesions quite efficiently in rat liver but lack cytotoxic and promoting properties for this tissue.

Amines↗
PubMed1983

The role of partial hepatectomy and of promoters in the formation of tumors in non-target tissues of trans-4-acetylaminostilbene in rats.

After repeated administration of trans-4-acetylaminostilbene to rats, DNA-bound metabolites accumulate to the greatest extent in liver and kidney, which are considered to be nontarget tissues for this carcinogen. To test whether the persistent DNA adducts represent procarcinogenic lesions, an initiation-promotion experiment was carried out using trans-4-acetylaminostilbene as an initiator and phenobarbital, DDT and diethylstilbestrol as promoters. In addition, partial hepatectomy was performed in some groups. Partial hepatectomy alone or in combination with promoters led to the formation of preneoplastic enzyme deficient foci, hyperplastic nodules and hepatoma in great yields. In addition, mammary tumors were observed with diethylstilbestrol promotion. The results support our proposal that aminostilbene derivatives produce procarcinogenic DNA-lesions in many, if not all, tissues and that secondary factors determine when and where tumors arise.

Adenoma, Bile Duct↗
PubMed1983

The effects of partial hepatectomy and of promoters on macromolecular binding of trans-4-acetylaminostilbene metabolites in liver and some extrahepatic tissues of rats.

Trans-4-acetylaminostilbene (trans-AAS) is a complete carcinogen for sebaceous glands and an initiator for liver in rats. Partial hepatectomy alone or in combination with phenobarbital, 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane or diethylstilbestrol produce liver tumors in trans-AAS pretreated rats. The effects of such secondary treatments on the macromolecular binding of [3H]trans-AAS metabolites was studied in several tissues. Partial hepatectomy was performed either 24 h before or after a single trans-AAS dose, and binding to proteins, RNA and DNA was measured 1, 3, and 17 d after the last treatment. Initial DNA-binding in liver was, if at all, somewhat lower than in controls, and then decreased more rapidly independent of the time of partial hepatectomy. In extrahepatic tissues, exposure and initial macromolecular binding was considerably higher, and elimination differentially delayed, if partial hepatectomy preceded dosing. With subsequent partial hepatectomy, initial binding was similar to controls, but elimination of DNA-binding was retarded in lung and glandular stomach. In a similar experiment, promoters were added to the feed 1 d after a single trans-AAS dose and macromolecular binding was determined 2 and 16 d thereafter. DNA-binding was little affected in liver, and in extrahepatic tissues at the first time point. In lung and glandular stomach its elimination was retarded, while in kidney DNA-binding even increased during promoter feeding. It is concluded that the secondary treatments have little impact on the primary lesion in the target tissue liver, but profoundly alter the disposal of trans-AAS metabolites which leads to increased tissue doses in extra-hepatic tissues.

Animals↗
PubMed1983

Role of tissue exposure and DNA lesions for organ-specific effects of carcinogenic trans-4-acetylaminostilbene in rats.

trans-4-Acetylaminostilbene is acutely toxic to the glandular stomach and produces sebaceous gland tumors in rats quite specifically. Metabolism, tissue exposure to reactive metabolites, DNA binding and persistence of DNA lesions are implicated in tissue susceptibility, but nothing indicates that one of these parameters determines the biological effect. All tissues are exposed to reactive metabolites, liver as a nontarget tissue ranking highest. DNA binding in this tissue, however, is not irrelevant to tumor formation, but rather indicates the presence of initiating lesions. They can be amplified by partial hepatectomy and/or promoters, such as phenobarbital, DDT and diethylstilbestrol. Liver tumors are formed in high yields with these treatments, and mammary tumors also occur. trans-4-Acetylaminostilbene is therefore considered to be an incomplete carcinogen in these tissues and may initiate cells in other tissues as well. Apparently it lacks promoting properties which are supposed to be unrelated to reactive metabolites. It is concluded that DNA lesions do not reflect tissue risk, but rather secondary effects ultimately determine where the process of tumor formation starts and how fast it develops.

Animals↗
PubMed1981

[Screening for prevention and early detection of cervical cancer in the German Democratic Republic-- an analysis (author's transl)].

The cytological mass screening to prevent invasive carcinomas by detection and therapy of intraepithelial neoplasia and to detect early stages of invasive carcinomas is the most important basis for cervical cancer control. An analysis of epidemiological effects caused by mass screening programs in two districts (Berlin, capital of the GDR; Rostock) demonstrates during the last 7 years a marked increase of detected ca in situ followed by a clear decrease, a decrease of morbidity of cervical cancer (49.4/100,000 :36.1/100,000 women) and an increase of earlier stages, especially stage Ia. The highest decrease of morbidity could be observed in women aged 40--49 years (111.6 : 61.0) followed by those aged 50--59 years (91.1 : 76.1). Preliminary results demonstrate the benefit of screening program and the practicability of organization form used in the capital Berlin. A further analysis demonstrates screening activities in the whole country. a continuous increase of cytological capacities in many districts is the remarkable result of the activities and gives the assurance for further success of the cytological screening program decided for the German Democratic Republic.

Adult↗
PubMed1981

Significance of metabolic activation and binding to nucleic acids of aminostilbene derivatives in vivo.

Comparison of metabolite binding of several aminostilbene-related compounds to rat liver macromolecules in vivo supported the concept that metabolic activation is a prerequisite for biologic activity. Carcinogenic trans-4-dimethylaminostilbene and trans-4-acetylaminostilbene bound more strongly to DNA than the biologically less active cis-4-acetylaminostilbene and 4-dimethylaminobibenzyl by more than ten times. Hydroxamic acid esters did not appear to be the major metabolites which ultimately reacted with nucleic acids. The primary biochemical lesions are not correlated with tissue susceptibility. Total binding of trans-4-dimethylaminostilbene metabolites to nucleic acids was highest in the liver, about one-fifth of that total amount in the kidney, less than one-fifth in the lung and glandular stomach (which is the target tissue for acute toxicity), and still less in the forestomach and Zymbal's gland, the tissue in which tumors arise after repeated administration of test compounds to female Wistar rats. In the nontarget tissues, i.e., liver and kidney, nucleic acid binding was not only initially high but also persistent. Therefore, the exposure-related, primary biochemical lesion could not be linked to the biologic lesion. Tissue-specific parameters, other than those related to metabolic activation, are proposed to determine the biologic effect.

Animals↗
PubMed1980

Dose-response relationship in the primary lesion of strong electrophilic carcinogens.

The carcinogen trans-4-dimethylaminostilbene was administered orally to female Wistar rats in doses ranging from 5 x 10(-10) to 1.8 x 10(-4) M/kg and covalent binding in liver, blood, kidney and stomach determined after 24 h as a measure for the availability of reactive metabolites. Total binding to proteins in all these tissues and binding to rRNA and DNA in liver and kidney increased linearly with dose over the entire dose range up to 3.5 x 10(-5) M/kg. The increase deviated from linearity only at the highest dose (1.8 x 10(-4) M/kg). In this case it was less than proportional. The result provides experimental evidence for the notion that first order kinetics prevail down to extremely small doses, in the present experiment 25 ng per animal. It is concluded that metabolic activation, distribution of reactive metabolites and their reaction with cellular macromolecules is independent of dose at low doses. This implies that the production of primary lesions is also independent of dose and that a pharmacokinetically determined threshold does not exist for trans-4-dimethylaminostilbene down to nanogramdoses.

Animals↗