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R Schulte-Hermann

Publications and source records attributed to R Schulte-Hermann.

At least 109 records · Page 6Linked to original sources
PubMed1985

Quantitative histological and histochemical studies on the occurrence and stages of controlled cell death (apoptosis) during regression of rat liver hyperplasia.

Hyperplasia of the rat liver can be induced by cyproterone acetate (CPA). The fate of this hyperplasia after cessation of CPA treatment has been studied and the following findings were obtained: Liver DNA content decreased by about 25% within a few days after CPA withdrawal. In histological sections some hepatocytes showed degenerative changes. Among these, small membrane bounded bodies ("apoptotic bodies"; ABs) with or without chromatin were most numerous. Their incidence coincided with the phase of DNA elimination. Inflammatory reactions were not observed. Their small size and occurrence in clusters suggests that many of these ABs are formed by fragmentation of dying hepatocytes. Liver DNA was prelabelled with 3H-thymidine. Autoradiographic evaluation showed that many hepatocytes contained labelled nuclei, but unlabelled ABs. This finding strongly suggests that ABs, after the fragmentation stage, can be phagocytized by intact hepatocytes. About 80% of all ABs were found within hepatocytes. Extracellular ABs (early stage) contained no or very few active lysosomes. Intracellular ABs were sometimes surrounded by lysosomes, while others were in various stages of digestion. These observations suggest that the lysosomes of the phagocytizing hepatocytes degrade intracellular ABs, whereas intraapoptotic lysosomes seem to be inactive until the late stages of this degradation. Hepatocytes that did not replicate during CPA-induced liver growth appear to die off preferentially after CPA withdrawal. Retreatment with CPA greatly reduced the number of ABs within 4 h. Phenobarbital, another stimulus of liver growth, had the same effect. These findings suggest that the present type of cell death can be inhibited by growth stimuli and is therefore a controlled event serving to eliminate an excess of cells, rather than a manifestation of toxic injury to hepatocytes. The findings also suggest that this type of cell death and elimination is a rapid process completed within a few hours. It is concluded that cell death under the present experimental conditions probably occurs through apoptosis.

Animals↗
PubMed1984

Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters.

Numerous drugs, hormones and environmental pollutants induce liver growth by hypertrophy and/or hyperplasia, and promote preferential growth of putative preneoplastic foci in the liver. In the present study the regression of hyperplasia after cessation of inducer/promoter treatment was studied in normal liver and in liver foci. High doses of cyproterone acetate (CPA), a synthetic sex steroid, were administered to rats and produced a doubling of liver size; after cessation of treatment liver size declined, and 27% of the total liver DNA disappeared within 6 days. In histological sections from the involuting liver no necroses, but numerous apoptotic bodies (ABs) were found; retreatment with CPA interrupted the formation of ABs. These findings suggest that elimination of excess liver DNA after cessation of CPA treatment is due to controlled cell death by apoptosis. In a further series of experiments putative preneoplastic foci were produced by a single dose of N-nitrosomorpholine and subsequently stimulated to grow by 10 or 28 weeks of phenobarbital (PB) treatment. After withdrawal of PB numerous ABs were present in normal liver and in the foci; in both, retreatment with PB decreased the appearance of ABs. It appears that inhibition of cell death by PB may contribute to tumour promotion. Under all conditions tested more ABs were found in the foci than in non-focal parts of the liver, suggesting an enhanced cell turnover in foci. The apparent sensitivity of foci to mechanisms controlling cell death might eventually provide a means for elimination of preneoplastic lesions.

Animals↗
PubMed1984

Glutathione S-transferases in chemically induced tumors.

Rats were treated with N-nitrosomorpholin and subsequently with phenobarbital. After several weeks of phenobarbital treatment, foci of altered cells and tumors developed in the livers of the animals. In liver tumors, the activity of glutathione S-transferase was higher than in the surrounding tissue and remained elevated even after the withdrawal of the promoter. Like the glutathione S-transferase from normal liver, tumor glutathione S-transferase activity is composed of several, predominantly basic, isoenzymes with an apparent molecular weight of approximately 45,000.

Animals↗
PubMed1984

Aberrant expression of adaptation to phenobarbital may cause selective growth of foci of altered cells in rat liver.

According to the multistage concept of carcinogenesis, promoters induce selective or preferential multiplication of initiated cells, thereby accelerating one of the rate-limiting steps in cancer formation. The driving force for this selective growth of initiated cells is not known. In normal liver, various liver tumour promoters induce expression of adaptive programmes. One such programme, induced by phenobarbital, consists of organ growth and an increase in the activity of various enzymes involved in the metabolism of lipophilic substrates. In foci of altered rat liver cells (the putative progeny of initiated cells), expression of the programme is still possible and is coupled to certain regulatory defects (excessive, unbalanced proliferation; independence from position-specific restrictions within the hepatic acinus; autonomous expression of some adaptive changes). Promoters seem to switch on this aberrant expression of the programme of adaptation, thereby leading to preferential growth of foci.

Animals↗
PubMed1983

Assay of some endogenous and synthetic sex steroids for tumor-initiating activity in rat liver using the Solt-Farber system.

Endogenous (estradiol-17 beta; progesterone) and synthetic (ethinyl estradiol; cyproterone acetate; norethindrone acetate; norethynodrel) sex steroids were evaluated for tumor-initiating activity in the rat liver using the Solt-Farber system. All steroids were negative. This provides further evidence that tumor formation in long-term rodent bioassays by these compounds may be due to epigenetic mechanisms.

Androgen Antagonists↗
PubMed1983

The role of growth of normal and preneoplastic cell populations for tumor promotion in rat liver.

A number of different compounds, including phenobarbital, hypolipidemic drugs such as clofibrate and nafenopin, the sex steroids progesterone, cyproterone acetate, estradiol and mestranol, chlorinated hydrocarbons such as DDT, hexachlorocyclohexane, and TCDD and the antioxidant butylhydroxytoluene, appears to promote the development of liver tumors from previously induced initiated cells. The mechanisms of tumor promotion by several representative prototypes of these compounds were studied in rat liver in vivo. All liver tumor promoters mentioned above stimulate growth of normal liver. The growth response is due to cellular hypertrophy and/or increased rate of DNA (and cell) replication and/or decreased rate of cell death. Hepatocytes in foci or islands of altered cells (putatively preneoplastic) show higher rates of replication than normal liver cells; various different liver tumor promoters cause a further increase of proliferation of focal cells. The increased proliferative activity is found in different island phenotypes and thus seems to be a useful marker of the putative preneoplastic state. The focal cells respond to several factors limiting proliferation in normal liver, suggesting that they are not autonomous with respect to growth control. Early preneoplastic foci grow slowly without promotion, despite the relatively high rates of cell replication. Thus their cells seem to have a much shorter life-time than normal hepatocytes or to undergo reversion to the normal phenotype. Promoters seem to accelerate island enlargement by increasing cell replication and delaying cell death or remodeling. Thus, tumor promoters enhance the manifestation of the proliferation advantage of the putative initiated cell population. In addition, promoters cause increases in the number of detectable islands. This can partially be explained by enlargement of existing islands, but phenotypic changes that would enhance the probability of detection of remodelling islands and growth of dormant initiated cells, probably contribute to the apparent increase of island number. Putative preneoplastic foci of unknown origin are frequent in the liver of aged Wistar rats. They are morphologically and functionally very similar to those induced by carcinogens and are responsive to the mitogenic effect of tumor promoters. Promotion of these "spontaneous" foci may explain tumor appearance after long-term application of promoters.The findings may provide a basis for improved identification of initiated hepatocytes (and of initiating hepatocarcinogens) and for detection of tumor promoters. All suspected liver tumor promoters tested so far induced enhanced preneoplastic cell proliferation after single doses. The long-term carcinogenicity bioassay as currently performed does not discriminate between initiating and promoting properties of a test compound if the animals used develop spontaneous preneoplastic lesions in the organ affected.

Animals↗
PubMed1983

Synchronization of hepatic DNA synthesis by scheduled feeding and lighting in mice treated with the chemical inducer of liver growth alpha-hexachlorocyclohexane.

A single dose of alpha-hexachlorocyclohexane (alpha-HCH) induces liver enlargement in adolescent mice. Concomitantly, the DNA content of the organ increases, and DNA synthesis is enhanced in parenchymal cells after a lag phase ('pre-replicative period') of 12-20 hr. DNA replication appears not to be followed by mitosis. Adaptation of the mice to a controlled feeding and lighting schedule provides synchronization of the hepatic DNA synthesis response to alpha-HCH. This appeared due to the provision, by the feeding and lighting schedule, of permissive signals which are required for stimulation of hepatic DNA synthesis in addition to alpha-HCH. One such signal is provided by food consumption before alpha-HCH administration, i.e. in the G0 phase. A second signal is provided after alpha-HCH administration in the late prereplicative period by feeding a protein-containing diet, and by other events, possibly related to the light-dark shift. Without this signal, the majority of hepatocytes stimulated to replicate DNA is arrested and accumulates at a stage a few hours before the start of DNA synthesis. The signal provides release from the block fairly synchronously. Both permissive signals seem also operative in the control of 'physiological' DNA synthesis in the liver of untreated mice. In conclusion, use of alpha-HCH and proper timing of feeding and lighting periods should provide an experimental model helpful for studying the interaction of growth stimuli with endogenous regulators of hepatic DNA replication.

Animals↗
PubMed1983

Promotion of spontaneous preneoplastic cells in rat liver as a possible explanation of tumor production by nonmutagenic compounds.

Foci of putative preneoplastic cells were detected in the livers of untreated aged Wistar rats of both sexes. The foci exhibited markers similar to those of their counterparts in carcinogen-treated rats such as increased cytoplasmic basophilia, clearness of cytoplasm, or expression of gamma-glutamyltransferase. Rates of DNA synthesis in foci were higher than in normal liver and were further increased by single doses of liver mitogens assumed to promote liver tumor development (phenobarbital, alpha-hexachlorocyclohexane, cyproterone acetate, nafenopin). Thus, cells in the spontaneous foci appear to possess a defect in growth control, rendering them more susceptible to endogenous and exogenous growth stimuli. This defect has been found previously in carcinogen-induced foci and may be used as a marker for putative preneoplastic cells. The spontaneous foci are present at low incidence in 8-month-old rats; at 2 years, all of 50 rats studied possessed foci. These observations suggest that nongenotoxic compounds can produce liver tumors if they promote tumor development from preneoplastic foci. Therefore, long-term bioassay for carcinogenicity will not discriminate between initiating and promoting compounds if preneoplastic lesions develop in control animals.

Aging↗
PubMed1983

Kinetics of DNA synthesis in feeding-dependent and independent hepatocyte populations of rats after partial hepatectomy.

The effects of food consumption on the kinetics of hepatic DNA synthesis after partial hepatectomy (PH) have been studied in rats. Short-term (4-24 hr) fasting before or after PH resulted in depression and/or delay of DNA synthesis on days 1, 2 and 3 of regeneration. This depression was found in hepatocytes and, to a lesser extent, in littoral cells. Re-feeding resulted in an increase of DNA synthesis within 3-8 hr. The results suggest that two different hepatocyte subpopulations exist in regenerating rat liver: one which proceeds to DNA synthesis without apparent exogenous signals, and another one which needs, in addition to the specific mitogenic action of PH, food intake as a secondary permissive signal in order to initiate DNA synthesis. In the latter population food consumption appears to be required at two different stages: (1) in G0 or the early pre-replicative phase (PRP); (2) in the late PRP 3-8 hr before initiation of DNA synthesis. In the latter stage dietary protein is needed, but no so in the former. The dependence on feeding in the late PRP increases relatively with time after PH. No evidence was found to suggest a different distribution of the two cell populations throughout the liver acinus. The findings support the hypothesis that the known effects of the light-dark rhythm on the timing of DNA synthesis after PH are mediated by the natural feeding rhythm of rats fed ad libitum. In addition they offer a means for improving the synchrony of hepatocyte proliferation in regenerating rat liver.

Animals↗
PubMed1981

Enhanced proliferation of putative preneoplastic cells in rat liver following treatment with the tumor promoters phenobarbital, hexachlorocyclohexane, steroid compounds, and nafenopin.

Putative preneoplastic islands were induced in rat liver by diethylnitrosamine or nitrosomorpholine administered either as single high doses or continuously for 40 days at low dose levels. Following recovery periods of 3 weeks to 11 months, islands were identified by means of a positive gamma-glutamyl transferase reaction and/or altered morphology. DNA synthesis, by means of [3H]thymidine autoradiography, as well as mitotic activity were determined. Under all conditions studied, proliferation rates of island cells were significantly higher than those of normal unaltered hepatocytes. Single doses of liver mitogens known or assumed to promote liver tumor development (phenobarbital, alpha-hexachlorocyclohexane, cyproterone acetate, nafenopin, and pregnenolone-16 alpha-carbonitrile) were administered. Twenty-four to 30 hr later, this treatment produced even higher proliferative activities in island cells and increased the DNA synthesis index up to 50%, while proliferation in normal liver cells increased slightly to moderately. Thus, cells of putative preneoplastic islands appear to possess an inherent defect of growth control rendering them more susceptible to endogenous and exogenous growth stimuli. These findings partially explain why the mitogens mentioned induce rapid enlargement of preneoplastic foci and may provide a clue for further studies on the mechanism of tumor promotion in the liver. In addition, the results may form the basis for a short-term test to detect promoting activity of chemical compounds.

Animals↗
PubMed1981

Failure to discriminate initiation from promotion of liver tumors in a long-term study with the phenobarbital-type inducer alpha-hexachlorocyclohexane and the role of sustained stimulation of hepatic growth and monooxygenases.

alpha-Hexachlorocyclohexane (alpha-HCH) was administered p.o. to female Wistar rats for periods of up to 33 months; doses were 20 mg/kg/day, 200 mg/kg every second week, or 420 mg/kg every third week. Increases of liver size, DNA, RNA, and protein (by 50 to 100%) and of drug-metabolizing enzyme activities (up to 300%) observed previously after single doses of alpha-HCH were found to persist after approximately one-third, 1, and 2 years of treatment. At 1 and 2 years, DNA synthesis was measured by [3H]thymidine uptake and was no higher than in controls. All changes regressed upon withdrawal of alpha-HCH after 1 year of treatment. These findings provide no evidence to suggest a protracted development of toxicity or of growth autonomy in the majority of liver cells. Foci of altered cells, neoplastic nodules, and in 2 animals hepatocellular carcinoma were detected histologically in the livers of 24 of 34 treated rats. In livers of 10 of 22 untreated control rats, foci of altered cells developed "spontaneously" between 12 and 34.5 months. If neoplastic lesions were induced by a single dose of diethylnitrosamine, 75 or 150 mg/kg, subsequent treatment with alpha-HCH led to the appearance of hepatocellular carcinoma with 7 months. Altogether, hepatocellular carcinoma within 7 months. Altogether, hepatocellular carcinomas were found in 18 of 21 rats treated with both agents but in only 3 of 26 animals treated with diethylnitrosamine alone. The results show that determination of tumor numbers alone in a long-term animal experiment does not allow one to decide whether alpha-HCH (and similar "xenobiotic inducers") is an initiating carcinogen or merely promotes tumorigenesis from "spontaneous" lesions. Our findings support the latter possibility by the failure to detect evidence suggesting initiating potential of alpha-HCH, by the enhanced mitotic response to alpha-HCH, by the enhanced mitotic response to alpha-HCH in foci of altered cells as reported elsewhere, and by the observation of a permanent stimulatory action on liver growth during prolonged exposure to alpha-HCH.

Animals↗
PubMed1980

Adaptive responses of rat liver to the gestagen and anti-androgen cyproterone acetate and other inducers. I. Induction of drug-metabolizing enzymes.

Treatment of female Wistar rats with cyproterone acetate (CPA) was shown to cause pronounced increases of hepatic microsomal monooxygenase activity towards the following substrates: ethylmorphine (EM), aminopyrine (AP), benzphetamin (BPA) and benzo[a]pyrene (BP). Minor increases were seen using p-nitroanisole (pNA) and aniline (AN). Monooxygenase activity reached maximal levels within 24 h. The effects were dose-dependent, the threshold dose being about 4 mg/kg, and were reversible within 6 days. The results of comparative studies with several 'classical' microsomal enzyme inducers, i.e. pregnenolone-(16 alpha)-carbonitrile (PCN), phenobarbital (PB), alpha-hexachlorocyclohexane (alpha-HCH) and 3-methylcholanthrene (3-MC) suggest that CPA belongs to the PCN-type and alpha-HCH to the phenobarbital type of inducers. In male rats CPA induced only moderate increases of monooxygenase activities which can be explained by decreased testosterone scretion due to anti-gonadotropic effect of CPA.

Adaptation, Physiological↗
PubMed1980

Adaptive responses of rat liver to the gestagen and anti-androgen cyproterone acetate and other inducers. II. Induction of growth.

Treatment of female Wistar rats with cyproterone acetate (CPA) leads to considerable enlargement of the liver. The organ content of water, dry mass, protein, RNA, and DNA increased in parallel with the enlargement; only lipid accumulation showed a slight excess. The changes were maximal after treatment for 3 days and increased in a dose-dependent manner, the threshold dose being 5--10 mg CPA/kg DNA synthesis was strongly enhanced after a lag phase of 12--14 h; a maximal rate of synthesis was attained after 18--24 h. The number of parenchymal cells involved in DNA synthesis and mitosis were increased up to 20-fold. Sinusoidal cells participated only slightly in the growth process, and their number decreased relative to the number of parenchymal cells. These results indicate that CPA induces (presumably adaptive) liver growth essentially by parenchymal hyperplasia; of the model inducers used for comparison only pregenolone-16 alpha-carbonitrile (PCN) produced a similarly strong hyperplastic response while liver enlargement elicited by a alpha-hexachlorocyclohexane (alpha-HCH), phenobarbital (PB) and 3-methylcholanthrene (3-MC) was partly or exclusively due to hypertrophy. Liver growth was also observed in male rats treated with CPA, but was less pronounced in this sex. After discontinuation of treatment, liver enlargement and the increase of DNA regressed partially within 1--3 weeks; this regression seemed to be due to sequestration of old cells which were not involved in replication after CPA treatment. The relationship between induction of liver growth by CPA and hepatoma formation in rats is discussed.

Adaptation, Physiological↗
PubMed1980

Adaptive responses of rat liver to the gestagen and anti-androgen cyproterone acetate and other inducers. III. Cytological changes.

Treatment of rats with cyproterone acetate (CPA) induces liver growth. Intact hepatocytes and cell nuclei were isolated from enlarged livers and their volumes or diameters were determined by electronic and microscopic methods. No changes in mean hepatocyte volume or ploidy were observed. However, there was a marked fall in the frequency of binuclear hepatocytes (from 43% to 7%) and a concomitant increase of nuclear ploidy. This effect probably resulted from CPA-induced replication of binuclear hepatocytes. The total number of hepatocytes replicating in response to CPA was estimated on the basis of these data and was found to be up to 75% of all parenchymal cells. Similar cytological changes were observed in the liver after treatment with pregnenolone-16 alpha-carbonitrile (PCN) and, to a lesser extent, with alpha-hexachlorocyclohexane (alpha-HCH). In contrast, physiological liver growth in adolescent rats was characterized by only small changes in binuclearity and nuclear ploidy, and by increases of cellular ploidy. Thus, ploidy analyses may be a useful tool to characterize the type of growth stimulation. Following discontinuation of treatment the cytological changes induced by CPA or alpha-HCH were not reversible in a matter of 3 weeks.

Adaptation, Physiological↗
PubMed1980

Feedback inhibition of hepatic DNA synthesis.

alpha-Hexachlorocyclohexane (alpha-HCH) and some other xenobiotic inducers were used to elicit adaptive increases in mono-oxygenase activity, size and DNA content of rat liver. After elimination of the inducers, organ size and mono-oxygenase activity returned to normal whereas the DNA content of the liver remained increased. Upon renewed treatment with an inducer the adaptive responses uncoupled. While mono-oxygenase induction and liver enlargement did occur, DNA replication was largely suppressed. These findings show that in the hyperplastic state the liver is resistant to stimulation of DNA synthesis by the inducers. It is concluded that the DNA content of the liver (or the number of liver cells) is controlled by a feedback system which monitors an excess of DNA (cells) and suppresses cell replication if the content of DNA exceeds the normal level. Organ mass has little, if any, effect on the operation of this feedback system.

Animals↗