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J Schuppler

Publications and source records attributed to J Schuppler.

At least 19 recordsLinked to original sources
PubMed1990

Toxicological studies on a benzofurane derivative. I. A comparative study with phenobarbital on rat liver.

The benzofurane derivative benzbromarone (BBR) previously has led to liver tumor formation after long-term treatment of rats, but no indications of genotoxicity were detected. The present studies were designed to elucidate the mechanism(s) possibly involved in liver tumor formation by BBR. Female Wistar rats were used. Phenobarbital (PB) served as a positive control. (1) Short-term treatment (7 days) with daily doses of 2 to 100 mg/kg BBR led to adaptive responses in the liver, i.e., growth (increases in DNA, RNA, and protein) and induction of monooxygenases. These changes were also observed after feeding BBR for 8, 33, 77, and 102 weeks at doses of 2, 10, and 50 mg/kg/day but tended to weaken with time. Similar effects were obtained with PB fed at 2, 10, or 50 mg/kg/day. However, unlike PB, BBR did not enhance the expression of cytochrome P450-PB as demonstrated by immunostaining of histological liver sections. (2) BBR feeding for 102 weeks, but not for 77 weeks, produced some neoplastic liver nodules and at 50 mg/kg produced one hepatocellular carcinoma (HCC). Thus, BBR was tumorigenic in the present study, but was clearly weaker than PB which had induced liver nodules and HCCs at 77 weeks and even more markedly at 102 weeks. (3) To check for tumor-initiating activity 100 mg/kg BBR was given 14 hr after a two-thirds hepatectomy followed by promotion with PB (50 mg/kg) for 15 weeks. No phenotypically altered liver foci were detected. (4) To test for tumor-promoting activity rats received a single dose of N-nitrosomorpholine (250 mg/kg), and subsequently BBR or PB at doses of 2, 10, and 50 mg/kg/day. While PB markedly enhanced the development of neoplastic nodules and HCCs, BBR had only a weak enhancing effect on the induction of HCC, which was not dose related. gamma-glutamyl transpeptidase-positive foci dramatically increased in PB-treated animals, in contrast they showed no response after 2 and 10 mg/kg BBR and even decreased after 50 mg/kg BBR. (5) With PB changes in liver growth, monooxygenase activity, foci expansion, and tumor promotion all correlating with tumorigenesis in a quantitative manner, apparent no-observed-effect-levels are somewhat below 2 mg/kg (or 10 mg/kg for liver enlargement). (6) These studies suggest that BBR belongs to a group of nongenotoxic, growth-stimulating drugs with tumorigenic potential in rat liver. Its effects on the liver are different from those of PB, but seemed to resemble those of peroxisome proliferators, a hypothesis studied in the subsequent papers.

Animals↗
PubMed1986

Facilitated expression of adaptive responses to phenobarbital in putative pre-stages of liver cancer.

Female rats received N-nitrosomorpholine to produce altered cell foci (potential cancer pre-stages) in the liver, followed by phenobarbital (PB) for 2 weeks. As indicators of adaptive responses we measured DNA synthesis cumulatively by infusion of [3H]thymidine for the entire period of PB treatment, and cytochrome P450-PB by immunocytochemistry on histological liver sections. Altered cell foci were identified by expression of gamma-glutamyltransferase (gamma-GT), and/or altered morphology. The following results were obtained. In normal parts of the liver PB induced DNA replication only in association with expression of P450-PB; both responses were restricted to the pericentral area of the liver lobule. In foci, PB treatment led to enhanced DNA synthesis. Furthermore, PB caused a 3-fold increase in the number of foci expressing cytochrome P450-PB, gamma-GT or both. Cumulative determination of DNA synthesis showed that this increase did not result from selective proliferation of single initiated cells. It is concluded that in foci also PB can induce expression of the adaptive increases in cytochrome P450-PB and DNA synthesis. Foci show the responses to PB more readily than normal hepatocytes, and irrespective of their position within the liver lobule. These findings suggest that expression of adaptive responses to inducing tumor promoters is facilitated in altered foci.

Adaptation, Physiological↗
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

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↗
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↗
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↗
PubMed1977

Effect of cyproterone acetate on prolactin secretion in the female Rhesus monkey.

Adult female rhesus monkeys were given cyproterone acetate orally in doses of 0.04, 0.4, 4 and 40 mg per kg per day for 12 weeks. Its effects were assessed on serum prolactin (PRL) concentration, the morphology of the PRL cells, and the development of the mammary glands. Serum PRL was relatively unchanged in the control animals from the fourth through the twelfth weeks of the study. In contrast, PRL was significantly elevated in each group of drug-treated animals during the same time periods. There was no development of the mammary glands nor was there any evidence of milk secretion in the control animals; however, in the monkeys given cyproterone acetate the mammary glands had extensive lobuloalveolar growth and milk-like secretion that could be expressed as early as the fourth or fifth week of the study. By immunocytochemistry and differential light microscopic staining techniques, the PRL cells in the pituitary glands of the experimental animals were found to be more numerous and much larger than those present in the controls. They displayed a well developed Golgi complex and had an abundance of cytoplasmic RNA. These data suggest that PRL secretion is markedly enhanced by cyproterone acetate.

Animals↗