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PubMed1985

Correlation of results of agglutination assays with concanavalin A and carcinogenesis experiments on promoters of bladder cancer.

The promoting effects of various chemicals and dietary constituents on bladder carcinogenesis were examined by means of a short-term assay, in which maintenance of concanavalin A agglutination of isolated rat bladder cells caused by a subcarcinogenic dose of N-butyl-N-(4-hydroxybutyl)nitrosamine was used as an indicator. Twenty-seven chemicals were examined as possible promoters. Positive results in this assay were consistent with established promoting effects in the cases of sodium saccharin, saccharin, sodium L-ascorbate, sodium cyclamate, DL-tryptophan, butylated hydroxyanisole, butylated hydroxytoluene, L-thioproline and phenacetin. Allopurinol was the only established promoter that gave negative results in the agglutination assay. Thus, this method is useful for rapid evaluation of the specific promoting effect of a chemical on bladder carcinogenesis.

Agglutination Tests↗
PubMedDate not supplied

Sweetening agents from natural sources.

Sweetness is an important taste sensation to humans. The absence of suitable sweeteners as alternatives to cyclamates and saccharin has led to a renewed interest in sweeteners form natural sources. A brief review of the history of sweetener usage provides a basis for understanding our present heavy consumption of sweet substances. The structure of naturally-occurring compounds possessing a sweet taste range from simple sugars to complex, intensely sweet proteins. The structural types include monoterpenes, diterpenes, triterpenes, flavonoids, steroid saponins, dipeptides, and proteins. Some of these substances are not, strictly-speaking, natural but are derived from natural sources by relatively minor chemical modification. The properties of two non-sweet substances, miraculin and gymnemic acid, are included because of their close relationship to the subject of sweeteners. Miraculin causes sour substances to taste sweet and gymnemic acid selectively blocks sweet taste perception. The second part of the paper presents some of the work on monellin, the intensely sweet protein from "serendipity berries" (Dioscoreophyllum cumminsii). The physico-chemical studies of monellin provide convincing evidence that it is, indeed, a protein. Structural studies using denaturants and specific chemical modifications have provided a beginning of our understanding of the molecular basis of the sweet taste of monellin.

Chemical Phenomena↗
PubMedDate not supplied

[Critical test of the activity of tetramisole phosphate on gastrointestinal helminths of sheep].

The phosphate sale of tetramizol assayed in naturally infested sheep by subcutaneous infection at the dosis of 8,66 mg/kg revealed very high efficiency against strongylid gastro-intestinal nematodes; its efficiency was comparable that found by several authors for the hydrochloride and cyclamate salts of the same drug, also by subcutaneious injection, at the dosis of 10 mg/kg. In what concerns helminths belonging to the genera Strongyloides and Capillaria our results were not conclusive enough.

Animals↗
PubMed1984

[Failure to activate Epstein-Barr virus genome in a latently-infected human lymphoblastoid cell line with urine containing a bladder carcinogenesis promoter].

We assessed the possibility to detect promoters of bladder carcinogenesis by a short-term in vitro assay utilizing the activation of Epstein-Barr virus (EBV) expression in EBV genome-carrying human lymphoblastoid cells. This system is composed of EBV-nonproducer Raji cells as the indicator, n-butyrate as the EBV-inducer and the test substance. None of eight known bladder carcinogens (2-naphthylamine, 2-acetylaminofluorene, N-butyl-N-(4-hydroxybutyl)nitrosamine, N-butyl-N-(3-carboxypropyl) nitrosamine, N-methyl-N-nitrosourea, N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide, benzidine, cyclophosphamide) or five promoters (sodium saccharin, sodium cyclamate, urea, allopurinol, DL-tryptophan) were detected by this system. Normal urine from 20 rats did not activate the EBV genome. Neither the 0.45 micron membrane filtrates nor ether extracts of urine obtained from rats given one of 4 bladder carcinogens, 4 promoters or phorbol 12-myristate 13-acetate reacted with this system, whereas those from rats given either vincristine or vinblastine did, although their activity for promoting bladder carcinogenesis is not known. Urine samples from 42 patients with bladder cancers, when tested as filtrates, ether extracts or XAD-2 resin adsorbates, did not activate EBV expression. These results suggest that EBV-activating substances contribute little to promotion of bladder carcinogenesis and that this test might not be applicable for screening of tumor promoters in urine.

Animals↗
PubMed1983

Tumor promoter receptors regulating neurite formation in cultured human neuroblastoma cells.

The mouse skin tumor promoter phorbol-12,13-dibutyrate (PDBU) reversibly enhanced neurite outgrowth in SH-SY5Y human neuroblastoma cells, whether serum was present or absent. The half-maximum response in serum occurred at 10 nM. The binding of [20-3H]phorbol-12,13-dibutyrate [( 3H]PDBU) was studied. Five mouse skin tumor promoters, which included teleocidin, mezerein, and three structural congeners of phorbol, enhanced neurite outgrowth and inhibited binding of [3H]PDBU, but two nonpromoting phorbol congeners did neither. Saccharin and cyclamate, promoters in rat bladder, did not inhibit [3H]PDBU binding. Binding of 10 nM [3H]PDBU at 37 degrees was maximal within 5 min and stable for at least 5 hr. Down modulation of binding was not detected. Following binding at 37 degrees, the dissociation rate in excess PDBU was biphasic, whether measured at 37 degrees or at 4 degrees. The Scatchard curve was also consistent with two types of sites, about 2.5 X 10(5) sites/cell with Kd = 8.5 nM and 1.2 X 10(6) sites with Kd = 125 nM. Negative cooperativity was not observed. In short-term assays, nerve growth factor (NGF) did not alter [3H]PDBU binding, and phorbol ester promoters did not alter 125I-NGF binding. Furthermore, [3H]PDBU binding was unaltered following growth of cells for 1 week in PDBU or NGF, conditions under which neurite outgrowth was continuously enhanced, and other phenotypic expressions of differentiation are known to be increased. Specific [3H]PDBU binding sites were present in five neuroblastoma cell lines, two of which are responsive and three unresponsive by neurite outgrowth to promoters and NGF, suggesting the possibility of a common lesion in distal steps in the unresponsive lines.

Axons↗
PubMed1984

Toxicology of saccharin.

Saccharin, like most of the artificial sweeteners, was discovered quite by accident. The controversy regarding its use as a food additive is reflected by the number of chronic/carcinogenic studies conducted to assess its safety. Two chronic studies were conducted prior to the ban of cyclamates in 1969, at which time 10 additional single-generation studies were initiated using the mouse, rat, and hamster. None of these studies resulted in overt regulatory action. However, subsequent to completion of three two-generation chronic rat feeding studies, saccharin was banned as a food additive in Canada, but a moratorium was placed on its proposed ban in the United States. These events gave rise to a great deal of scientific research into the possible mechanism(s) by which saccharin elicited bladder tumors in rats, and efforts to find epidemiological evidence that saccharin caused cancer in man. At the present time neither effort has produced unequivocal results; however, it seems certain that this latest saccharin controversy may result in changes to the regulations dealing with food additives.

Animals↗
PubMedDate not supplied

Using epidemiology to regulate food additives: saccharin case-control studies.

The increasing use of nonnutritive sweeteners and the widely publicized 1969 ban on cyclamate led to additional investigations in rodents of the carcinogenic potential of saccharin. Preliminary results of a long-term feeding study indicated formation of bladder tumors in rodents, and collective experimental evidence has demonstrated that high doses of the synthetic sweetener saccharin can cause bladder cancer in rodents. Based on the results of that and other rodent studies indicating an increased risk of bladder cancer associated with saccharin, the Commissioner of the Food and Drug Administration announced the agency's intention to propose a ban on saccharin. This intention was made known in April 1977 under the Delaney Clause of the Food, Drug, and Cosmetic Act. The clause essentially states that no additive shall be deemed safe if it is found to induce cancer in man or animals, or if it is found, after tests appropriate for the evaluation of the safety of food additives, to induce cancer in man or animals. Also in 1977, a group of epidemiologists began to assess the available epidemiologic information to determine the potential human risk. This report describes the assessment of several human epidemiologic studies available then and the results of more recent epidemiologic studies.

Epidemiologic Methods↗
PubMed1984

Drugs, food additives and natural products as promoters in rat urinary bladder carcinogenesis.

The promoting effects of various chemicals on urinary bladder carcinogenesis in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were studied. Male Fischer 344 rats were given BBN at 0.01% or 0.05% in their drinking-water for four weeks. One of the following chemicals was then administered in the diet for 32 or 34 weeks: acetazolamide, allopurinol, phenobarbital, phenacetin, ortho-phenylphenol, sodium ortho-phenylphenate, diphenyl, sodium L-ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, sodium saccharin, aspartame, sodium cyclamate, stevioside, DL-tryptophan, quercetin, caffeine, nicotine and hippuric acid. Phenacetin, sodium ortho-phenylphenate, sodium L-ascorbate and butylated hydroxyanisole were significant promoters of urinary bladder neoplasia in rats initiated with BBN. Sodium saccharin, diphenyl, butylated hydroxytoluene, allopurinol, and DL-tryptophan caused moderate or slight promotion of neoplastic changes in the experimental animals. No change in tumour yield was observed after administration of the other chemicals.

Animals↗
PubMed1984

Reduced trisialoganglioside synthesis in chemically but not mos-transformed mouse epidermal cells.

A specific decrease in the net de novo synthesis ([1-14C]-glucosamine incorporation) of cell surface trisialoganglioside (GT) occurs in preneoplastic mouse JB6 epidermal cells in response to tumor-promoting phorbol esters, mezerein, or epidermal growth factor, all of which promote neoplastic transformation in JB6 cells, but not in response to the bladder promoter sodium cyclamate, a nonpromoter in JB6 cells. The ganglioside showing elevated synthesis after mezerein or epidermal growth factor exposure is monosialoganglioside 1, whereas disialoganglioside 1b synthesis is elevated after phorbol ester exposure. Primary mouse epidermal cells and putatively initiated epidermal cell lines selected for their resistance to induction of terminal differentiation by high calcium are resistant to promotion of anchorage-independent transformation by 2-week exposure to 12-O-tetradecanoylphorbol-13-acetate. In both cell types, little or no decrease in GT synthesis occurs in response to short-term 12-O-tetradecanoylphorbol-13-acetate exposure, thus extending further our previous observation that this GT response is restricted to promotable cells. A decreased synthesis of GT also occurs consistently in cell lines transformed by 12-O-tetradecanoylphorbol-13-acetate or N-methyl-N-nitro-nitrosoguanidine as compared with their nontransformed counterparts but not in cell lines transformed by a cloned integrated murine sarcoma provirus containing the oncogenic sequence v-mos. Thus, reduced cell surface GT synthesis may be important both in the induction and in the maintenance of the chemically transformed but not viral oncogene mos-transformed phenotype in mouse epidermal cells.

Animals↗
PubMed1983

[Glycine uptake in brush border vesicles isolated from the rat intestinal cells].

The uptake of glycine in osmotically active brush border membrane vesicles (obtained by the Mg++ precipitation method) has been studied and a partial characterization of its transport system has been established. The glycine uptake in these vesicles was stimulated by the presence of sodium and in the presence of an inwardly directed Na+ -gradient glycine was accumulated inside the vesicles. The effect of Na+ was specific; other monovalent cation as Li+, K+, Rb+ and choline were uneffective in the stimulation of glycine uptake, under the same experimental conditions. Preliminary experiments show an important role of some anions on the glycine uptake. A strong inhibition in the uptake rate was found when the measurements were carried out in the presence of sodium cyclamate, while in the presence of NaSCN the measured uptake values were similar to those observed in the presence of NaCl.

Animals↗
PubMed1981

Urinary bladder carcinogenesis with N-substituted aryl compounds: initiation and promotion.

Aromatic amines have been implicated in the etiology of bladder cancer in humans since Rehn observed the disease in 3 workers in the German aniline dye industry in 1895. 2-Naphthylamine was identified 40 years later as one of the carcinogens in tests involving the feeding of the chemical to dogs. The discovery of N-2-fluorenylacetamide as a carcinogen in rodents inducing tumors of the bladder and other organs provided a more inexpensive and rapid model for the study of bladder carcinogenesis. The metabolic activation pathways of aromatic amine and amide compounds has been extensively examined. In the 1960's, organ-specific rodent models were discovered with the use of N-butyl-N-(4-hydroxybutyl) nitrosamine, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, or N-methyl-N-nitrosourea. Recent experiments have demonstrated that bladder carcinogenesis can be divided into two stages similar to the initiation-promotion model in mouse skin. Possible promoters have included sodium saccharin, sodium cyclamate, and tryptophan. Certain metabolites of the latter compound are also N-substituted aryl compounds. Lastly, recent studies of the relationship of urine to the carcinogenic process in the bladder indicate that it can act as a promoting agent as well as a carrier of carcinogenic substances.

Amines↗
PubMed1994

[Does the diabetic patient need special diabetic food?].

At present the diet recommended by the Czech Diabetological Society does not fundamentally differ from the diet recommended to the population of the Czech Republic as a whole. The diet must contain high-fibre foods, provide 55% of the energy as carbohydrates, 30% of the energy should be derived from fats and the protein content should be less than 1 g of protein per kg body weight. The cholesterol intake should not exceed 300 mg/day. The system of intensified insulin therapy made a flexible schedule time, of food intake for type I diabetics possible. For diabetics type II the basic provision is a low energy diet which leads to body weight reduction, as the great majority of these patients is overweight. Products described as "dia" or products where on the wrapping it is maintained that they are suitable for diabetics can be divided into two groups, depending on the sweetener used. Products containing non-caloric sweeteners (saccharin, aspartam, acesulfam or so far not permitted cyclamate) have a markedly reduced energy content and are thus suitable in particular for type II diabetics. Products sweetened with fructose, xylitol, sorbitol have as a rule the same or a similar energy values as sucrose containing products and are of no advantage for diabetics type II who are frequently obese. This is why it will be useful to abandon labelling such as "dia-product" or "product suitable for diabetics". This description should not be permitted and the term "low-energy food" should be used. It will be necessary to define precise criteria for these foodstuffs.

Diabetes Mellitus↗
PubMed1994

Two isoforms of a chloride channel predominantly expressed in thick ascending limb of Henle's loop and collecting ducts of rat kidney.

Complementary DNAs encoding rat kidney chloride channels (ClC-K2L and ClC-K2S) were isolated by a polymerase chain reaction cloning strategy. Degenerate primers were designed based on the significant amino acid identity of the previously cloned chloride channels (ClC-0, -1, -2, and -K1). The 687-amino acid protein encoded by ClC-K2L is about 80% identical to rat ClC-K1 and about 40% identical to ClC-0, -1, and -2. ClC-K2S encodes a 632-amino acid protein in which 55 amino acids containing the putative second membrane-spanning domain of ClC-K2L are deleted. Chloride currents induced by both clones were very similar in terms of inhibitor sensitivity and anion selectivity (Br- > I- > Cl- >> cyclamate-). Northern blot with total ClC-K2L as a probe under high stringency revealed its message predominantly in kidney, especially in the outer and inner medulla. Reverse transcription polymerase chain reaction technique using microdissected nephron segments revealed that the main site of expression of both clones in kidney was the thick ascending limb of Henle's loop and collecting ducts, where the existence of a variety of chloride channels and their importance for maintaining body fluid homeostasis have been demonstrated. These results suggest that ClC-K2L and -K2S are chloride channels in the thick ascending limb and collecting ducts and may be important routes for transcellular chloride transport like ClC-K1.

Amino Acid Sequence↗
PubMedDate not supplied

[Clastogenic activity of dietary sugar substitutes].

The present paper describes the possible clastogenic activity of the following synthetic sugar substitutes, such as cyclamate in daily doses of 11 and 110 mg/kg, saccharin, 5 and 50 mg/kg, acesulfam, 15 and 150 mg/kg, sucralose, 15 and 150 mg/kg, aspartame, 40 and 400 mg/kg, orally given to C57Bl/6 mice during 5 days. No clastogenic activity was found in the compounds tested.

Animals↗
PubMed1995

Laparoscopy as a means of monitoring liver tumor induction in nonhuman primates.

Nonhuman primates are not commonly used in the study of carcinogenesis. For several years, the National Cancer Institute (NCI) has funded a large study to evaluate the relative susceptibility of primates to the effects of several known rodent carcinogens, various cancer chemotherapeutic agents, and several food additives/contaminants, such as cyclamate, saccharin, and aflatoxin. The current colony is comprised of over 300 macaque monkeys which have received a particular test material beginning shortly after birth and continuing for periods of at least 10 years or until tumor is detected. In 1985, a study of the potential carcinogenic effect of the heterocyclic aromatic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), was initiated. Subsequently, studies on two other heterocyclic aromatic amines were initiated, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx) in 1988 and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in 1990. Tumors have been induced thus far only by IQ, and this data will be presented by Dr. Richard Adamson, while the detailed pathology of the neoplasms will be presented by Dr. Unnur Thorgeirsson. Palpation of the liver and monitoring of liver enzymes are not effective means for detecting early evidence of liver tumor. Laparoscopy, on the other hand, can be done easily and quickly and is an effective means of visualizing the liver and for obtaining samples of liver and suspected tumor tissue. Repeated laparoscopic examinations using videotape to document the size, location, and appearance of developing tumors allow more precise monitoring of the carcinogenic process.

Animals↗
PubMed1998

Synthesis and biological activity of chelator-peptide T conjugates.

The solid phase procedure was used to prepare two peptide T derivatives in which the 4-[(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]benzoyl unit is linked to their N-terminus. In a human monocyte chemotaxis assay, both chelator-peptide conjugates showed a high binding property to the CD4 receptor, comparable to the parent H-D-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH2 and its pentapeptide fragment T(4-8)-NH2. These encouraging results make the above cyclam-oligopeptides candidates for the development of the CD4 receptor imaging agents.

Amino Acid Sequence↗
PubMed1999

Angiotensin II stimulates macula densa basolateral sodium/hydrogen exchange via type 1 angiotensin II receptors.

Angiotensin II (AngII) enhances tubuloglomerular feedback responses and is considered to be a specific modulator of feedback activity. The sites at which AngII interacts with the signal transmission process remain unknown. In certain renal epithelia, AngII stimulates Na/H exchange activities. Evidence for the regulation of macula densa apical Na/H exchange by AngII was recently reported. Because macula densa cells also express a basolateral Na/H exchanger, the possibility that AngII stimulates this exchanger activity was investigated. In preparations of isolated perfused thick ascending limb with attached glomerulus dissected from rabbit kidney, the intracellular pH (pHi) of macula densa cells was measured with fluorescence microscopy using 2',7'-bis(2-carboxyethyl)-5-(and -6)carboxyfluorescein. Perfusion and bathing solutions were iso-osmotic Cl-free Ringer's solutions modified using N-methyl-D-glucamine and cyclamate as the Na and Cl substitutes, respectively. Control pHi, during perfusion with 0 mM Na and 150 mM Na in the bath, averaged 7.21+/-0.07 (n=10). Removal of Na from the bath (i.e., basolateral solution) decreased pHi by 0.39+/-0.06 units (n=5, P < 0.01). Addition of 10(-9) M AngII to the bath resulted in a significant increase in the Na-dependent acid load. This increase in Na-dependent cell acidification was completely blocked by coadministration of the AngII type 1 (AT1) receptor blocker candesartan (10(-8) M). In addition, AngII increased the rate of pHi recovery from the acid load induced by readdition of bath Na. This stimulatory effect of AngII was also completely reversed by coadministration of the AT1 receptor blocker candesartan. These results indicate that AngII stimulates macula densa basolateral Na/H exchange via AT1 receptors and therefore may affect tubuloglomerular feedback signal transmission, at least in part, through direct effects on macula densa transport processes.

Angiotensin II↗