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1. [(14)C]Cyclamate was not metabolized when incubated with the liver, spleen, kidney or blood of rats of rabbits kept on a cyclamate-containing diet, and that had become converters of cyclamate into cyclohexylamine. 2. [(14)C]Cyclamate was converted into cyclohexylamine when incubated under anaerobic conditions with the contents of the caecum, colon or rectum or with the faeces of cyclamate-pretreated rats. Similar results were obtained with cyclamate-pretreated rabbits. With cyclamate-pretreated guinea pigs, which did not readily convert cyclamate into cyclohexylamine, the colon contents showed only low activity in this respect. 3. The faeces of a human converter of [(14)C]cyclamate into cyclohexylamine were also very active, but became less active when cyclamate was removed from his diet. 4. On subculturing the organisms from the contents of the colon and rectum of rats, the ability to convert cyclamate into cyclohexylamine was lost during three subcultures, but the loss of the activity was considerably decreased by subculturing in the presence of cyclamate. 5. Incubation of rat faeces in broths containing cyclamate increased their ability to metabolize cyclamate, but similar treatment of rabbit and human faeces suppressed this activity. 6. When rats are kept on a cyclamate diet the number of clostridia in the faeces increased considerably. In human dietary cyclamate did not appear to alter the counts of various faecal micro-organisms. 7. The gut organisms that appear to develop the ability to convert cyclamate into cyclohexylamine are clostridia in rats, enterobacteria in rabbits and enterococci in man. 8. [(14)C]Cyclohexylamine injected into the caecum or colon of rats is readily absorbed and excreted in the urine. 9. It appears that on continued intake of cyclamate the gut flora develop the ability to convert cyclamate into cyclohexylamine, which is then absorbed and excreted mainly in the urine, although a small proportion is metabolized to other compounds.
1. (14)C-labelled cyclamate has been administered to guinea pigs, rabbits, rats and humans. When given orally to these species on a cyclamate-free diet, cyclamate is excreted unchanged. In guinea pigs some 65% of a single dose is excreted in the urine and 30% in the faeces, the corresponding values for rats being 40 and 50%, for man, 30-50% and 40-60%, and for rabbits, 90 and 5%, the excretion being over a period of 2-3 days. 2. Cyclamate appears to be readily absorbed by rabbits but less readily by guinea pigs, rats and humans. 3. If these animals, including man, are placed on a diet containing cyclamate they develop the ability to convert orally administered cyclamate into cyclohexylamine and consequently into the metabolites of the latter. The extent to which this ability develops is variable, the development occurring more readily in rats than in rabbits or guinea pigs. In three human subjects, one developed the ability quite markedly in 10 days whereas two others did not in 30 days. Removal of the cyclamate from the diet caused a diminution in the ability to convert cyclamate into the amine. 4. In rats that had developed the ability to metabolize orally administered cyclamate, intraperitoneally injected cyclamate was not metabolized and was excreted unchanged in the urine. The biliary excretion of injected cyclamate in rats was very small, i.e. about 0.3% of the dose. 5. The ability of animals to convert cyclamate into cyclohexylamine appears to depend upon a continuous intake of cyclamate and on some factor in the gastrointestinal tract, probably the gut flora.
PHA-stimulated human peripheral lymphocytes were used as a model system for assessing the in vitro effects of calcium cyclamate. Techniques of autoradiography, cytological staining, cell counting, liquid scintillation and karyotyping were used to study the cytogenetic damage and biochemical effects of calcium cyclamate when assayed in 24 hour intervals for 96 hours. The cells were exposed to 10(-2) and 10(-3) molar concentrations of calcium cyclamate in TC 199 medium with fetal calf serum and antibiotics. These studies were carried out in three (3) phases. Phase I was primarily orientation studies of the effects of cyclamates and included running preliminary test checks, the establishment of parameters of dosage, assessing growth patterns and selecting key chromosomal aberrations. Sixty four (64) of the metaphase spreads showed morphologically detectable changes and aberrations. It was also noted that the addition of cyclamate increased mitotic rate of lymphocyte cells in cultures. Phase III arranged research designs to determine more precise characterization of chromosomal observations and morphological effects. Among other findings it was noted that of 13 types of observations only ten were found in the experimental group. The introduction of cyclamates increased the stability of the leucocyte cultures. These studies reinforced the findings on the increase of mitotic rate. Phase III extended protocols to include autoradiography and scintillation counting. It was determined that calcium cyclamate impaired the synthesis of deoxribonunucleic acid (as depicted by decreased incorporation of tritiated thymidine), reduced grain counts in autoradiographs and increased chromosome aberrations in cyclamate treated PHA stimulated peripheral blood lymphocytes in vitro. Morphological changes and growth rates showed significant effects. These studies indicate that calcium cyclamate has variable significant effects on leucocytes growth and chromosome morphology.
The present experiments were designed to assess whether caffeine, a substance that potentiates human perception of some artificial sweeteners, might also enhance perception of such substances by rats. In Experiment 1, rats were given varied concentrations of saccharin, cyclamate, and caffeine in 2-choice tests. 'Indifference thresholds' for these substances were 3.9 X 10(-4) M, 1 X 10(-3) M, and 1.6 X 10(-7) M, respectively. In Experiment 2, concentrations of saccharin and cyclamate just above and below indifference were used as stimuli in a flavor avoidance learning (FAL) paradigm. 'Suprathreshold' concentrations of saccharin and cyclamate produced reliable FAL while 'subthreshold' concentrations did not. In Experiment 3, rats were exposed to a low concentration of caffeine followed by presentations of subthreshold concentrations of saccharin or cyclamate as stimuli in a FAL paradigm. Saccharin FAL was observed but cyclamate FAL was not, suggesting that caffeine preexposure selectively potentiated detection of saccharin. In Experiment 4, animals were given saccharin or cyclamate with or without prior exposure to caffeine in a FAL paradigm. During subsequent tests, animals were presented with saccharin or cyclamate following exposure to caffeine saccharin or cyclamate mixed with caffeine saccharin or cyclamate alone. Saccharin FAL was observed following caffeine preexposure, but mixing with caffeine had no effect. These findings of selective potentiation are consistent with previous studies of human sensitivity after caffeine preexposure. Moreover, the present results support the notion that inhibitory A1 adenosine receptors are involved in modulating the perceived intensity of some flavors.
A group of 194 diabetic patients were given calcium cyclamate (1 g/day as cyclamic acid equivalents) for a period of 7 days. Blood and urine samples were collected to determine the formation of cyclohexylamine, which is an indirectly acting sympathomimetic amine. Blood pressure and heart rate were recorded before and after treatment. Urine samples were collected each day and analyzed for cyclamate (to check compliance) and cyclohexylamine (to monitor the development of metabolizing activity). After 7 days intake most individuals (78%) did not excrete significant amounts of cyclohexylamine (less than 0.1% of the daily dose of cyclamate) but a small number (8; 4% of the group) excreted more than 20% of the daily dose as cyclohexylamine in the urine. Similar interindividual variations were found in the plasma concentrations of cyclohexylamine after 7 days intake of cyclamate, with 8 individuals having concentrations of 300-1942 ng/ml. The changes in cardiovascular parameters in these 8 subjects between pre- and postdosing were similar to those found in 150 subjects with plasma cyclohexylamine concentrations less than 10 ng/ml. Twenty of the subjects were restudied after receiving calcium cyclamate for 2 weeks at a daily dose equivalent to 2 g of cyclamic acid (0.66 g tds). Plasma concentrations of cyclohexylamine, heart rate, and blood pressure were measured every 30 min for a period of 8 hr (one dose interval) after the final dose. Twelve patients had plasma concentrations of cyclohexylamine greater than 10 ng/ml (89-2043 ng/ml) at the start of the dose-interval investigations. There were no transient increases or decreases in plasma concentrations of cyclohexylamine which might have resulted in a transient change in blood pressure or heart rate. These data indicate that the metabolism of cyclamate (2 g/day) to cyclohexylamine would not affect blood pressure or heart rate even in individuals with high metabolizing ability.
Sodium cyclamate is an effective artificial sweetner, which has been banned from the U.SD. market because of alleged carcinogenic properties. It appears that cyclohexylamine, liberated from cyclamate as a result of bacterial mtabolism, is the proximate carcinogen. In an effort to elucidate the extent to which analogues of cyclamate would enter into the bacterial metabolic pathway, as well as any stereochemical requirements which might exist, several 2-alkaly analogues of sodium cyclamate were prepared. It was found that trans-N-(2-methylcyclohexyl)sulfamate (trans-2a) and trans-N-(2-ethylcyclohexyl)sulfamate were hydrolyzed by freshly collected fecal suspensions from rats fed cyclamate, but not from control rats, at the same rate as cyclamate itself. trans-N-(2-Isopropylcyclohexyl)sulfamate (trans-2c) was not hydrolyzed at all. Surprisingly, two of the analogous cis compounds (cis-2a and cis-2c, respectively) were hydrolyzed by fecal suspensions from control, as well as from cyclamate-fed, rats. Moreover, cis-2a was hydrolyzed by incubating it in medium only. Thus, it is apparent that stereochemical influences on the chemical properties of these compounds are substantial. These results do not appear to point the way toward a safe, nonmetabolizable sweetening agent.
The mechanism underlying the Na channel blocking action of guanidyl-side armed cyclam (G-cyclam) was studied using conventional patch-clamp methods. G-cyclam applied to the cytoplasmic surface of the membrane reduced the amplitude of single Na channel currents without inducing a flickering block. This effect was enhanced by depolarization and was fully reversible upon washout of the drug. The relationship between the concentration of G-cyclam and the reduction of unitary current could be expressed mathematically assuming one-to-one stoichiometry. During maximal suppression of the single channel current by G-cyclam approximately 40% of the current remained. Low concentration of G-cyclam (3 x 10(-4) M) prolonged, while higher concentration (3 x 10(-3) M) shortened the mean open time suggesting the involvement of two processes in the Na channel blocking action of this agent. It appears that low concentration of G-cyclam induce rapid and frequent transition between open and less conductive state resulting in a reduced current, and higher concentration make the channel nonconductive with slower single channel kinetics.
The direct effects of sodium saccharin and sodium cyclamate on the morphology of organ cultures of normal rat bladder have been studied by histology and scanning electron microscopy (SEM). Untreated cultures retained histologically normal urothelia up to 89 days with cell surface features characteristic of mature, fully differentiated superficial cells and maturing intermediate cells. Continuous treatment with either sodium saccharin (6 or 12 mM) or sodium cyclamate (12 or 24 mM) induced progressive abnormalities in the cultured urothelium. Acute toxicity was not seen but focal necrosis was observed with the higher dose of each compound and histological abnormalities were more severe with the higher doses. Sodium saccharin induced mild hyperplasia of the urothelium on the surface of the culture and foci of altered epithelial polarity from 14 days; abnormal nuclear staining plus changes in the basal lamina were evident from 28 days and were pronounced from 56 days onwards. Hyperplasia of the urothelium over the explants was mild but there were extensive epithelial outgrowths onto the culture support. In general, sodium cyclamate induced more severe changes than did sodium saccharin, with alterations in epithelial cell polarity plus basal cell changes from 14 days and focal nodular urothelial hyperplasia over the explant and gross hyperplasia between the explant and culture support and in the outgrowth from 28 days. The severe and rapid surface changes, evident by SEM, were similar both in saccharin-treated and in cyclamate-treated cultures. There was some early loss of superficial cells to reveal underlying immature cells which, together with the remaining mature cells, developed abnormal blebs and processes. From 14 days small immature cells were located at the culture surface between the mature cells. These were covered by a variety of membrane protrusions including long pleomorphic microvilli. Sodium cyclamate-treated cultures mostly had fewer small membrane protrusions than sodium saccharin-treated cultures but more pleomorphic microvilli. These morphological changes induced in the rat urothelium in vitro by direct treatment with sodium saccharin and sodium cyclamate are thus similar to those described previously in association with in vivo long-term feeding studies of sodium saccharin to rats and with both in vivo and in vitro treatment of the rat urothelium with the bladder carcinogen N-methyl-N-nitrosourea (MNU).
In the late 1960s the artificial sweetener cyclamate was implicated as a bladder carcinogen in rats. This finding and other concerns about its safety ultimately led to a ban on cyclamate in the U.S. and restrictions on its use in many other countries. Since that time, the carcinogenic potential of cyclamate and cyclohexylamine, its principal metabolite, has been reevaluated in a group of well-controlled, well-designed bioassays that have failed to substantiate the earlier findings. This review of the published and unpublished literature on cyclamate attempts to evaluate the carcinogenicity question and other important aspects of the toxicity of cyclamate and cyclohexylamine, including their effects on various organ systems, their genotoxic potential, and their effects on reproduction. In addition, the physiological disposition of cyclamate is reviewed, with particular attention directed toward the site and extent of its conversion to cyclohexylamine.