retinol-acetate and Body-Weight

Relationships between increased adiposity and fat-soluble vitamin storage and metabolism are poorly understood. To examine these associations, 6% or 21% dietary fat was fed to rats for 11 weeks and tissue vitamin A storage determined. Two levels of supplemental vitamin A were administered. At the end of the tenth week, 3,4-didehydroretinol (DR) was administered orally, and its kinetics were followed for 1 week in serum and tissues. Model-based compartmental analysis was applied to these data. Kidney total retinol (R) concentrations were elevated in rats fed 6% compared with 21% dietary fat (n = 24/group). The fractional transfer coefficient (FTC) describing the movement of tracer from plasma to extravascular stores was two times higher in the 6% compared with the 21% fat group. Consistent with the elevated renal R in 6% fat fed rats, there was a 2-fold increase in the FTC representing tracer distribution from plasma to kidney in the 6% compared with 21% fat group. Taken together with a fat main effect on renal vitamin A, our data support the evidence that faster turnover of kidney R may help set the mechanism governing vitamin A tissue distribution during deficiency. Rats fed 21% versus 6% dietary fat conserved hepatic R more efficiently.

Topics: Adipose Tissue; Adiposity; Animals; Body Weight; Dietary Fats; Diterpenes; Liver; Male; Models, Biological; Obesity; Rats; Rats, Sprague-Dawley; Retinoids; Retinyl Esters; Vitamin A; Vitamin A Deficiency

To establish the pathophysiology of retinoid induced hyperostosis.. Radiographical, histological, ultrastructural, and immunohistochemical features of retinoid induced hyperostosis were evaluated using C3H-Heston mice and Balb mice.. Dose dependent and progressive ossification was noted at extraosseous sites of both mouse strains. New bone formation was seen not only in the extraosseous tissues, but subchondral bone showed prominent proliferation. Major histopathological abnormalities appeared to take place in the chondrocytes near the osteochondral junctions, and some of the metaplastic chondrocytes near the osteochondral junction expressed osteocalcin and type I collagen, extracellular molecules normally present in bone. Species dependent responsiveness was also noted.. Longterm administration of retinoids may induce an aberrant differentiation of the articular and entheseal chondrocytes near the osteochondral junctions, and the affected cells appeared to produce extracellular components including osteocalcin and type I collagen.

Topics: Animals; Body Weight; Cell Division; Chondrocytes; Collagen; Diterpenes; Hyperostosis; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Ossification, Heterotopic; Osteocalcin; Radiography; Retinoids; Retinyl Esters; Vitamin A

Decreased plasma concentrations of vitamin A (retinol) and retinol-binding protein have been previously identified in human subjects with type I diabetes mellitus. The present study was undertaken to investigate the effects of streptozotocin-induced diabetes in rats of three different strains including Wistar Furth, Sprague Dawley and Wistar, on plasma and liver concentrations of vitamin A. The diabetic animals gained less weight than nondiabetic controls even though they ate 50% more food. The hepatic vitamin A concentration was increased at three weeks after the onset of diabetes in all three strains of rats but the magnitude of increase was greater in Wistar than either Wistar Furth or Sprague Dawley rats. This increased storage of vitamin A in diabetic animals most likely is due to increased food intake. The plasma concentrations of vitamin A, on the other hand, remained unaffected in Wistar Furth and decreased moderately (P < 0.02) in Sprague Dawley but severely (P < 0.0001) in Wistar rats. The fact that the plasma vitamin A levels in diabetic Wistar and Sprague Dawley rats were markedly reduced despite their increased hepatic store suggest an impairment in the transport of vitamin A from the liver. The circulatory levels of vitamin A in Wistar rats are more sensitive to the diabetic state, which is in agreement with those observations seen in diabetic patients. Because of this similarity, it is reasonable to suggest that Wistar should be the choice of rat strain for future experimental studies involving vitamin A and diabetes relationships.

Topics: Animal Feed; Animals; Blood Glucose; Body Weight; Chromatography, High Pressure Liquid; Diabetes Mellitus, Experimental; Disease Models, Animal; Diterpenes; Eating; Glycosuria; Liver; Male; Rats; Rats, Inbred Strains; Rats, Inbred WF; Rats, Sprague-Dawley; Rats, Wistar; Retinyl Esters; Vitamin A

The effect of vitamin A deficiency and vitamin A replacement on spermatogenesis in golden hamsters was studied using a light microscope. Male golden hamsters were fed a vitamin A deficient (VAD) diet from 3 weeks of age. Hamsters with a VAD diet reached maximum body weight at about 13 weeks. After 17 weeks, the body weight of the hamsters began to decrease. When their body weight decreased to 70 g, only Sertoli cells, spermatogonia, and a few spermatocytes were present within the seminiferous tubules. Administering retinol acetate (vitamin A) combined with a conventional diet to the VAD hamsters induced a reinitiation of spermatogenesis with stage-synchronization. At 9, 10, and 11 weeks after vitamin A replacement, the testes with active spermatogenesis possessed only a few successive stages of the seminiferous epithelial cycle.

Topics: Animals; Body Weight; Cell Cycle; Cricetinae; Diterpenes; Epithelium; Male; Mesocricetus; Reference Values; Retinyl Esters; Seminiferous Tubules; Sertoli Cells; Spermatocytes; Spermatogenesis; Spermatogonia; Vitamin A; Vitamin A Deficiency

The chemopreventive actions of sodium selenite (SS), magnesium chloride (MC), ascorbic acid (AA) and retinyl acetate (RA), given singly or in combinations, on mammary carcinogenesis induced by 30 mg of 7,12-dimethylbenz[a]anthracene (DMBA) in female adult rats were evaluated. Administration of modulators was carried out from the age of 40 +/- 3 days to 240 +/- 3 days. When DMBA alone was given 100% of the rats developed mammary tumors. When modulators were given singly the tumor incidences were reduced to 51.77% (SS), 46.4% (MC), 57.1% (AA) and 48.1% (RA). When the modulators were given in combination of twos, the tumor incidences were further reduced to 29.5% (SS + MC), 31% (SS + AA), 29.6% (SS + RA), 25.9% (MC + AA), 31.8% (MC + RA) and 34.6% (AA + RA). Administration of modulators in combinations of threes resulted in still further reduction of tumor incidences to 22.2% (SS + MC + AA), 19.2% (SS + MC + RA), 16% (MC + AA + RA) and 23.1% (AA + RA + SS). When all four modulators were given concurrently the tumor incidence was only 12%. Further, the number of tumors per tumor-bearing animal declined with the increase in the number of agents used in combination for modulation.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Adenofibroma; Animals; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Body Weight; Diterpenes; Drug Administration Schedule; Female; Magnesium Chloride; Mammary Neoplasms, Experimental; Rats; Retinyl Esters; Selenic Acid; Selenium; Selenium Compounds; Vitamin A

Vitamin A inhibits the development of some chemically-induced tumours. Since polybrominated biphenyls (PBBs) are hepatic tumour promoters and they affect vitamin A homeostasis in rats, we put forward the hypothesis that dietary levels of vitamin A would influence tumour promotion by PBBs. In the study described here, female Sprague-Dawley rats were initiated on day 1 by ip administration of diethylnitrosamine. On day 7 after initiation, the rats were fed a vitamin A-deficient basal diet that was supplemented with either 2000 IU (low-vitamin A) or 200,000 IU (high-vitamin A) retinyl acetate/kg feed. From day 30 after initiation until the end of the study the following PBBs were added to the diets: Firemaster BP-6 (10 ppm), 2,4,5,2',4',5'-hexabromobiphenyl (10 ppm) or 3,4,5,3',4',5'-hexabromobiphenyl (1 ppm). The control animals received low- or high-vitamin A diets containing no PBBs. On day 180, the rats were necropsied, sections of various tissues were stained for histopathological examination and an evaluation of hepatic enzyme-altered foci was performed. Numbers of gamma-glutamyl transpeptidase-positive foci/cm3 liver and the mean volumes of these foci were lower in the high-vitamin A groups than those in the corresponding low-vitamin A groups, but these differences were not significant. The percentage of the liver volume occupied by foci was significantly greater in the low-vitamin A with 345-HBB group than in the corresponding high-vitamin A group. Thus, high dietary levels of vitamin A had some inhibitory effect on the promotion of hepatic-altered foci by 345-HBB in initiated rats.

Topics: Animals; Body Weight; Diet; Diterpenes; Female; Liver; Liver Neoplasms, Experimental; Polybrominated Biphenyls; Rats; Rats, Inbred Strains; Retinyl Esters; Vitamin A

Menhaden oil, which has hypolipidemic and anticarcinogenic activity, reduces the hypertriglyceridemia caused by retinyl acetate. Male Sprague-Dawley rats were dosed daily for 30 days by gavage with either corn oil (CO); menhaden oil (MO); 20, 80, and 250 mg/kg retinyl acetate (ROAc) in CO; or 20, 80, or 250 mg/kg ROAc in MO. Hypertriglyceridemia by ROAc was reduced by coadministration of MO, and serum cholesterol values were reduced to levels similar to those for rats receiving MO alone. Coadministration of MO reduced the ROAc-induced fracture incidence at 80 mg/kg but not at 250 mg/kg. For groups dosed with ROAc and CO or MO, there were no differences in weight-gain depression, elevation of serum alkaline phosphatase, or reduction of food consumption, suggesting that reduced absorption of ROAc was not the basis for the activity of MO. The reduction in retinoid toxicity by MO suggests a need for further study of the toxicity and anticarcinogenicity of retinoid/menhaden oil combinations.

Topics: Alkaline Phosphatase; Animals; Body Weight; Cholesterol; Cytoplasm; Diterpenes; Eating; Fish Oils; Jejunum; Male; Rats; Rats, Inbred Strains; Retinyl Esters; Triglycerides; Vitamin A

Two groups of female ACI rats were placed on powdered AIN-76 diets containing retinyl acetate (412,000 i.u. per kg diet) and two groups of rats were placed on placebo diets. Two weeks later one group from each diet was subcutaneously implanted with a 20 mg pellet containing 1 mg of 17 alpha-ethinylestradiol (EE2) mixed with cholesterol, and the remaining groups received 20 mg cholesterol pellet implants. The four groups of animals were maintained on their respective diet for 24 weeks after pellet implantation. The EE2-treated rats were hyperphagic and weighed less than the cholesterol-treated rats. Retinyl acetate had no effect on food consumption or body wt changes. None of the rats that received pellets composed of cholesterol only exhibited mammary carcinomas (MC) or pituitary tumors. All rats with an EE2 implant had pituitary tumors: 88% of the rats on the placebo diet had one or more MC; 70% of the rats on the retinyl acetate diet had one or more MC. The difference between the two EE2-treated groups for incidence of animals with at least one MC was not significant (chi 2). However, the EE2-treated rats on the placebo diet had approximately twice as many MC as the EE2-treated rats on the retinyl acetate diet. Thus, retinyl acetate inhibited estrogen-induced mammary carcinogenesis in female ACI rats, without evidence of gross toxicity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Diterpenes; Eating; Ethinyl Estradiol; Female; Mammary Neoplasms, Experimental; Neoplasms, Multiple Primary; Rats; Rats, Inbred ACI; Retinyl Esters; Vitamin A

The potential modifying effect of retinyl acetate (RA) on butylated hydroxyanisole (BHA)-induced rat forestomach tumorigenesis was examined. Male F344 rats, 5 weeks of age, were maintained on diet containing 1% or 2% BHA by weight and simultaneously on drinking water supplemented with RA at various concentrations (w/v) for 52 weeks. In groups given 2% BHA, although marked hyperplastic changes of the forestomach epithelium were observed in all animals, co-administration of 0.25% RA significantly (P less than 0.05) increased the incidence of forestomach tumors (squamous cell papilloma and carcinoma) to 60% (9/15, 2 rats with carcinoma) from 15% (3/20, one rat with carcinoma) in the group given RA-free water. In rats given 1% BHA, RA co-administered at a dose of 0.05, 0.1, 0.2 or 0.25% showed a dose-dependent enhancing effect on the development of the BHA-induced epithelial hyperplasia. Tumors, all papillomas, were induced in 3 rats (17%) with 0.25% RA and in one rat (10%) with 0.05% RA co-administration. RA alone did not induce hyperplastic changes in the forestomach. These findings indicate that RA acted as a co-carcinogen in the BHA forestomach carcinogenesis of the rat.

Topics: Animals; Body Weight; Butylated Hydroxyanisole; Cocarcinogenesis; Diterpenes; Drug Administration Schedule; Epithelium; Kidney Papillary Necrosis; Male; Neoplasms, Experimental; Organ Size; Rats; Rats, Inbred F344; Retinyl Esters; Stomach Neoplasms; Vitamin A

Vitamin A-deficient diet affected the body weight or growth of Heteropneustes fossilis, a freshwater siluroid rich in 3-4,dehydroretinol. The fish lost body weight after 20-30 days of administration of vitamin A-deficient diet. Cessation of growth occurred owing to vitamin A-deprivation, whereas control fish after supplementation of vitamin A continued their growth. Initial growth of the fish after administration of vitamin A-deficient diet is regulated by its initial vitamin A-reserve, whereas successive deficiency lead to the cessation of growth or weight loss. Supplementation of retinyl acetate to vitamin A-deficient fish compensate the loss of body weight.

Topics: Animals; Body Weight; Diet; Diterpenes; Fishes; Intestines; Liver; Retinyl Esters; Vitamin A

Male F344 rats were administered phenobarbital, polychlorinated biphenyl (PCB), retinol acetate, indomethacin, 6-amino-caproic acid, dexamethasone (DEX) or diethylmaleate (DEM) for one week and then were treated with these chemicals plus butylated hydroxyanisole (BHA) for a further four weeks. Histopathologically, the incidence of BHA-induced forestomach hyperplasia was significantly lower in rats treated with PCB, DEX or DEM than in those treated with BHA alone. However, the inhibition by PCB and DEX was only partial and might have been due to decreased food intake. On the other hand, DEM completely inhibited the hyperplastic response to BHA at a dose of 0.25%, and even at lower doses it demonstrated significant inhibition without any decrease in body weight or food intake. The result that DEM, a tissue glutathione depleting agent, can inhibit BHA-associated forestomach hyperplasia strongly suggests that tissue glutathione may be intimately involved in the induction of forestomach hyperplasia by the antioxidant in rats.

Topics: Aminocaproic Acid; Animals; Body Weight; Butylated Hydroxyanisole; Dexamethasone; Diet; Diterpenes; Drug Interactions; Eating; Indomethacin; Liver; Male; Maleates; Organ Size; Phenobarbital; Polychlorinated Biphenyls; Rats; Rats, Inbred F344; Retinyl Esters; Stomach; Vitamin A

Mice fed a semipurified, vitamin A-deficient diet (A- mice) and control animals fed the same diet with added retinyl acetate (A+ mice) were used to investigate the effect of vitamin A deficiency on primary immunoglobulin responses to protein antigens. At age 6 weeks, A- mice had serum retinol concentrations that were 46% of A+ controls. When immunized with a single antigen dose, these mice produced an antigen-specific IgM response equivalent to controls, but their IgG1 and IgG3 responses were sharply diminished (less than 30% of A+ controls). At age 8 weeks, A- mice had 20% of A+ serum retinol concentrations and less than 17% of A+ liver retinyl palmitate levels. Responding to a single antigen dose, A- mice produced approximately equal to 70% as much IgM as A+ controls. Their IgG1 response was less than 30% and their IgG3 response less than 3% of A+ controls. The IgG1 response kinetics were identical in A- and A+ mice. Diminished serum antibody responses in A- mice were attributable to fewer immunoglobulin-secreting plasma cells rather than to a decline in IgM or IgG secretion rate per cell. Total serum IgG3 levels, irrespective of antigen specificity, were slightly elevated in A- mice compared to A+ controls. The inefficient clonal expansion of responding B lymphocytes and contrasting impairment of IgM and IgG responses observed in vitamin A-deficient mice are discussed with respect to a possible helper/inducer-T-lymphocyte defect.

Topics: Animals; Antibody Formation; Body Weight; Diterpenes; Hemocyanins; Immunoglobulin G; Immunoglobulin M; Kinetics; Mice; Muramidase; Retinyl Esters; Vitamin A; Vitamin A Deficiency

The effect of feeding 0.02% retinyl acetate on the development of cryptogenic neoplasms and the life span of C3H/HeJ (+) mice of both sexes was studied. The survival at 105 weeks was 58% in untreated males and 28% in untreated females vs. 39% in treated males and 14% in treated females. The average weight in treated groups was also 10-15% lower. The incidence (percent) of neoplasm-bearing animals and total neoplasms was 87% and 57, respectively, in female controls vs. 93% and 55 in treated females. In male controls, these values were 57% and 39 compared with 50% and 38 in treated males. In treated animals, there was no reduction in the most common neoplasms, that is, neoplasms of the mammary gland and liver. The numbers of ovarian neoplasms and lung adenomas were slightly lower. Therefore, retinyl acetate exerted, at best, only a slight inhibitory effect on development of some types of cryptogenic neoplasms in mice.

Topics: Animals; Body Weight; Diterpenes; Female; Hemangioma; Liver Neoplasms, Experimental; Longevity; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Neoplasms, Experimental; Ovarian Neoplasms; Retinyl Esters; Vitamin A

The effect of high levels of dietary fat and retinyl acetate (ROA) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary tumor development and growth was examined. Female Sprague-Dawley rats, 51-53 days of age, were treated ig with 5 mg DMBA. At 55-57 days of age, the animals were divided into the following dietary treatment groups: A) 4.5% fat [control fat (CF)]; B) CF + 1.0 mmol ROA/kg diet (CF + ROA); C) 20.0% fat [high fat (HF)]; and D) HF + ROA. HF diets significantly increased mammary tumor multiplicity, with or without ROA, but did not significantly influence mammary tumor growth. ROA treatment reduced mammary tumor multiplicity regardless of the level of dietary fat and inhibited mammary tumor growth in the presence of normal levels of dietary fat. High levels of dietary fat did not significantly influence normal mammary gland growth and development. ROA significantly decreased normal mammary gland growth and development regardless of the level of dietary fat. Blood retinoids in rats fed ROA were primarily in the form of retinyl esters, i.e., retinyl linoleate, retinyl palmitate-oleate, and retinyl stearate. Free retinol levels in blood were not significantly influenced by ROA feeding. Blood retinyl ester levels were lower in rats fed the HF + ROA diet as compared to rats fed the CF + ROA diet.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Body Weight; Cocarcinogenesis; Dietary Fats; Diterpenes; Female; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Rats; Rats, Inbred Strains; Retinoids; Retinyl Esters; Time Factors; Vitamin A

The carcinogenicity of retinol acetate [(RAC) CAS: 127-47-9], a synthetic derivative of retinol, was tested by continuous oral administration in the drinking water of F344/DuCrj rats for 104 weeks. Groups of 50 male and 50 female rats were given solutions of 0.25 or 0.125% RAC in the form of gelatinized beadlets suspended in distilled water. Control groups consisting of the same numbers of rats were given 0.25% of placebo beadlets. All of the surviving animals were killed at 108 weeks, 4 weeks after the cessation of the RAC treatments. The survival rates were 72-84% and were sufficiently high for statistical comparison of all groups. Inhibition of body weight gain was marked in females of the high-dose group. Higher incidences of malignant pheochromocytomas, benign pheochromocytomas, and hyperplasias of the adrenal medulla were observed in the RAC-treated groups. The combined incidences of tumors of the adrenal medulla in males and females of the high-dose groups and the incidence in females of the low-dose group were significantly higher than the incidence in the controls. Conversely, statistically significant decreases were found in the incidences of the mammary gland tumors in males of the high-dose group, of thyroid tumors in females of the high-dose group, and of clitoral gland tumors in females of both high- and low-dose groups. It was concluded that RAC given orally possesses potential for increasing the incidence of pheochromocytomas in male and female F344 rats in a dose-related manner under the conditions of this bioassay.

Topics: Adrenal Gland Neoplasms; Animals; Blood; Body Weight; Diterpenes; Dose-Response Relationship, Drug; Drinking; Female; Male; Pheochromocytoma; Rats; Rats, Inbred F344; Retinyl Esters; Sex Factors; Vitamin A

Possible involvement of lipid peroxide (LPO) in the occurrence of diabetic retinal lesion was investigated using streptozotocin-induced diabetic rats. Young male Wistar rats weighing 100-150 g were made diabetic by daily intraperitoneal injection of 30 mg/kg streptozotocin (STZ) for 5 days. Five weeks after the termination of STZ-treatment, when animals maintained typical hyperglycemia, the tissue level of LPO, estimated by the thiobarbituric acid method in the presence of 0.5 mM EDTA, was found to be augmented in the kidney. At 7 to 9 weeks after the STZ-treatment, the content of LPO in the retina also exhibited a significant increase, while those in the serum, brain and peripheral nerves showed no alteration. This increment of LPO in the kidney and retina was accompanied by the concomitant reduction of fat-soluble antioxidants determined by the ferric chloride-bipyridyl reaction, and insulin treatment (10 u/rat/day, s.c.) completely eliminated the increased formation of LPO in these organs. When diabetic rats were treated with retinol acetate, which had an inhibitory effect on LPO formation in retinal homogenate, the increase in LPO content was found to be significantly suppressed, especially in the retina. These results suggest that the STZ-induced diabetic state may elicit an increased formation of LPO in the retina and kidney, both of which are known to be main organs having typical diabetic lesions.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Cerebellum; Diabetes Mellitus, Experimental; Diterpenes; Kidney; Lipid Peroxides; Male; Rats; Rats, Inbred Strains; Retina; Retinyl Esters; Time Factors; Vitamin A

Three experiments were conducted with broiler chicks to study the effect of different levels of choice animal tallow on absorption of vitamins A and E. The first experiment involved 9 dietary treatments in a 3 X 3 factorial arrangement, consisting of 3 levels of vitamin A (2,000, 10,000, and 18,000 IU/kg) and 3 levels of animal fat (0, 3, and 6%). Liver vitamin A concentration significantly increased linearly (P less than .01) with increasing dietary vitamin A. The effect of dietary fat on liver vitamin A concentration was not significant. The highest liver vitamin A concentration occurred with 3% added fat (5.2% total dietary fat). The second experiment consisted of 7 levels of dietary fat (0, 1, 2, 3, 4, 5 and 10%), each fed with a constant vitamin A (14,500 IU/kg). Increasing fat significantly (P less than .05) increased liver vitamin A concentration in a quadratic manner at 4 and 6 weeks of age (P less than .01). The highest liver vitamin A concentration corresponded to 5% added fat (5.3% total fat). The third experiment involved 9 treatments in a 3 x 3 factorial arrangement with supplemental vitamin E at 0, 10, and 100 IU/kg and animal fat at 0, 3, and 6% of the diet. Plasma vitamin E significantly increased in a quadratic manner (P less than .01) with increasing vitamin E and increased linearly (P less than .01) with increasing fat. Plasma vitamin A concentration also increased (P less than .01) with increasing fat. The fat x vitamin E interaction was significant (P less than .01).

Topics: alpha-Tocopherol; Animals; Body Weight; Chickens; Dietary Fats; Diterpenes; Fats; Intestinal Absorption; Liver; Retinyl Esters; Tocopherols; Vitamin A; Vitamin E

The effect of vitamin A on cyclophosphamide mutagenicity was measured both in vitro and in vivo. In the Ames test in Salmonella typhimurium TA1535 with mouse-liver S-9 mix, the addition of retinol, retinyl acetate or retinyl palmitate caused a dose-dependent inhibition of cyclophosphamide mutagenicity. In the micronucleus test in male NMRI mice fed low, normal or high levels of vitamin A, the induction of micronuclei in bone marrow by an ip dose of cyclophosphamide was unaffected by vitamin A status. Thus, this study provides no evidence that activation of a procarcinogen in the liver or bone marrow of mice can be modified by vitamin A. One of the possible reasons for the observed absence of inhibition by vitamin A in vivo may be a lack of correlation between the oral dose of retinoid and the resulting level of vitamin A in the bone marrow. The difference between results in vitro and in vivo may also have been due to a difference in the availability and potency of added vitamin A in vitro compared with the forms absorbed and stored in vivo.

Topics: Animals; Body Weight; Bone Marrow; Cell Nucleus; Cyclophosphamide; Diterpenes; In Vitro Techniques; Liver; Male; Mice; Microsomes, Liver; Mutagenicity Tests; Mutagens; Retinyl Esters; Salmonella typhimurium; Vitamin A

All-trans [11-3H]4,4- difluororetinyl acetate was synthesized by treating methyl all-trans [11-3H]4- oxoretinoate with diethylaminosulfurtrifluoride , followed by reduction and acetylation of the product. After oral administration of the radioactive difluoro analog in oil to rats, difluororetinol , difluororetinyl palmitate and related esters, 4- oxoretinol , 4- oxoretinoic acid and polar conjugated derivatives were identified in the intestine, liver, kidney and/or blood. The major metabolic products were difluororetinyl palmitate and related esters, which were stored in the liver. The presence of the difluoro analog in liver oil from treated rats was confirmed by 19F-NMR spectroscopy. Neither retinol nor retinyl esters were detected as products of the metabolism of the difluoro analog. Nonetheless, all-trans difluororetinyl acetate showed 26 +/- 12% of the biological activity of all-trans retinyl acetate in the rat growth assay. Presumably, the difluoro analog is active per se in growth rather than by conversion to retinol or to one of its known growth-promoting metabolites. In general, however, the difluoro analog was metabolized in a manner very similar to vitamin A. The vitamin A moiety of administered difluororetinyl acetate and retinyl acetate was poorly stored (1.8-3.3%) in the liver of vitamin A-depleted rats, confirming and extending past reports that the liver storage mechanism is severely impaired when initial liver stores are very low.

Topics: Animals; Biological Assay; Body Weight; Diterpenes; Feces; Kinetics; Liver; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Inbred Strains; Retinyl Esters; Tissue Distribution; Tretinoin; Vitamin A

Experiments were made to study some indicators of the metabolism in the body and non-lactation mammary gland under administration of different doses of retinol acetate. Particular attention was paid to the animals' body and mammary gland weight, to the measurement of RNA and total protein in the epithelial cells, nuclear and cytoplasmic areas in the epitheliocytes. Administration to experimental animals of vitamin A in a dose of 30 000 IU, that does not provoke toxic hypervitaminosis, simulates vital activity of the cells, manifesting in the increased area of the nuclei and cytoplasm, in the enlargement of the total cytoplasm protein and of the content of nuclear RNA and cytoplasm, in the increased weight of the mammary gland and body weight. Administration of vitamin A in a dose of 80 000 IU leading to the occurrence of toxic hypervitaminosis symptoms reduces vital activity of the cells of mouse non-lactation mammary gland which manifests in the reduction of the body and mammary gland weight, of the area of the nuclei and cytoplasm of the epitheliocytes, fall of the total cytoplasm protein and RNA of the nucleus and cytoplasm.

Topics: Animals; Body Weight; Cell Nucleus; Cytoplasm; Diterpenes; Female; Mammary Glands, Animal; Mice; Organ Size; Proteins; Retinyl Esters; RNA; Vitamin A

The administration of a 250-ppm retinyl acetate dietary supplement for various periods relative to intragastric administration of 50 mg benzo[a]pyrene (BP) significantly inhibited the induction of mammary cancers in virgin female inbred LEW/Mai rats. with day of BP administration taken as time 0, groups receiving the retinoid from weeks -2 to +1, +1 to +90, +20 to +90, and -2 to +90 showed a significant reduction in tumor response as compared to controls. The inhibition of carcinogenesis achieved by a +1 to +20 administration schedule was temporary; the tumor yield was suppressed initially but returned to control levels by week 60. Autoradiographic analysis of mammary glands from 50-day-old rats indicated that a 2-week exposure to supplemental retinyl acetate significantly reduced the mammary gland parenchymal cell labeling index in ductal, alveolar, and terminal end bud structures. Beginning the retinyl acetate supplement 1 week after the administration of BP significantly reduced the number of terminal ductal hyperplasias. The inhibition of carcinogenesis achieved by a short period of retinyl acetate administration before and during the period of carcinogen availability as well as the inhibition achieved by long-term postcarcinogen retinoid exposure may involve an antiproliferative effect on the rat mammary gland.

Topics: Animals; Benzopyrenes; Body Weight; Cell Division; Diet; Diterpenes; Female; Hyperplasia; Intubation, Gastrointestinal; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Precancerous Conditions; Rats; Rats, Inbred Lew; Retinyl Esters; Vitamin A

The influence of feeding a pharmacological level of either selenium (SE), retinyl acetate (RA), or selenium and retinyl acetate (SE + RA) on N-methyl-N-nitrosourea-induced mammary carcinogenesis was studied in female Sprague Dawley rats. Rats received 50 mg N-methyl-N-nitrosourea per kg body weight at 50 days of age. Seven days after carcinogen treatment, groups of 25 rats each were placed on laboratory chow diet supplemented with either a placebo or 300 mg RA, 4 mg SE, or 300 mg RA plus 4 mg SE per kg diet. Animals were palpated for detection of mammary tumors twice each week, and the study was terminated 130 days after N-methyl-N-nitrosourea was given. In comparison to the placebo group, treatment with RA or RA + SE reduced tumor incidence, lessened the average number of tumors per rat, and prolonged tumor latency. RA + SE had the greatest inhibitory effect on the carcinogenic process. The effect of combined treatment with RA and SE was additive in nature. The length of the estrous cycle was increased by treatment with RA + SE, and some pathological changes of the ovary and uterus were noted. This investigation provides the first evidence of an additive inhibitory effect resulting from combined treatment with RA and SE.

Topics: Analysis of Variance; Animals; Body Weight; Diet; Diterpenes; Drug Synergism; Estrus; Female; Mammary Neoplasms, Experimental; Methylnitrosourea; Pregnancy; Rats; Retinyl Esters; Selenium; Time Factors; Vitamin A

Studies were designed to determine the efficacy of retinyl acetate (RA) in preventing mammary tumorigenesis in C3H-Avy female mice. Mice were fed a stock diet supplemented with RA beadlets at concentrations of 83, 41, and 21 mg/kg diet. Control animals received stock diet supplemented with placebo beadlets. The RA diet was started at conception in 1 group of animals whose mothers were fed RA from the time of mating. Two other groups of animals were placed on the RA diet at weaning or at 3 months of age. Mice were killed and necropsied 1 month after the appearance of the first mammary tumor or at 15 months of age if no tumor developed. No significant difference in incidence of mammary carcinomas was found between control and RA-fed mice. The incidence was 80--90% in all groups. The number of tumors per mouse (1.6--2.1) and the tumor latency period (10.2--11.6 mo) were not influenced by RA in the diet. Two unexpected observations were made: 1) Control mice autopsied at 12 months of age or older showed a 70% incidence of hepatomas, whereas the incidences were approximately 11, 17, and 46% in mice fed 83, 41, and 21 mg RA/kg diet, respectively. 2) Severe damage to most articulations was induced by RA, even at the dose of 21 mg/kg diet, which failed to cause any other sign of toxicity.

Topics: Animals; Body Weight; Diterpenes; Female; Joint Diseases; Liver Neoplasms, Experimental; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Maternal-Fetal Exchange; Mice; Mice, Inbred C3H; Pregnancy; Retinyl Esters; Vitamin A

Biological properties of axerophthene, the hydrocarbon analog of retinol, have been studied both in vitro and in vivo. In tracheal organ culture axerophthene reversed keratinization caused by deficiency of retinoid in the culture medium; its potency was of the same order of magnitude as that of retinyl acetate. Axerophthene supported growth in hamsters fed vitamin A-deficient diets although less effectively than did retinyl acetate. Axerophthene was considerably less toxic than was retinyl acetate when administered repeatedly in high doses to rats. Administration of an equivalent p.o. dose of axerophthene caused much less deposition of retinyl palmitate in the liver than did the same dose of retinyl acetate, while a greater level of total retinoid was found in the mammary gland after administration of axerophthene.

Topics: Animals; Body Weight; Diterpenes; Female; Keratins; Liver; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Organ Culture Techniques; Rats; Retinyl Esters; Trachea; Vitamin A; Vitamin A Deficiency