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PubMed1986

Demonstration of cellular retinoic acid binding protein (CRABP) in chick embryo tendon cells and effects of retinoids on collagen synthesis in tendon and sterna.

The binding of all-trans-retinoic acid (all-trans RA) to specific cytosol proteins and the effects of retinoids on procollagen synthesis were studied in chick-embryo tendon cells. For the receptor assay, tendon cytosols were incubated with [3H]all-trans-RA in the presence or absence of 100-fold excess of nonlabeled all-trans-RA up to 20 hr at +4 degrees and unbound retinoid was removed by charcoal-dextran treatment or by gel filtration chromatography. The results indicated that chick-embryo tendon cells contained cellular retinoic acid binding protein (CRABP). The binding of [3H]all-trans-RA could be displaced by 13-cis-retinoic acid, but not by retinol or etretinate. In contrast no CRABP could be found in cartilage cells isolated from sterna or in whole sterna. The treatment of tendon cytosol with proteases (pronase, trypsin, chymotrypsin) abolished the specific binding of [3H]all-trans-RA. Gel filtration studies on Sephadex G-100 indicated an apparent molecular weight of 14,500-15,000 daltons for the all-trans-retinoic acid binding protein. All-trans-RA markedly decreased procollagen synthesis in isolated chick-embryo tendon cells, the inhibition being concentration dependent; the decrease was about 58% of the control in the presence of 10(-5) M all-trans-RA. Similar decrease was noted with 13-cis-RA and etretinate, while retinol was less effective. In isolated cartilage cells the dose of 10(-5) M of all-trans-retinoic acid decreased drastically total protein and collagen synthesis. The mannosylation of procollagen, the conversion of procollagen to collagen and the size of procollagen chains were not significantly affected. The results of the present study indicate that CRABP is not expressed in sterna of chick-embryos, and in contrast high levels of CRABP could be found in tendons. However, retinoids modulated collagen synthesis in both tissues. Thus it is possible that retinoids can affect the metabolism of different collagen types also in clinical use.

Animals↗
PubMed1990

Uptake, processing and release of retinoids by cultured human retinal pigment epithelium.

Upon absorption of a photon, the 11-cis retinaldehyde chromophore of rhodopsin is isomerized and reduced to all-trans retinol (vitamin A) in the photoreceptor outer segments, whereupon it leaves the photoreceptors, and moves to the retinal pigment epithelium (RPE). To clarify the function of the RPE in the regeneration of 11-cis retinaldehyde, we delivered all-trans retinol to monolayer cultures of human RPE. During delivery the retinol was associated with its putative natural carrier, interphotoreceptor retinoid binding protein (IRBP). IRBP has been proposed as a carrier protein involved in the exchange of retinoids between the photoreceptors and the retinal pigment epithelium. The retinoid composition of RPE cells and culture medium was analyzed by HPLC following several incubation periods. The RPE monolayer was found to process all-trans retinol into two distinct end-products: all-trans retinyl palmitate, which remained within the RPE monolayer: and 11-cis retinaldehyde which was released into the culture medium. These results demonstrate retinoid isomerase, retinol oxidoreductase and retinyl ester synthetase activity in human RPE cells cultured under the appropriate conditions. They show that IRBP can serve as a carrier of retinol through an aqueous medium to the RPE, and they illustrate that the visual cycle can be studied in vitro.

Cells, Cultured↗
PubMed1986

Retinoid stimulation of epidermal differentiation in vivo.

Retinoids are potent inducers of epidermal hyperplasia in vivo. Epidermal transglutaminase activity and stratum corneum turnover were examined in all-trans-retinoic acid and arotinoid ethyl ester treated hairless mice, to evaluate the possible contribution of decreased epidermal cell loss to the induction of hyperplasia by retinoids. Stratum corneum turnover was enhanced, and the absolute amounts (activity/cm2), but not the specific activities, of soluble and particulate transglutaminase increased following retinoid treatment. Since epidermal differentiation was enhanced after retinoid treatment, the hyperplastic response is due to increased cell formation and not decreased cell loss.

Animals↗
PubMed1996

Retinoid receptors in human lung cancer and breast cancer.

Retinoids, the natural and synthetic vitamin A derivatives, are known to inhibit the proliferation of lung cancer and breast cancer cells and the growth of carcinogen-induced bronchogenic squamous cell carcinoma and mammary tumors, and have been used as chemoprevention agents against both types of cancer. However, clinical trials of retinoids in patients with advanced lung cancer and breast cancer have not been successful. In studying how retinoid sensitivity is lost in cancer cells, we have found that lack of the retinoic acid receptor beta (RAR beta) gene expression and its abnormal regulation by retinoic acid (RA) are common features in human lung cancer and breast cancer cells. The absence and abnormal RA regulation of RAR beta correlates with the loss of anti-proliferation effect of RA in hormone-independent breast cancer cells, and is due to different abnormalities found in cancer cells. Furthermore, expression of RAR beta gene in hormone-independent breast cancer cells restores their RA sensitivity. These data demonstrate that RAR beta can mediate the growth inhibitory effect of RA and suggest that the lack of RAR beta may contribute to retinoid resistance in certain cancer cells.

Breast Neoplasms↗
PubMed1984

Structure-activity relationships of retinoids in developmental toxicology. I. Studies on the nature of the polar terminus of the vitamin A molecule.

The teratogenic activities of all-trans-retinoyl fluoride, all-trans-3-retinylidene-2,4-pentanedione, all-trans-2-retinylidene-1,3-cyclopentanedione, all-trans-2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione, all-trans-2-retinylidene-5-p-methoxyphenyl-1,3-cyclohexanedione, all-trans-2-retinylidene-1,3-cyclooctanedione, all-trans-5-[2,6-dimethyl-8-(2,6,6-trimethylcyclohexen-1-yl)-1,3, 5,7-octatetrae n-1-yl]tetrazole, ethyl all-trans-9-(exo-2-bicyclo[2.2.1.]heptyl)-3,7-dimethyl-2,4,6,8- nonatetraenoate, ethyl all-trans-4-[2-methyl-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3- butadien-1-yl]benzoate, 13-cis-N-(4-hydroxyphenyl)retinamide, and 13-cis-N-(2-hydroxyethyl)retinamide were determined in the hamster and compared with that of all-trans-retinoic acid. Administration of a single oral dose of the retinoids failed to induce signs of the hypervitaminosis A intoxication syndrome in any of the dams, and the maternal weight gain was not significantly different from the vehicle control value, except following intubation of the retinamides where maternal weight gain was significantly depressed. All of the retinylidene 1,3-diketones studied here were devoid of significant teratogenic activity. The retinamides failed to induce either an elevated mean litter frequency of malformed fetuses or a syndrome of anomalies similar to that induced by administration of an equimolar dose of all-trans-retinoic acid. All of the other retinoids induced a syndrome of malformations similar to that induced by administration of all-trans-retinoic acid and were associated with a significant increase in the number of litters containing one or more malformed fetuses and an elevated mean litter frequency of malformed fetuses. The teratogenic activity in the hamster of this series of retinoids was independent of structural modifications in either the beta-cyclogeranylidene ring or the polyene chain of the molecule. The results of the present study suggest that the changes in teratogenic activity associated with structural modification of vitamin A at C15 were primarily dependent upon the presence of or biotransformation to a free carboxyl or a moiety with an equivalent pKa at C15, not upon the molecular size of the substituent or the stereochemical position about C13. Since major structural modifications of vitamin A were made without the substantial loss of teratogenic activity, the structural requirements of retinoids for induction of terata were not extraordinarily exacting.

Animals↗
PubMed1984

Early and differential decrease in natural retinoid levels in C57BL/Rij and DBA/2 mice by 3,4,3',4'-tetrachlorobiphenyl.

3,4,3',4'-Tetrachlorobiphenyl (TCB) administered by weekly ip injections of 1.5 to 100 mg kg-1 for 4 weeks induced a dose dependent decrease in retinoids in female C57BL/Rij and DBA/2 mice (5 to 7 weeks of age). However, the response differed between the two strains of mice. In C57BL/Rij mice, a dose dependent decrease in liver retinol (up to 60%), retinyl palmitate (up to 40%), and serum retinol (up to 80%) occurred, while in DBA/2 mice a decrease in serum retinol (up to 80%) only was observed. The effects of 3,4,3',4'-TCB on retinoid levels were more pronounced than on toxicity (e.g., decrease in thymus and body weight, increase in liver weight, and induction of AHH activity). This finding suggests that reduction in retinoid levels is a very sensitive parameter for the toxicity of polychlorinated biphenyls (PCBs). In addition, in these experiments the induction of aryl hydrocarbon hydroxylase (AHH) did not correlate with the decrease in retinoid levels in C57BL/Rij and DBA/2 mice, suggesting that the mixed function oxidase (MFO) system is not involved.

Animals↗
PubMed1984

Rod outer segment membranes: good acceptors for retinoids?

The exchange of all-trans retinoids (retinal, retinol, retinylpalmitate) between PC-vesicles, PC-vesicles and liver microsomes or PC-vesicles and rod outer segment membranes is investigated using 11,12(3)H labeled compounds. In the first two systems, retinal and retinol exchange rapidly, retinyl acetate slowly and retinyl palmitate not at all. Rod outer segment membranes however take up relatively small amounts of retinoids (retinylpalmitate less than retinol less than retinal) and rapidly lose 60-90% of their label in the presence of PC-vesicles. E.G. retinoids clearly favour the PC-vesicle membrane. Apparently, rod outer segment membranes have a much lower affinity for retinoids than other artificial or natural membranes investigated so far.

Animals↗
PubMed1985

Evaluation of the sensitive step of inhibition of chondrogenesis by retinoids in limb mesenchymal cells in vitro.

The sensitive step of inhibition of chondrogenesis in vitro by retinoids was investigated in modified micromass cultures of limb bud mesenchymal cells from mouse embryos of day 11 and 12. Evaluation of chondrogenesis was performed after alcian blue staining, using a simple random hit counting of cartilage nodules. All-trans-retinoic acid, 13-cis-retinoic acid, and a newly developed arotinoid, RO 13-6298, were tested for their ability to inhibit chondrogenesis. We found that inhibition of chondrogenesis depended on the dosage and the duration of treatment with the different retinoids. Further analysis showed that chondrogenesis in limb bud mesenchymal cells from the proximal part was irreversibly inhibited after one hour of treatment, whereas distal cells showed a reduction of cartilage development only after a treatment period of 12 and more hours. In respect to the doses of the retinoids, proximal cells were about one magnitude more vulnerable than distal cells. These proximo-distal differences were obtained with 13-cis-retinoic acid at 10 micrograms/ml, with all-trans-retinoic acid at 1 microgram/ml and with arotinoid RO 13-6298 with 10 ng/ml. It is supposed that the late blastemal stage of chondrogenic differentiation before the onset of matrix synthesis is the step which is most vulnerable to retinoid treatment.

Animals↗
PubMed1996

Retinoid-regulated expression of BCL-2 and tissue transglutaminase during the differentiation and apoptosis of human myeloid leukemia (HL-60) cells.

Retinoids induce terminal differentiation and subsequent apoptosis in the human myeloid leukemia (HL-60) cell line. We have previously shown that in HL-60 cells, ligand activation of retinoic acid receptors (RARs) is sufficient to induce differentiation but ligand activation of retinoid X receptors (RXRs) is necessary for the retinoid-induced apoptosis of these cells. In the present studies we have characterized the effect of retinoids on the expression of two apoptosis-linked gene products, BCL-2 and tissue transglutaminase. BCL-2 is a membrane-associated protein whose expression has been linked to the suppression of apoptosis in many cells. Tissue transglutaminase is a protein cross-linking enzyme that accumulates in many cells undergoing apoptotic cell death. Our data suggest that ligand activation of RARs in HL-60 cells results in a global suppression of BCL-2 expression whereas ligand activation of both RARs and RXRs triggers the selective accumulation of tissue transglutaminase in the apoptotic HL-60 cells.

Apoptosis↗
PubMed1990

Computer-automated structure evaluation (CASE) of retinoids in teratogenesis bioassays.

The potential usefulness of the retinoids, a large group of synthetic compounds chemically and structurally related to vitamin A, in the treatment of severe dermatologic diseases and in the prophylaxis and therapy against cancer is severely limited because of their potential teratogenicity. CASE analysis of published retinoid data from the hamster teratogenicity assay and the limb bud "spot" culture system has targeted the hydrophobic region of the retinoids as having the greatest effect on the range of potencies studied. In addition, log p's (as calculated by the CASE program) below a certain value appear to unilaterally result in nonteratogenic retinoids in the in vivo hamster assay system.

Animals↗
PubMed1986

The effects of retinoid treatment and antiestrogens on the growth of T47D human breast cancer cells.

The ability of all-trans-retinoic acid, 13-cis-retinoic acid, the free acid of etretinate (RO 10-1670), the 'arotinoid' RO 13-6298 and its free acid RO 13-7410 to affect the growth of T47D human breast cancer cells in vitro was investigated. The growth of T47D cells was inhibited by all of the retinoids tested, with the arotinoids being up to 100 times more effective than all-trans-retinoic acid. The presence of cellular retinoic acid binding protein (cRABP) was indicated by the cellular uptake of [3H]all-trans-retinoic acid. Maximum binding was 460 fmol/micrograms DNA. All of the retinoids with a polar terminal free carboxyl group readily competed for the binding sites, but none of the retinoids competed for the estrogen or progesterone receptor. Co-treatment of the T47D cells with 0.1 microM all-trans-retinoic acid and either tamoxifen (1 microM) or hydroxytamoxifen (10 nM or 0.1 microM) produced an additive effect on growth inhibition. No such additive effect was observed when T47D cells were co-treated with arotinoids and antiestrogens. The results showed that the T47D cells can serve as a useful model in vitro to test the effects of the synthetic retinoids and antiestrogens on steroid receptor-positive human breast cancer.

Binding, Competitive↗
PubMed1989

Inhibition of growth and development of the transplantable C-6 glioma cells inoculated in rats by retinoids and carotenoids.

Experimental data were provided to demonstrate the inhibitory effects of retinoids (retinal, retinoic acid, retinyl acetate and retinyl palmitate) and carotenoids (beta-carotene, lycopene and crocetin) on the growth and development of the C-6 glioma cells inoculated in rats. In the pretreatment experiments, most of these compounds could prolong the latency period of T50 (time for 50% tumor incidence). At week 7, the growth inhibition was 57-67% (P less than 0.02) with carotenoids and 40-55% (P less than 0.05) with retinoids. In the post-treatment experiments, the growth inhibition was 30-55% (P less than 0.05) with carotenoids and 21-42% (P less than 0.05) with retinoids. No significant hepatotoxic effect was observed in all treated groups as indicated by the constant levels of serum enzymes (e.g. aspartate amino-transferase, alanine amino-transferase and alkaline phosphatase) and bilirubin. The mechanisms of tumor inhibition through the enhancement of anti-tumor immunity by both carotenoids and retinoids were discussed.

Animals↗
PubMed1989

A highly potent antiangiogenic activity of retinoids.

Four retinoids, i.e. retinol (vitamin A), retinoic acid, retinyl acetate and synthetic chalcone carboxylic acid (Ch 55), were examined for their effects on embryonic angiogenesis using 4.5-day chorioallantoic membranes of chick embryo. The effects of these retinoids were compared with that of antibiotic herbimycin A, which was the most powerful inhibitor of the angiogenesis reported previously. The four retinoids strongly inhibited embryonic angiogenesis; the order of inhibitory activity was Ch 55 greater than retinoic acid greater than herbimycin A greater than retinyl acetate based on the dose required for the half-maximal inhibitory effect. The present results suggest that retinoids are effective inhibitors of angiogenesis, and can be applied for the management of certain diseases accompanied by aberrant angiogenesis, particularly that which occurs during progressive growth of solid tumors.

Animals↗
PubMed1991

Retinoids and carotenoids in bovine pineal gland.

The retinoids and carotenoids in bovine pineal gland were analyzed by high-performance liquid chromatographic methods. The major retinoid observed was all-trans retinol, with an average level of 579 pmol/g wet tissue. In agreement with a previous report, retinal was not detected; however, we could not detect any retinyl ester in bovine pineal gland. Methods similar to those used in studying metabolism of vitamin A in the bovine eye were used to study the esterification and isomerization reactions of retinoids in the pineal gland. Neither esterification nor isomerization reactions occurred. These results suggest that the key retinoids and enzymes involved in visual function are absent in the bovine pineal gland. The major carotenoid, which has not previously been reported in pineal gland, was beta-carotene at an average level of 1830 pmol/g wet tissue.

Animals↗
PubMed1994

Retinoid X receptor homodimers function as transcriptional activators in yeast.

The possibility that different retinoids activate transcription from a specific retinoic acid (RA)-responsive element known as site A via different homo and heterodimeric versions of RA receptors cannot be evaluated in mammalian cells because they contain endogenous RA receptors (RAR). However, this limitation can be overcome by using yeast cells, which do not contain endogenous RAR, to study retinoid signaling pathways. Here, we describe heterologous expression of the human retinoid X receptor (RXR alpha) in yeast and hormone-dependent activation of a reporter construct containing site A upstream from a yeast promoter fused to the lacZ gene of Escherichia coli. Western blot analysis of yeast extracts containing RXR alpha revealed a distinct immunoreactive polypeptide co-migrating with the mammalian-produced RXR alpha. Electrophoretic mobility shift assays demonstrated that RXR alpha produced in yeast binds efficiently to site A in the absence of 9-cis-RA. However, transcription activation experiments showed that RXR alpha transactivates a yeast basal promoter linked to site A only in the presence of 9-cis-RA. We conclude that RXR alpha homodimers bind to site A in the absence of 9-cis-RA, but function as ligand-dependent transactivators in yeast cells. This retinoid-responsive transcription unit created in yeast cells provides a powerful genetic tool for the systemic unraveling of the synergistic interactions between RXR alpha and its heterodimeric partners.

Base Sequence↗
PubMed1995

Transplacental pharmacokinetics of a synthetic retinoid which is not bound by mouse embryonic cellular retinoic acid-binding protein.

Teratogenicity is a major side effect of retinoids, a class of compounds used in dermatology and oncology. The binding of retinoids to cellular retinoic acid-binding protein (CRABP) has been suggested to be important for the mechanism of retinoid embryopathy. Here data are presented on the transplacental pharmacokinetics of CD394 (4-[3-(1-adamantyl)-4-methoxybenzamido] benzoic acid) which does not bind to murine embryonic CRABP, although it is active in rat whole embryo culture and teratogenic in the rabbit in vivo. A single intragastric dose of CD394 (10 mg/kg) was administered to mice on day 11 of gestation. The extent of placental transfer of CD394, determined by HPLC, resembled more that of 13-cis-retinoic acid which also does not bind to CRABP, than that of the CRABP-binding all-trans-retinoic acid. CMax values of CD394 obtained after 1-2 h were: 1368 +/- 652 ng/ml for plasma, 203 +/- 132 ng/g for embryo and 856 +/- 563 ng/g for placenta. AUC (area-under-the-concentration-time-curve) values (0-12 h) were: 4319 ng x h/ml for plasma, 751 ng x h/g for embryo and 3163 ng x h/g for placenta. Thus, CD394 reached the embryo, although embryonic AUC values were less than one fifth of the maternal plasma AUC values. CD394 did not alter endogenous retinol concentrations in plasma, embryo, yolk sac or placenta. Our results indicate that CD394 reaches the embryo in vivo without binding to CRABP, although embryonic concentrations stayed well below plasma levels. This supports the opinion that binding to embryonic CRABP is not a prerequisite for reaching effective embryo concentrations and for the teratogenicity of retinoids.

Animals↗
PubMedDate not supplied

Structure-activity and dose-response relationships in the neural and behavioral teratogenesis of retinoids.

The therapeutic use in the human teratogenic range of retinoid compounds (Accutane; Tigason) for the treatment of dermatologic disorders has refocused attention on the teratogenicity of vitamin A-related compounds. This article reviews rodent data on three retinoids: vitamin A (retinol), all-trans retinoic acid (tretinoin), and 13-cis retinoic acid (isotretinoin) with respect to effects on central nervous system (CNS) malformations and postnatal death, growth reduction, and behavioral dysfunction. All three retinoids have been shown to effect these endpoints in a dose-dependent manner whereby smaller doses are necessary to produce each consecutive endpoint at the same stage of gestation. Whereas gestation days (GD) 8-10 are the most sensitive for the induction of gross CNS malformation, GD 11-13 appear most sensitive in effecting postnatal endpoints in rats with normal gross morphology. With respect to structure-activity relationships, retinol appears to have less than 1/4 the potency of all-trans retinoic acid, and isotretinoin may have much less than 1/8 the potency of all-trans retinoic acid in disrupting development with respect to all endpoints. The systematic relationships across endpoints argue for common controlling variables. For these retinoids, all-trans retinoic acid and its metabolites are proposed as the active agents of developmental toxicity.

Animals↗
PubMed1993

Retinoid-induced beta-adrenergic inhibitory effect associated with increased thymidine incorporation of fetal rat keratinizing epidermal cells (FRSK cells).

Using fetal rat keratinizing epidermal cells (FRSK cells) we investigated the effects of retinoids on the cyclic AMP system. The beta-adrenergic adenylate cyclase response was significantly decreased by the treatment of cells with 1 x 10(-6) M Ro 10-1670. The effect was observed by 12 h and remained for at least 48 h. The decreased beta-adrenergic response was accompanied by increased adenosine- and forskolin-induced cyclic AMP accumulations. Thymidine incorporation of FRSK cells was also increased by the retinoid treatment. Northern blot hybridization showed that none of the messages (the beta2-adrenergic receptor, the stimulatory guanine nucleotide binding protein (Gs-alpha), or the inhibitory guanine nucleotide binding proteins (Gi-2 alpha, Gi-3 alpha)) were significantly altered by the retinoid treatment. We have already reported that the beta-adrenergic response as well as the beta2-adrenergic receptor mRNA is increased by the dexamethasone treatment of FRSK cells. The addition of both Ro 10-1670 and dexamethasone in the incubation medium resulted in the loss of the beta-adrenergic augmentation effect by dexamethasone. These results indicate that retinoids decrease the beta-adrenergic response and increase the thymidine incorporation of FRSK cells. This is contrary to the previous results using pig epidermal organ culture system.

Acitretin↗