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PubMed1995

Evaluation of topical retinoids for cutaneous pharmacological activity in Yucatan microswine.

The pharmacological effects of retinoids on skin have been studied primarily in test systems using small animals, such as mice and rabbits. Because of potentially significant differences in skin permeation and metabolism between small animals and humans, we have used Yucatan microswine as an alternative model for testing topical retinoids. Microswine skin resembles human skin, functionally and anatomically, more closely than most other species. In these studies, microswine skin was treated topically with retinoids for 5 consecutive days per week for 5 weeks. We found microswine epidermis to be functionally responsive to retinoids in that it undergoes hyperplasia and shows an increase in transepidermal water loss (TEWL). All-trans-retinoic acid, and its analogs, 13-cis-retinoic acid, 4-hydroxy-retinoic acid and 4-oxo-retinoic acid all caused epidermal thickening and increased TEWL. The three analogs were less potent than all-trans-retinoic acid. A synthetic retinoid, TTNPB, potently induced epidermal hyperplasia and increased TEWL, but a close structural analog, m-carboxy-TTNPB, which is also inactive on nuclear retinoic acid receptors, was without effects on microswine epidermis. These findings show that microswine are useful for evaluating the cutaneous effects of topical retinoids. This model could be of value in identifying retinoids with potential clinical activity.

Administration, Cutaneous↗
PubMed1986

The in vitro characterization of the inhibition of mouse brain protein kinase-C by retinoids and their receptors.

The mechanism of the in vitro inhibition of Ca2+-, phosphatidylserine-dependent protein kinase C (PK-C)2 by the purified holo (ligand-saturated) forms of cellular retinol-binding protein (cRBP) and cellular retinoic acid-binding protein (cRABP) was studied. We report here that the PK-C-inhibitory action of holo-cRBP and holo-cRABP is due to their respective ligands, all-trans-retinol and all-trans-retinoic acid; the reduced phosphorylation of the holo-retinoid-binding proteins and brain cytosolic proteins is not the result of a retinoid-induced soluble phosphatase or protease activity; retinoids reduce PK-C affinity for calcium and phosphatidylserine in vitro; and the structure-function activity of the retinoids and the specific interaction of these compounds with their binding proteins are important in blocking the activity of PK-C. These observations suggest that the inhibitory effect of retinoids on plasma membrane-associated PK-C activity pays a significant role in defining the early epigenetic aspects of PK-C-dependent tumor promotion and may be a physiological mechanism by which retinoids induce terminal differentiation in cell types that do not express soluble retinoid-binding proteins.

Animals↗
PubMed1997

Retinoid signalling and axial patterning during early vertebrate embryogenesis.

There are many indications that active retinoids are regulatory signals during vertebrate embryogenesis. Treating vertebrate embryos with retinoids can cause teratogenic defects, including specific derangements of the main body axis. Other data show that early vertebrate embryos contain physiologically relevant concentrations of active retinoids and express retinoid binding proteins and receptors; that knockouts of retinoid receptors can induce homeotic defects; and that relevant developmental control genes are regulated by retinoid response elements. Here, we discuss the possibility that retinoids are developmental signals which regulate axial patterning in the early vertebrate embryo.

Animals↗
PubMed2005

Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade.

Despite advances in treatment, breast cancer continues to be the second leading cause of cancer mortality in women. Statistics suggest that while focus on treatment should continue, chemopreventive approaches should also be pursued. Previous studies have demonstrated that naturally occurring retinoids such as 9-cis retinoic acid (9cRA) can prevent breast cancer in animal models. However, these studies have also shown that these compounds are too toxic for general use. Work from our laboratory showed that an RXR-selective retinoid LGD1069 prevented tumor development in animal models of cancer with reduced toxicity as compared to an RAR-selective retinoid TTNPB. In the present study, we investigated the mechanisms by which receptor-selective retinoids inhibit the growth of normal and malignant breast cells. Our results demonstrate that the synthetic retinoids tested are as effective as 9cRA in suppressing the growth of normal human mammary epithelial cells (HMECs) and estrogen receptor-positive (ER-positive) breast cancer cells. Although the receptor-selective retinoids induce minimal amounts of apoptosis in T47D breast cancer cells, the predominant factor that leads to growth arrest is G1 cell cycle blockade. Our data indicate that this blockade results from the downregulation of Cyclin D1 and Cyclin D3, which in turn causes Rb hypophosphorylation. Non-toxic retinoids that are potent inducers of cell cycle arrest may be particularly useful for the prevention of breast cancer.

Antineoplastic Agents↗
PubMed1987

In vitro effects of retinoids on murine thymus-dependent and thymus-independent mitogenesis.

The effects of three retinoids: all-trans-retinoic acid (RA), 13-cis-retinoic acid (13-cis-RA), and N-(4-hydroxyphenyl)retinamide (4-HPR) on murine splenic lymphocyte proliferative responses to mitogens were evaluated. The responses to T-cell mitogens, PHA and Con A, and a T-cell-dependent B-cell mitogen, PWM were significantly potentiated by these retinoids. However proliferative responses to a B-cell mitogen, Escherichia coli LPS were unaffected or inhibited. All three retinoids at concentrations ranging from 10(-6) to 10(-15) M significantly potentiated Con A-induced proliferative responses. In response to PWM, 10(-13) M RA, 10(-12) M 13-cis RA, and 10(-11) M 4-HPR were the lowest concentrations producing significant potentiation. Endpoint concentrations of retinoids significantly potentiating responses to PHA were; 10(-9) M RA, 10(-8) M 13-cis RA, and 10(-6) M 4-HPR. These responses were independent of retinol contained in fetal calf serum supplemented medium since responses were reproduced in serum-free medium devoid of retinol. Optimal potentiation by retinoids of responses to these T-cell-dependent mitogens were found at superoptimal concentrations of mitogen suggesting a selective inhibition of T-suppressor cells. Thus, potentiation of T-cell-dependent mitogen responses provides the most sensitive biological assay yet described for detection of retinoid activity and is a reproducible system to explore the cellular and molecular mechanisms of retinoid-mediated immunopotentiation.

Animals↗
PubMed1986

Structure-activity relationships of retinoids in developmental toxicology. II. Influence of the polyene chain of the vitamin A molecule.

The comparative teratogenic potencies of 7,8-dihydroretinoic acid, 7,8-dehydroretinoic acid, 9,10-dihydroretinoic acid, 9-cis-retinal, hydroxenin, oxenin, the C15 analog of all-trans-retinoic acid, abscissic acid, beta-C14 aldehyde, beta-ionone, and psuedoionone were determined in golden Syrian hamsters and compared with that of all-trans-retinoic acid. A single oral dose of each retinoid on Day 8 of gestation failed to induce signs of retinoid intoxication in the dams and the maternal weight gain was not affected significantly, except after treatment with beta-C14 aldehyde, pseudoionone, and the lowest dose of 9-cis-retinal, where maternal weight was depressed. A significant teratogenic response was observed after intubation of 7,8-dihydroretinoic acid, 7,8-dehydroretinoic acid, or 9-cis-retinal. The highest dose of hydroxenin (equivalent to nearly seven times an equimolar teratogenic dose of all-trans-retinoic acid) showed a limited teratogenic response. None of the remaining retinoids induced terata. The results suggest that the side chain plays an important role in retinoid embryotoxicity and that even minor structural alterations of retinoids at the side chain can abolish teratogenic activity. The present results indicate that a polyene chain of greater than five carbon atoms was necessary for retinoid teratogenic activity and that the presence of the ring, the nine-carbon side chain, and the acidic polar terminus was insufficient to ensure teratogenic activity. Retinoid teratogenicity in hamsters required the hydrophobic ring, a terminal polar group with an acidic pKa, and the hydrophobic, curved plane of the tetraene chain.

Animals↗
PubMedDate not supplied

Modulation of in vitro T cell alloreactivity by synthetic retinoids.

Diversity of the effects of retinoids on virtually all components of the immune system makes them important immunomodulators. We recently suggested the mechanism of the inhibitory effect of some synthetic retinoids on lectin-induced T cell proliferation, acting predominantly on events occurring after the interaction of IL-2 and its receptor. To identify further immunomodulatory effects, two synthetic retinoids, etretinate and tretinoin, have been studied in a model of the in vitro proliferative response of rat T lymphocytes to alloantigens. Both retinoids, present at non-toxic concentrations, significantly decreased the lymphocyte proliferation in the unidirectional mixed lymphocyte reaction. In experiments designed to examine whether decreased proliferative response to alloantigens is a result of the reduced antigen presenting properties of stimulator cells caused by retinoids, it was shown that preincubation of allogeneic stimulator cells with either etretinate, or tretinoin enhanced rather than reduced their capacity to stimulate fresh responder lymphocytes. Finally, examination of the effect of retinoids on the generation of non-specific suppressor T cells by Con A showed that tretinoin and etretinate potentiated the induction of cells which inhibit alloantigen-stimulated proliferation of fresh responder cells. Thus, our results strongly support the concept that, besides a direct inhibitory effect of synthetic retinoids on alloresponsive T cells, an additional indirect mechanism may exist, which involves potentiation of the induction of suppressor T cells.

Animals↗
PubMed1991

Differential effects of retinoids on pokeweed mitogen induced B-cell proliferation vs immunoglobulin synthesis.

The effects of three retinoids, all-trans-retinoic acid (RA), 13-cis-retinoic acid (cRA), and N-(4-hydroxyphenyl) retinamide (4-HPR) on mouse splenocyte responses to pokeweed mitogen (PWM) and Escherichia coli lipopolysaccharide (LPS) in vitro were evaluated. All three retinoids caused a dose dependent increase in the proliferative response to PWM. The retinoids hierarchy of efficacy based on potentiation of PWM-induced splenocyte proliferation was RA greater than cRA greater than 4-HPR. 13-cis-retinoic acid and 4-HPR also resulted in significant increases in Ig secretion in response to PWM. However, RA did not produce a significant increase in secretion compared with cells treated with PWM alone. The efficacy hierarchy of retinoids ability to potentiate Ig secretion was 4-HPR greater than cRA greater than RA. All three compounds did not affect Ig secretion from LPS-stimulated splenocytes and produced dose dependent decreases in proliferation. Both inhibition of LPS-induced proliferation and potentiation of PWM-induced proliferation were maximal when the retinoids were added during the first hour of culture. These results indicate that retinoids have a differential effect on Ig secretion and B-cell proliferation based on structural differences of the retinoids. Potentiation of proliferation and Ig secretion are both T-cell dependent and could be a result of increased lymphokine synthesis by the T-cells or increased responsiveness to the effects of the T-cell produced lymphokines.

Animals↗
PubMed1988

Alterations in retinoid concentrations in several extrahepatic organs of rats by 3,4,3',4'-tetrachlorobiphenyl.

In this study, the effect of polychlorinated biphenyls on retinoid homeostasis was investigated in Sprague-Dawley rats, by analysing [3H]retinoid concentrations in peripheral organs, following exposure to 3,4,3',4'-tetrachlorobiphenyl (TCB). The rats were rendered retinoid-deficient through dietary restriction, followed by dietary supplementation with [3H]retinol for 14 days, in order to facilitate determination of retinoid concentrations in various tissues. At day 7 of [3H]retinol supplementation the rats were exposed to a single i.p. dose of 15 mg TCB dissolved in corn oil/kg body weight. In corn oil-treated control rats, the highest concentrations of [3H]retinoid radioactivity, consisting mainly of retinol and several retinylesters, were obtained in the liver (greater than 10(6) cpm/g,), followed by the kidney and the lung, while only minor concentrations were found in skin and heart. Exposure to TCB resulted in a significant reduction of both retinol and retinylester concentrations in the liver (to 25% of controls) and the lung (to 44% of controls), while in the heart a reduction of retinol to 35% of controls was observed. No significant alterations in retinoid concentrations were observed in the skin and kidney. It is suggested that the reductions in retinoid concentrations might contribute to the toxicological alterations reported in these organs upon exposure to TCB.

Animals↗
PubMed1995

Chemical structure--teratogenicity relationships, toxicokinetics and metabolism in risk assessment of retinoids.

Retinoic acid, an oxidative metabolite of vitamin A, is involved in the control of many biological processes including embryonic development and excess as well as deficiency of retinoids has been found to be teratogenic. The effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors, the RARs and RXRs, which exhibit specific temporal and spatial expression during development. Evidence accumulates that any alteration of this complex retinoid system may be related to teratogenic effects. Here we investigate the influence of toxicokinetic parameters, including aspects of metabolism and placental transfer, on the teratogenic potency of retinoids. It is demonstrated that activation (oxidation of retinoic acids; hydrolysis of glycoconjugates) and deactivation reactions (isomerization from trans- into cis-configuration; beta-glucuronidation) relate to teratogenesis. The beta-glucuronides of retinoic acids show poor placental transfer and prolonged presence in the maternal organism. Non-retinoid compounds such as antiepileptic agents may exert some of their teratogenicity via alteration of endogenous retinoid levels.

Abnormalities, Drug-Induced↗
PubMed2004

Kinetics of human alcohol dehydrogenase with ring-oxidized retinoids: effect of Tween 80.

Human alcohol dehydrogenases (ADH1 and ADH4) actively use retinoids oxidized at the cyclohexenyl ring (4-oxo-, 4-hydroxy-, and 3,4-didehydro-retinoids), which are functional compounds in several cells and tissues (i.e., in human skin). Remarkably, activities with 4-oxo-retinal and 4-hydroxy-retinol (kcat = 2050 min(-1) for ADH4) are the highest among retinoids, similar to those of the best aliphatic alcohols. Thus, ADH1 and ADH4 provide a metabolic pathway for the synthesis of the corresponding retinoic acids. Tween 80, a widely used detergent in the retinoid activity assay, behaves as a competitive inhibitor. The Km values for all-trans-retinol (2-3 microM), estimated in the absence of detergent, are 10-fold lower than those obtained at the usual 0.02% Tween 80. This suggests a contribution of ADH to retinoid metabolism more relevant than previously expected. However, Tween 80 stabilizes retinoids in water solution and provides a reliable and reproducible assay, suitable for comparing different ADHs and different retinoid substrates.

Alcohol Dehydrogenase↗
PubMed2006

Molecular and metabolic retinoid pathways in human amniotic membranes.

Vitamin A (retinol) and its active derivatives (the retinoids) are essential for the growth and development of the mammalian fetus and placenta. The amniotic membranes are extra-embryonic structures that are indispensable for normal gestation in mammals. Although placental involvement of retinoids is clearly established, little is known about the roles of retinoids for the associated amniotic membranes. The aim of this study was to define the metabolic and molecular pathways of retinoic signaling in human fetal membranes. The expression of retinoid receptors (RARalpha, beta and RXRalpha, beta) was established at transcript and protein levels. Enzymes involved in retinoic acid generation were also detected. The enzymatic generation of functional retinoids was confirmed using specific inhibitors of retinol metabolism. Finally, the functionality of retinoid pathways was demonstrated by inducing established retinoid target gene expression. Our results clearly demonstrated that the molecular and metabolic actors of retinoic signaling pathways are functional in human fetal membranes.

Amnion↗
PubMed2004

Docosahexaenoic acid reduces haloperidol-induced dyskinesias in mice: involvement of Nur77 and retinoid receptors.

BACKGROUND: Treatment of schizophrenia's symptoms with typical antipsychotic drugs shows some efficacy, but the induction of extrapyramidal symptoms represents a serious handicap, which considerably limits their usefulness. Recent evidence suggests that Nur77 (nerve growth factor-induced B) and retinoids are involved in biochemical and behavioral effects of antipsychotic drugs associated with striatal functions. METHODS: We evaluated the effect of retinoid ligands on oral dyskinesias (vacuous chewing movements) induced by haloperidol in wild-type and Nur77-deficient mice. RESULTS: Nur77 gene ablation (knockout) or administration of a retinoid antagonist induced vacuous chewing movements and exacerbated those induced by haloperidol, whereas the retinoid agonist docosahexaenoic acid (an omega-3 polyunsaturated fatty acid) reduced them. Both the prodyskinetic effect of the retinoid antagonist and the antidyskinetic effect of docosahexaenoic acid are dependent on the presence of Nur77, since these drugs remained inactive in Nur77 knockout mice. CONCLUSION: These results suggest that nuclear receptors Nur77 and retinoid X receptor are involved in haloperidol-induced dyskinesias and that retinoid agonists may represent a new way to improve typical antipsychotic drug therapy.

Analysis of Variance↗
PubMed2005

Retinoids as chemoprevention for head and neck cancer: where do we go from here?

The retinoids, natural and synthetic derivatives of vitamin A, have a promising role in the chemoprevention of head and neck squamous cell carcinoma despite facing the limitations of toxicity as well as innate and acquired resistance. Adhering to the concept of field cancerization and following multi-step carcinogenesis, premalignant lesions of the head and neck have long been the focus of intervention with retinoids. Similarly, these agents have been applied towards preventing second primary malignancies from developing following curative therapy for upper aerodigestive cancers. Despite encouraging response rates, the need for overcoming innate and acquired retinoid resistance as well as minimizing retinoid-related toxicity will likely be relegated to the new generation of receptor-selective, synthetic retinoids. In the interim, retinoid-non-retinoid combinations as well as other classes of chemopreventive agents seem to provide promise in curtailing the incidence of aerodigestive malignancies.

Chemoprevention↗
PubMed2003

Chromatographic analysis of endogenous retinoids in tissues and serum.

We present a reliable, highly sensitive, and versatile method for the simultaneous determination of endogenous polar (acidic) and apolar (retinol, retinal, and retinyl esters) retinoids in various biological matrices. Following a single liquid extraction of retinoids from tissues or plasma with isopropanol, polar retinoids are separated from apolar retinoids and neutral lipids via automated solid-phase extraction using an aminopropyl phase. After vacuum concentration to dryness and reconstitution of the residue in appropriate solvents, the obtained fractions are injected onto two different high-performance liquid chromatography (HPLC)-systems. Polar retinoids are analyzed on a RP18 column (2.1mm ID) using a buffered gradient composed of methanol and water and on-column-focusing large-volume injection. Apolar retinoids are separated on a normal-bore RP18 column using a nonaqueous gradient composed of acetonitrile, chloroform, and methanol. Both HPLC systems are coupled with UV detection, and retinoids are quantitated against appropriate internal standards. The method was validated with regard to recovery, precision, robustness, selectivity, and analyte stability. Using 400 microl serum or 200mg tissue, the limits of detection for all-trans-retinoic acid were 0.15ng/ml or 0.3ng/g, respectively. The corresponding values for retinol were 1.2ng/ml or 2.4ng/g, respectively. This method was successfully applied to mouse, rat, and human tissue and serum samples.

Adult↗
PubMed2002

Retinoids and steroids regulate menstrual phase histological features in human endometrial organotypic cultures.

OBJECTIVE: To determine whether organotypic cultures of human endometrium can be manipulated with hormones to exhibit histological features resembling different menstrual cycle phases. DESIGN: Human menstrual cells were collected and cultured in monolayer and organotypic cultures. SETTING: Healthy volunteer in an academic research environment. PATIENT(S): An individual premenopausal woman. INTERVENTION(S): Endometrial cultures were grown in collagen gels for 4 weeks, and exposed to various steroid and retinoid treatments. MAIN OUTCOME MEASURE(S): Histological features and expression of cytokeratins, vimentin, and reticulin. RESULT(S): Cultures developed multiple glands and surface epithelium that exhibited positive cytokeratin and negative vimentin staining. Single stromal cells inside the collagen exhibited negative cytokeratin and positive vimentin staining. Networks of reticulin fibers produced by the cells were increased by estrogen, decreased by progesterone, and unaffected by retinoids. Contraction of the collagen gels was inhibited by retinoids that activated retinoic acid receptors (RARs), but not by a retinoid specific for retinoid X receptors (RXRs). The combination and timing of retinoid and steroid hormone treatments were demonstrated to induce tissue architecture and histological features that resembled either proliferative or secretory phases. CONCLUSION(S): Growth of menstrual cells in collagen can be manipulated with retinoids and steroids to resemble histological features of the proliferative and secretory phases.

Adult↗
PubMed2003

Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling.

Vitamin A and its derivatives, the retinoids, have recently been reported to be implicated in the synaptic plasticity of the hippocampus and in cognitive functions. Acting via transcription factors, retinoids can regulate gene expression via their nuclear receptors [retinoic acid receptors (RARs) and retinoid X receptors (RXRs)]. We recently showed that a moderate (about 30%) hypoexpression of brain (and hippocampal) retinoid signalling, like that naturally occurring in the aged brain of mice, might be related to a selective relational memory deficit. To further assess this hypothesis, the present study investigated the effects of Vitamin A deprivation of varying duration both on the brain expression of retinoid receptors (RARbeta and RXRbeta/gamma) and two associated target genes [tissue-type transglutaminase (tTG) and neurogranin, (RC3)], and on radial maze discrimination learning using young adult mice as subjects. We observed that irrespective of its duration (i.e. 31 or 39 weeks), Vitamin A deprivation resulted in a significant reduction (25-30%) in the expression of brain RARbeta, RXRbeta/gamma and tTG mRNAs. Conversely, only the 39-week condition was found to induce a significant decrease in brain RC3 mRNAs contents and a selective relational memory impairment. Finally, daily administration of retinoic acid (RA) failed to reverse the 39-week Vitamin A deficiency (VAD)-related cognitive deficit and to fully normalise the associated brain retinoid hyposignalling. In particular, there was no evidence for an up-regulating effect of RA on whole brain (and hippocampal) RC3 mRNAs of the 39-week-depleted mice. The results show that post-natal VAD may induce a selective memory impairment and give further support to the hypothesis that the fine regulation of retinoid-mediated gene expression is important for optimal brain functioning and higher cognition.

Animals↗
PubMed1992

Retinoids for the future: oncology.

A major incentive for the development of the synthetic retinoids has been their potential for the treatment and prevention of cancer. Early studies demonstrated that treatment with isotretinoin or etretinate alone could result in the regression of some existing skin cancers. However, even at high doses the response rates were poor. Greater efficacy has been observed with retinoids used in the prevention of cancer of the skin and oral cavity in high-risk patients. The potential for retinoids as chemopreventive agents is being further explored as selected retinoids are being targeted to specific malignancies, such as fenretinide for breast cancer chemoprevention. The effectiveness of tretinoin as a treatment for promyelocytic leukemia has raised enthusiasm for retinoids as cancer therapeutic agents. Furthermore, evidence of synergy between the retinoids and a variety of cytokines as enhances of differentiation chart a bright future for retinoids in oncology.

Animals↗