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PubMed1988

Effects of retinoids on macrophage function and IL-1 activity.

The effects of three retinoids, all-trans-retinoic acid (RA), 13-cis-retinoic acid (cRA), and N-(4-hydroxyphenyl) retinamide (4-HPR), on macrophage function were evaluated. In vitro, RA, cRA, and 4-HPR caused a greater than twofold increase in phagocytosis of IgG-sensitized bovine erythrocytes (IgG-ORBC) by a mouse macrophage cell line (RAW). Significant increases in phagocytosis were produced by retinoid concentrations as low as 2 x 10(-10) M. RA also significantly increased phagocytosis of IgG-sensitized ORBC by BALB/c peritoneal macrophages in vitro. The ability of RAW macrophages to bind IgG-ORBC was significantly increased by 10(-6) to 10(-14) M RA. The potentiation of mitogenic responses of spleen cells to Con A and PWM by RA was relatively independent of macrophage function, i.e., splenocytes that were macrophage-depleted were responsive to the potentiating effects of RA. The effects of retinoids on T-cell-dependent B-cell mitogenesis induced by PWM appeared not to be dependent on their previously reported capacity to alter prostaglandin synthesis. Treatment of spleen cells with 10(-6) M indomethacin did not abolish the potentiating effects of RA. However, RA in a dose-dependent fashion increased IL-1 activity at the level of the target T-cell. The greatest potentiation of IL-1 activity was at 10(-8) M RA. These results show that retinoids can modulate macrophage function at two different levels: potentiation of phagocytosis and potentiation of IL-1 activity at the level of the T-cell.

Animals↗
PubMed1995

Retinoid absorption from simple and mixed micelles in the rat intestine.

The absorption of three retinoid analogs etretinate (ET), acitretin (ETA), and motretinid (MOE) from two distinct micellar systems was studied in the rat intestine. Each of the three drugs was loaded into simple micelles consisting of 10 mM sodium taurocholate (NaTC) and mixed micelles consisting of 10 mM egg phosphatidylcholine (PC) and 10 mM NaTC. Following perfusion through the jejunum segments, both the fraction of drug disappearing from the segment and the permeability of the drug from the lumen into the gut wall (Peff) was greater with the mixed micelles as compared to the simple micelles. Perfusion flow rate had an influence on the Peff for ET and ETA. Similar trends as for the jejunum were seen in the ileum perfusions. The simultaneous uptake of PC and NaTC during the retinoid perfusions was monitored. There appeared to be a correlation between the Peff values for PC and that of the retinoids. The viability of the in-situ perfusion system was confirmed histologically. There is evidence to indicate that the permeability of the intestine is sensitive to subtle differences in the chemical structure of the retinoids.

Animals↗
PubMed2005

Transcriptional regulation of connexin 43 expression by retinoids and carotenoids: similarities and differences.

Gap junctions, connexons, are formed by assembly of trans-membrane connexin proteins and have multiple functions including the coordination of cell responses. Most human tumors are deficient in gap junctional communication (GJC) and restoration of GJC by forced expression of connexins reduces indices of neoplasia. Expression of connexin 43 (Cx43), the most widely-expressed connexin family member, is upregulated by cancer-preventive retinoids and carotenoids in normal and preneoplastic cells; an action considered of mechanistic significance. However, the molecular mechanism for upregulated expression is poorly understood. The retinoic acid receptor antagonist Ro 41-5253 was capable of suppressing retinoid-induction Cx43 luciferase reporter construct in F9 cells, but did not suppress reporter activity induced by the non-pro-vitamin A carotenoids astaxanthin or lycopene, indicating that retinoids have separate mechanisms of gene activation than non-pro-vitamin A carotenoids. Neither class of compound required protein synthesis for induction of Cx43 mRNA, nor was the 5.0 h half-life of Cx43 mRNA altered, indicating direct transcriptional activation. The responsive region was found within -158 bp and +209 bp of the transcription start site; this contains a Sp1/Sp3 GC-box to which Sp1 and Sp3 were bound, as revealed by electrophoretic mobility shift assays (EMSA), but no retinoic acid response element (RARE). Site directed mutagenesis of this GC-box resulted in increased basal levels of transcription and loss of responsiveness to a synthetic retinoid. In this construct astaxanthin and lycopene produced marginally, but not significantly higher, reporter activity than the control.

Animals↗
PubMed1991

Influence of retinoids on sister chromatid exchanges and chromosomes in cultured human embryonic palatal mesenchymal cells.

The cytogenetic effects of retinoids and their metabolites on human embryonic palatal mesenchymal (HEPM) cells were investigated in cell culture. Treatment with 13-cis, 4-oxo-13-cis-, and all-trans-retinoic acids did not induce chromosomal structural aberrations even at high concentrations in the presence or absence of metabolic activation system. The frequencies of sister chromatid exchanges (SCE) tended to decrease in HEPM cells treated with retinoids in the absence of S-9. 4-Oxo-13-cis-retinoic acid, which is one metabolite of 13-cis-retinoic acid, significantly decreased the SCE frequencies. The mitotic index decreased with increasing concentration of retinoic acids, indicating that retinoids inhibit cell proliferation in HEPM cells. We concluded that retinoids inhibit cell proliferation in HEPM cells in culture without causing DNA or chromosome damage.

Cells, Cultured↗
PubMed1999

1,25-Dihydroxyvitamin D(3) and 9-cis-retinoids are synergistic regulators of 24-hydroxylase activity in the rat and 1, 25-dihydroxyvitamin D(3) alters retinoic acid metabolism in vivo.

The RXR forms a heterodimer with the VDR to activate genes that are regulated by 1,25(OH)(2)D(3). In the absence of RXR's ligand, 9-cis-RA, RXR appears to be a silent partner to VDR. The effect of 9-cis-RA on VDR/RXR heterodimer formation and 1, 25(OH)(2)D(3)-mediated gene expression in vivo remains unclear. We examined the effect of exogenous 9-cis-RA or 9-cis-RA precursors, 9, 13-di-cis-RA and 9-cis-RCHO, on 1,25(OH)(2)D(3)-mediated induction rat renal 24-hydroxylase. The rats were treated as follows: (1) vehicle; (2) 1,25(OH)(2)D(3); (3) 1,25(OH)(2)D(3) + 9-cis-RA; (4) 1, 25(OH)(2)D(3) + 9,13-di-cis-RA; (5) 1,25(OH)(2)D(3) + 9-cis-RCHO; (6) 9-cis-RA; (7) 9,13-di-cis-RA; and (8) 9-cis-RCHO. 1, 25(OH)(2)D(3) was administered IP 18 h prior to sacrifice. The retinoids were administered every 4 h, starting 28 h prior to sacrifice. The last retinoid dose was administered 4 h prior to sacrifice. Treatment with 1,25(OH)(2)D(3) alone increased 24-hydroxylase from 35 +/- 6 (controls) to 258 +/- 44 pmol/min/g tissue. When 1,25(OH)(2)D(3) was administered with 9-cis-RA, 9, 13-di-cis-RA, or 9-cis-RCHO, 24-hydroxylases were 568 +/- 56, 524 +/- 56, and 463 +/- 62 pmol/min/g tissue, respectively. Furthermore, codosing of 1,25(OH)(2)D(3) and 9-cis-retinoids resulted in higher circulating concentrations of 9-cis-RA and 9,13-di-cis-RA when compared to rats dosed with 9-cis-retinoids alone. This was shown to be due to 1,25(OH)(2)D(3) increasing the half-life of 9,13-di-cis-RA by three to four times. These results show that 9-cis-RA can act synergistically with 1,25(OH)(2)D(3) in the regulation of 24-hydroxylase in vivo. Additionally, 1,25(OH)(2)D(3) regulates 9, 13-di-cis-RA metabolism in vivo.

Animals↗
PubMed1994

Physicochemical parameters affecting the charcoal adsorption assay for quantitative retinoid-binding measurement.

The different parameters affecting the accuracy and reliability of the dextran-coated charcoal adsorption assay for characterization of retinoic acid receptors ligand binding activity were investigated. Using dextran-coated charcoal (DCC) at a final 10 mg/ml concentration, an efficient adsorption of free [3H]retinoic acid was observed with a yield in the range 99.2 to 99.8% for ligand concentrations varying from 10(-9) to 10(-4) M. Nonspecific adsorption of retinoic acid reached 50% to polystyrene and silanized glass and 70% to uncoated glass. Results obtained by the DCC method and by gel-filtration assay were correlated; however, the DCC assay appeared easier to perform and gave more reproducible results. When a careful measurement of free retinoid concentration was performed, the apparent equilibrium dissociation constant (KD) of retinoic acid was 3.1 +/- 0.4 nM and the KD of CD367, a synthetic retinoid, was 1.8 +/- 0.3 nM. Optimal pH for the binding of [3H]retinoic acid or [3H]CD367 was in the range 7.5 to 8.5. Under the conditions described for the adsorption assay, bound retinoid measurement was linearly related to the protein concentration between 0.05 and 0.25 mg/ml. At a lower protein concentration, addition of bovine serum albumin exerted a stabilizing effect on retinoid binding, allowing an accurate measurement of the number of specific binding sites. Using retinoic acid as ligand, bacterial extracts often resulted in a level of nonspecific binding in the range 10-25%. It could be lowered (4-10%) when resorting to [3H]CD367.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed2001

A novel retinoid-response gene set in vascular smooth muscle cells.

A modified suppression subtractive hybridization assay was performed to uncover genes induced by all-trans retinoic acid in cultured smooth muscle cells (SMC). Northern blotting studies confirmed the induction of 14 genes, many of which have heretofore been unrecognized as retinoid-inducible. Temporal expression and cycloheximide studies allowed us to categorize these genes as either immediate-early (LOX-1, endolyn, Stoned B/TFIIA alpha/beta-like factor, Src Suppressed C Kinase Substrate, and tissue transglutaminase) or delayed (cathepsin-L, ceruloplasmin, epithelin, importin alpha, alpha(8)-integrin, lactate dehydrogenase B, retinol dehydrogenase, spermidine/spermine N(1)-acetyltransferase, and VCAM-1) retinoid-response genes. A survey of rat tissues showed two of the genes (tissue transglutaminase and alpha(8)-integrin) to be highly restricted to vascular tissue. In situ hybridization verified expression of both tissue transglutaminase and alpha(8)-integrin to SMC in balloon-injured rat carotid artery. These findings unveil a new retinoid-response gene set that should be exploited to define molecular pathways involved in the antagonistic effects of retinoids on SMC growth and neointimal formation.

Animals↗
PubMed1994

A concentration gradient of retinoids in the early Xenopus laevis embryo.

Previous studies have postulated that Xenopus embryos contain an endogenous retinoic acid (RA) concentration gradient from posterior to anterior during the process of primary axis formation, since RA is able to alter profoundly primary axis formation in Xenopus embryos, to increase the expression of some posterior markers, and to inhibit the expression of some anterior markers, including homeobox-containing genes. Here, we provide direct evidence for this hypothesis. By using a reporter cell system, we demonstrate that the endogenous biologically active retinoid concentration in whole Xenopus embryos increases 3-fold from the two-cell stage to the neurula stage, and that the active retinoid concentration in the dorsal marginal zone, a region wherein the Spemann's organizer is located, increases about 5-fold from the early gastrula to late gastrula stages, suggesting the developmental regulation of the retinoid levels. In the early neurula stage (stage 13-14), endogenous active retinoids are present in a concentration gradient with the highest level at the posterior end, about 10-fold higher than that at the anterior end, of the embryo. This concentration gradient may be established during gastrulation and may provide positional cues for primary axis formation.

Animals↗
PubMed1996

Estrogen induces retinoid receptor expression in mouse cervical epithelia.

Steroid hormones and retinoids are powerful regulators of normal epithelial differentiation and function in the mouse female reproductive tract, where their actions are mediated by nuclear receptors. The expression pattern, heterodimeric interactions, and availability of ligand of these transcription factors are thought to contribute to the biological response. Estrogen (E2) induces proliferation and squamous differentiation of the cervical and vaginal epithelium during the mouse estrous cycle, while progesterone and retinoids maintain the simple columnar epithelium of the endocervix and uterine horns. We wanted to investigate whether retinoid receptors are responsive to estrogen status during cervical epithelial differentiation induced by a single dose of estrogen in ovariectomized adult mice. Northern blot analysis demonstrated a prolonged induction of RXR alpha and RAR gamma gene expression by E2 in the mouse cervix and vagina. When the induction of RXR alpha and RAR gamma was compared to genes known to be responsive to E2, including estrogen receptor (ER) and c-fos, RXR alpha was induced within 0.5 h of hormone treatment, while RAR gamma induction was evident by 4 h. The induction of these retinoid receptors suggests that they may be implicated in epithelial growth and differentiation in response to E2. Moreover, potential heterodimeric interactions among these receptors indicate that normal, cyclical epithelial differentiation results from the interplay of these molecules. Using in situ hybridization analysis, RXR alpha transcripts were localized preferentially in the basal cells, while ER mRNA was expressed throughout the epithelium of the ectocervix and vagina. Furthermore, ER transcripts were highly expressed in the stratified squamous foci induced by mild vitamin A depletion in the columnar epithelium of the endocervix and uterine horns. Therefore, the induction of RXR alpha and RAR gamma by E2 and their expression pattern in relation to ER suggest that they are needed to coordinate specific genetic programs that result in cervical epithelial growth and differentiation.

Animals↗
PubMed1997

Modulation of the retinoic acid and retinoid X receptor signaling pathways in P19 embryonal carcinoma cells by calreticulin.

Calreticulin is a widely expressed calcium binding protein that can bind to an amino acid sequence motif, KXGFFKR, which is present in the cytoplasmic domain of all integrin alpha-subunits. Closely related sequences, KXFFKR and KXFFRR, are encoded in the DNA-binding domain of all members of the steroid/thyroid/retinoid receptor superfamily and it has recently been demonstrated that calreticulin inhibits their activity both in vitro and in vivo. Here we present novel evidence that calreticulin can interfere directly with the retinoic acid (RARs) and retinoid X (RXRs) receptor pathways. Calreticulin exhibits the ability to inhibit DNA-binding activity of both heterodimeric RAR/RXR and homodimeric RXR complexes in vitro. Inhibition of RXR binding to DNA is achieved with a concentration of calreticulin that is approximately fourfold lower than that required for inhibition of RAR/RXR binding to a cognate binding site. Coprecipitation experiments suggest a direct protein:protein interaction between calreticulin and retinoid receptors. Stable overexpression of calreticulin in P19 embryonal carcinoma cells significantly decreases the rapid activation of the endogenous RA-responsive RARbeta gene, abrogates the ability of endogenous RAR/RXR complexes to bind to DNA, and inhibits the emergence of the RA-induced differentiated phenotype. These data demonstrate that calreticulin can interfere with the two distinct retinoid signaling pathways through a mechanism likely involving direct protein:protein interactions and that disruption of the retinoid signal alters biological processes in vivo.

Amino Acid Sequence↗
PubMed1997

Altered sensitivity to retinoid-induced apoptosis associated with changes in the subcellular distribution of Bcl-2.

In the acute promyelocytic leukemia cell line NB4, Bcl-2 downregulation occurred as a late event of retinoid-induced differentiation. In the maturation-resistant NB4-R1 subclone, retinoids failed to downregulate Bcl-2 even in the situation of apoptosis massively induced by pan-agonists and RXR-selective agonists. We observed that NB4 and NB4-R1 cells differed with respect to the intracellular localization of Bcl-2 which showed a perinuclear localization in NB4-R1 cells, while Bax was broadly expressed in the cytoplasm and to only a minor extent in the perinuclear area. Therefore, the distinct intracellular localization of Bcl-2 and Bax was in general nonoverlapping. Bcl-2 remained massively expressed until cell disruption. Bax was not significantly upregulated in cells committed to death. However, Bax localization changed from a diffuse pattern to concentrate in few specific cytoplasmic area at a stage preceding the formation of apoptotic bodies. A human Bcl-2 transgene was transiently overexpressed in NB4-R1 cells which showed increased resistance to apoptosis induced by retinoids. Stably transfected clones of NB4-R1 cells showed an increased expression of Bcl-2 and a marked resistance to apoptosis. Interestingly, the overexpression of Bcl-2 restored a pattern of uniform Bcl-2 labeling in the cytoplasm and, remarkably, the colocalization of Bcl-2 with Bax. This work demonstrates that the ability of retinoid-induced cells to undergo apoptosis depends on the level of expression and the functional interaction between Bcl-2 and Bax.

Apoptosis↗
PubMed1994

Cell-type- and developmental-stage-specific metabolism and storage of retinoids by embryonic chick retinal cells in culture.

Biological functions of retinoids in the vertebrate retina include the role of 11-cis retinaldehyde as visual pigment chromophore, and possible effects of retinoic acid in histogenesis and cell survival. Qualitative and quantitative regulation of retinoid availability for these complex processes could involve several cell types, including retinal pigment epithelium, Müller glia and retinal photoreceptors and non-photoreceptor neurons; their relative contributions, however, have not been fully elucidated. Using purified cultures, we have carried out a study of cell-type-specific metabolism and storage of retinoids in chick embryo retinal photoreceptors and other neuronal cells, as compared to those of retinal glia. Retinal glia were found to synthesize both retinoic acid and retinyl esters, and to hydrolyse the latter; they also displayed retinol dehydrogenase activities. Cultured neurons and photoreceptors also synthesized and hydrolysed retinyl esters; their capacity for retinaldehyde synthesis from a retinol or retinyl ester substrate suggested the presence of retinol dehydrogenase activity. Retinoic acid was not synthesized in differentiated neuronal cultures, although some synthesis was detectable at early culture stages when the cells were still morphologically undifferentiated. These findings indicate that cell-type-specific metabolic activities are expressed during retinal cell differentiation in vitro, and that embryonic retinal photoreceptors and nonphotoreceptor neurons are active participants in the metabolism and storage of retinoids.

Animals↗
PubMed2002

Retinoids inhibit squamous cell carcinoma growth and intercellular communication.

BACKGROUND: Retinoids have been shown to inhibit the growth of squamous cell carcinoma and other malignancies. They have also been shown to alter gap junctional intercellular communication (GJIC) and the expression of connexins, the protein subunits of gap junctions. We report in this study that the alteration of GJIC by retinoids may be directly related to inhibitory effects on cell growth. MATERIALS AND METHODS: SCC-13 cells were treated with all-trans retinoic acid (tRA) and 13-cis retinoic acid (cRA) at 10(-7) and 10(-6) M concentrations in culture. No treatment and ethanol vehicle controls were included for each experiment. Serial cell counts of parallel cultures were performed to determine cell growth. The parachute technique was performed in combination with fluorescence activated cell sorting (FACS) analysis to determine GJIC. Northern and Western blot analysis were performed to assess connexin mRNA and protein expression. RESULTS: The growth rate was inhibited for cells treated with tRA (10(-6) M) (P < 0.05) and cRA (10(-6) M) (P = 0.068) vs. vehicle control. GJIC was significantly inhibited with both tRA (10(-7) and 10(-6) M) (P < 0.001) and cRA (10(-7) and 10(-6) M) (P < 0.001) at 24, 48, and 96 h as determined by FACS analysis. To correlate GJIC with cell growth, we studied the effect of glycyrrhetinic acid, a known inhibitor of GJIC. Glycyrrhetinic acid also significantly inhibited cell growth (P < 0.05) vs. control. Connexin 26 and connexin 43 mRNA and protein expression were not significantly altered after retinoid treatment. CONCLUSION: Retinoic acids inhibit both cell growth and GJIC in SCC-13 cells. Retinoids may inhibit cell growth through alteration of GJIC in SCC-13 cells.

Blotting, Northern↗
PubMed1997

Multiple factors contribute to the toxicity of the aromatic retinoid, TTNPB (Ro 13-7410): binding affinities and disposition.

The aromatic retinoid (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1 -propenyl] benzoic acid (TTNPB) is 1000-fold more potent as a teratogen than all trans-retinoic acid (tRA) in several species and in the inhibition of chondrogenesis in the mouse limb bud cell culture. Factors responsible for the potency of TTNPB were investigated including binding to nuclear retinoic acid receptors (RARs and RXRs), cytosolic binding proteins (CRABPs), and metabolic disposition of TTNPB. For competitive binding assays and saturation kinetics, nucleosol or cytosol fractions were obtained from COS-1 cells transfected with cDNAs encoding the appropriate nuclear receptor or binding protein. TTNPB binds to RAR alpha, beta, and gamma with Kds in the nanomolar range; however, these binding affinities are 10-fold less than those of tRA. Although the affinities are high for TTNPB, it is unlikely that the binding affinities to nuclear receptors alone account for the potency of TTNPB. The binding affinities of TTNPB for the CRABPs are significantly lower than those of tRA. TTNPB did not compete with [3H]9-cis RA for binding to RXR alpha, beta, or gamma. Mouse limb bud cell cultures, a well characterized model for retinoid teratogenesis, were used to compare the metabolic disposition of TTNPB and tRA. In the media of limb bud cell cultures treated with either retinoid, the disappearance of TTNPB was significantly slower than that of tRA over 72 hr. Both retinoids reached approximately equal concentrations in cell uptake experiments; however, TTNPB disappeared from the limb bud cell at a significantly slower rate than did tRA. Collectively, these results indicate that high affinity binding to RARs, lower affinity to CRABPs, and resistance to metabolism contribute to the potency of TTNPB.

Animals↗
PubMed1999

Multiple factors contribute to the toxicity of the aromatic retinoid TTNPB (Ro 13-7410): interactions with the retinoic acid receptors.

The aromatic retinoid, (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1 -propenyl] benzoic acid (TTNPB) is 1000-fold more teratogenic than all trans-retinoic acid (tRA) in several species. Factors that partially explain the potency of this retinoid include binding affinities to retinoid nuclear receptors (RARs) in the nanomolar range, reduced affinities for the cytosolic binding proteins (CRABPs), and slow rate of metabolism (M. A. Pignatello, F. C. Kauffman, and A. A. Levin, Toxicol. Appl. Pharmacol. 142, 319-327, 1997). The present work investigates the possible involvement of longer receptor occupancy and increased transcriptional activity of the ligand receptor complex in the greater toxicity of TTNPB. Ligand off-rates from nuclear receptors were determined in nucleosol fractions prepared from COS-1 cells transfected with cDNA encoding the appropriate RAR subtype. When assayed at 10 degrees C, [3H]TTNPB was displaced from the RARs at a significantly faster rate than that of [3H]tRA. The difference in displacement was reduced at 4 degrees C. These observations are consistent with the 10-fold lower affinity of TTNPB vs tRA for RARs and, therefore, do not explain the greater potency of TTNPB. The ability of TTNPB and tRA to activate the RARs was determined using a luciferase reporter gene transfected into JEG-3 cells with the appropriate RAR subtype. The expression of the reporter was driven by a retinoic acid response element (RARE) from the RAR beta gene, which was incorporated into the reporter plasmid. Dose-response for gene activation indicated that the potency of TTNPB and tRA in activating mRAR alpha, beta, and gamma was similar after 24 h with comparable EC50s in the nanomolar range. However, after 72 h, activation by TTNPB was greater than that of tRA as indicated by EC50s and threshold for activation. This study indicates that the higher potency of TTNPB in activating the RARs may be due to slower disappearance of the retinoid and, therefore, is a contributing factor to its greater toxicity.

Animals↗
PubMed2007

Contribution of targeted conditional somatic mutagenesis to deciphering retinoid X receptor functions and to generating mouse models of human diseases.

The last decade has witnessed an enormous rise in the interest for retinoid signalling and its cognate receptors, because of their central role in the coordination of development and homeostasis, through their ability to orchestrate the expression of numerous target genes. These receptors include six nuclear receptor (NR) family members, the retinoic acid receptor (RAR) alpha, beta and gamma, and the retinoid X receptor (RXR) alpha, beta and gamma, which are expressed in many cell types in mammals. Analysis of the development of mouse embryos bearing retinoid receptor null mutations demonstrated that these receptors transduce the effects of retinoic acid (RA, the active derivative of vitamin A) in vivo, and revealed impressive complexity. However, frequent redundancy in receptor functions and lethality of compound RAR-null mutants, as well as of RXRalpha-null mutants, precluded the characterisation of the functions of these receptors during late development and postnatally. We illustrate here how recent developments of conditional targeted somatic mutagenesis have opened new avenues in analysing the physiological functions of retinoid X receptor signalling in a variety of tissues and cell types, as well as in exploring the pathophysiological consequences of their alteration that led to novel mouse models of human diseases.

Adipocytes↗
PubMed1984

Ro 15-1570, a new sulfur-containing retinoid devoid of bone toxicity in rats.

Repeated ingestion of high doses of retinoids cause the so-called hypervitaminosis A syndrome. In rats the main symptoms are weight loss, alopecia, erythema, desquamation of the skin, and alterations of the skeletal system, including bone fractures. In the present study, three retinoids (Ro 15-1570, arotinoid ethylsulfone, 6 mg/kg; retinoic acid, 100 mg/kg and etretinate, 50 mg/kg) were administered orally to rats for 1 and 2 weeks, respectively, to six male and six female rats/group. All the above changes were induced by all three retinoids, with the exception that the arotinoid ethylsulfone Ro 15-1570 did not cause bone alterations. The absence of toxic effects on the bones by Ro 15-1570 was confirmed by X-ray-film examinations, densitometry of the X-rayed femora and tibiae, examination of the thickness of the femoral and tibial compacta in histological slides plus the determination of the femoral ash weight and its main inorganic constituents (calcium, magnesium, sodium, and potassium). The present demonstration that the arotinoid ethylsulfone Ro 15-1570 was devoid of bone toxicity constitutes major progress in the pharmacologic development of retinoids with a better balance between therapeutic and adverse effects.

Animals↗
PubMed1994

Human in vivo pharmacology of topical retinoids.

All-trans retinoic acid is used topically for treating a variety of dermatologic conditions ranging from acne to photoaged skin. Although the clinical effects of retinoic acid treatment are often considerable, relatively little is known about the basic mechanisms underlying such effects. With the development of an in vivo human assay we have investigated the pleiotypic effects of topical retinoids from the histologic to the molecular. Histologically, retinoic acid induces epidermal proliferation and differentiation coupled with dermal fibroblast production of collagen. Immunologic effects include stimulation of the antigen-presenting capacity of Langerhans cells and induction of keratinocyte ICAM-1 expression. At the biochemical level, retinoic acid regulates transglutaminase and tyrosinase activities and activates protein kinase C. Both polar metabolites and stereoisomers of all-trans retinoic acid are also biologically active. Molecular biologic techniques have revealed that elevation of mRNA for cellular retinoic acid binding protein II is a retinoid-related event and that nuclear receptors such as retinoic acid receptors and retinoid X-receptors may transduce the retinoid response.

Clinical Trials as Topic↗