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PubMed1997

The isolation and characterization of purified heterocomplexes of recombinant retinoic acid receptor and retinoid X receptor ligand binding domains.

Retinoic acid exerts many of its biological effects by interaction with heterocomplexes of nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). To further examine this interaction, a glutathione S-transferase (GST) fusion protein containing the ligand binding domain of human RXR alpha has been used to copurify the ligand binding domain of human RAR gamma by affinity chromatography over glutathione-agarose. Complexes of recombinant RAR-RXR ligand binding domains retaining full ligand binding capacity were purified, and their interactions with various retinoids were characterized by fluorometric titration and photoaffinity labeling. Analyses of the distribution of limiting amounts of [3H]-all-trans-retinoic acid between cytoplasmic retinoic acid binding proteins, CRABP-I and CRABP-II, and the purified heterocomplexes indicate that all-trans-retinoic acid binds with comparable affinity to CRABP-I and the heterocomplexes, but with approximately 10-fold less affinity to CRABP-II. The aromatic retinoid acitretin, which is used in the treatment of psoriasis, binds relatively poorly to the purified heterocomplexes, although it binds with high affinity to the CRABPs. Acitretin displaces [3H]-all-trans-retinoic acid from the CRABPs and increases retinoic acid occupancy of the heterocomplexes. These results suggest that certain retinoids could potentially perturb the distribution of endogenous retinoic acid between the CRABPs and the nuclear receptors and thus affect retinoid signaling. The purified recombinant complexes should provide a useful model system for further structural analysis of the dimerization interface between the RAR and RXR ligand binding domains.

Acitretin↗

PubMed1994

Synthesis of high specific activity [3H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties.

all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.

Animals↗

PubMed1997

Activation of the orphan receptor RIP14 by retinoids.

Retinoids are crucial regulators of a wide variety of processes in both developing and adult animals. These effects are thought to be mediated by the retinoic acid (RA) receptors and the retinoid X receptors (RXRs). We have identified an additional retinoid-activated receptor that is neither a retinoic acid receptors nor an RXR. RXR-interacting protein 14 (RIP14), a recently described orphan member of the nuclear receptor superfamily, can be activated by either all-trans-RA (tRA) or the synthetic retinoid TTNPB [[E]-4-[2-(5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalenyl)propen-1-yl]benzoic acid].RIP14 binds to DNA as a heterodimer with RXR. In the presence of either tRA or TTNPB, the addition of 9-cis-RA or the RXR-specific agonist LG1069 [4-[1-(3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tertrahydro-2-naphthyl)ethenyl]benzoic acid] results in additional activation. Mutations of the ligand-dependent transcriptional activation functions indicate that TTNPB activates the RIP14 component of the RIP14-RXR heterodimer, that 9-cis-RA and LG1069 activate RXR, and that tRA activates via both RIP14 and RXR. Despite the very effective activation of RIP14 by tRA or TTNPB, relatively high concentrations of these compounds are required, and no evidence for direct binding of either compound was obtained using several approaches. These results suggest that RIP14 is the receptor for an as-yet-unidentified retinoid metabolite.

Animals↗

PubMed1998

Metabolism to a response pathway selective retinoid ligand during axial pattern formation.

We report identification of 9-cis-4-oxo-retinoic acid (9-cis-4-oxo-RA) as an in vivo retinoid metabolite in Xenopus embryos. 9-Cis-4-oxo-RA bound receptors (RARs) alpha, beta, and gamma as well as retinoid X receptors (RXRs) alpha, beta, and gamma in vitro. However, this retinoid displayed differential RXR activation depending on the response pathway used. Although it failed to activate RXRs in RXR homodimers, it activated RXRs and RARs synergistically in RAR-RXR heterodimers. 9-Cis-4-oxo-RA thus acted as a dimer-specific agonist. Considering that RAR-RXR heterodimers are major functional units involved in transducing retinoid signals during embryogenesis and that 9-cis-4-oxo-RA displayed high potency for modulating axial pattern formation in Xenopus, metabolism to 9-cis-4-oxo-RA may provide a mechanism to target retinoid action to this and other RAR-RXR heterodimer-mediated processes.

Animals↗

PubMed2000

A ligand of peroxisome proliferator-activated receptor gamma, retinoids, and prevention of preneoplastic mammary lesions.

BACKGROUND: Chemoprevention of breast cancer is an active area of investigation. Recent in vivo and in vitro studies have shown that thiazolidinediones (e.g., troglitazone) and retinoids are able to inhibit the growth of breast cancer cells. Troglitazone mediates its action via peroxisome proliferator-activated receptor gamma (PPARgamma). We evaluated the ability of troglitazone, alone or in combination with retinoids, to prevent the induction of preneoplastic lesions by 7,12-dimethylbenz[a]anthracene (DMBA) in a mouse mammary gland organ culture model. METHODS: Mammary glands of BALB/c mice were treated with DMBA (2 microg/mL) to induce preneoplastic lesions in organ culture. Effects of troglitazone, all-trans-retinoic acid (retinoic acid; ligand for retinoic acid receptor [RAR] alpha), and LG10068 (ligand for retinoid X receptors [RXRs]), singly or in combination, on the development of lesions were evaluated. Expression of retinoid receptors (RARalpha and RXRalpha) and PPARgamma was determined by western blot analysis. Statistical significance was determined by generalized chi-squared analysis using the GENCAT software program and Bonferroni correction. All P values are two-sided. RESULTS: Troglitazone (at 10(-5) M) or retinoic acid (at 10(-6) M) markedly inhibited the development of mammary lesions (both P values <.05); however, together they did not enhance the effectiveness of the other. In contrast, LG10068 (at 10(-7) M or 10(-8) M) alone had very little ability to inhibit development of these lesions, but a combination of LG10068 (at 10(-8) M) and troglitazone (at 10(-5) M or 10(-6) M) almost completely inhibited (by 85% and 100%, respectively; both P values <. 05) the development of mammary lesions. The expression of PPARgamma and RXRalpha remained unchanged with the various treatments, whereas the expression of RARalpha was substantially reduced after treatment with the combination of retinoic acid and troglitazone. CONCLUSIONS: To our knowledge, this is the first report showing the possibility of a PPARgamma ligand having chemopreventive activity. Furthermore, an RXR-selective retinoid, LG10068, appears to enhance this activity.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1995

Synergistic activation of retinoic acid (RA)-responsive genes and induction of embryonal carcinoma cell differentiation by an RA receptor alpha (RAR alpha)-, RAR beta-, or RAR gamma-selective ligand in combination with a retinoid X receptor-specific ligand.

Retinoic acid receptor (RAR)-retinoid X receptor (RXR) heterodimers bind to cognate response elements in vitro more efficiently than do RAR or RXR homodimers, and both RAR and RXR partners have been shown to activate various promoters in transiently transfected cells. We have now investigated whether ligand-dependent activation of both heterodimeric partners is involved in induced expression of endogenous RA-responsive genes and in P19 and F9 cell differentiation. On their own, low concentrations of retinoids selective for either RAR alpha, RAR beta, or RAR gamma did not induce or very inefficiently induced the expression of several RA target genes or triggered differentiation. An RXR-specific synthetic retinoid was similarly inefficient at any concentration. In contrast, at the same concentrations, various combinations of RAR (RAR alpha, RAR beta, or RAR gamma) and RXR selective retinoids resulted in synergistic induction of all retinoic acid (RA) target genes examined, as well as in cell differentiation. However, the magnitude of this synergistic activation varied depending on both the RAR-RXR combination and the promoter context of the responsive genes. Promiscuous activation of the three RARs, or concomitant activation of RAR alpha and RAR gamma, at selective retinoid concentrations also resulted in induction of gene expression and cell differentiation. Taken together, our results are consistent with the conclusion that the RAR and RXR partners of RAR-RXR heterodimers can synergistically activate transcription of RA-responsive genes and can induce differentiation of P19 and F9 cells. Our results also indicate that there is a significant degree of functional redundancy between the three RAR types which, however, varies with the nature of the RA target genes.

Animals↗

PubMed1999

Allosteric regulation of the discriminative responsiveness of retinoic acid receptor to natural and synthetic ligands by retinoid X receptor and DNA.

Transcriptional activation by retinoids is mediated through two families of nuclear receptors, all-trans-retinoic acid (RARs) and 9-cis retinoic acid receptors (RXRs). Conformationally restricted retinoids are used to achieve selective activation of RAR isotype alpha, beta or gamma, which reduces side effects in therapeutical applications. Synthetic retinoids mimic some of all-trans retinoic acid biological effects in vivo but interact differently with the ligand binding domain of RARalpha and induce distinct structural transitions of the receptor. In this report, we demonstrate that RAR-selective ligands have distinct quantitative activation properties which are reflected by their abilities to promote interaction of DNA-bound human RXRalpha (hRXRalpha)-hRARalpha heterodimers with the nuclear receptor coactivator (NCoA) SRC-1 in vitro. The hormone response element core motifs spacing defined the relative affinity of liganded heterodimers for two NCoAs, SRC-1 and RIP140. hRXRalpha activating function 2 was critical to confer hRARalpha full responsiveness but not differential sensitivity of hRARalpha to natural or synthetic retinoids. We also provide evidence showing that lysines located in helices 3 and 4, which define part of hRARalpha NCoA binding surface, contribute differently to (i) the transcriptional activity and (ii) the interaction of RXR-RAR heterodimers with SRC-1, when challenged by either natural or RAR-selective retinoids. Thus, ligand structure, DNA, and RXR exert allosteric regulations on hRARalpha conformation organized as a DNA-bound heterodimer. We suggest that the use of physically distinct NCoA binding interfaces may be important in controlling specific genes by conformationally restricted ligands.

Adaptor Proteins, Signal Transducing↗

PubMed1994

Sensitive and specific detection of retinoid receptor subtype proteins in cultured cell and tumor extracts.

Subtype-specific antipeptide antibodies have been developed against each of the retinoic acid receptors (RARs alpha, beta, and gamma) and each of the retinoid X receptors (RXRs alpha, beta, and gamma). Each antibody reacts specifically with its respective recombinantly expressed protein but not with any of the other retinoid receptor subtypes, by both immunoblot and immunoprecipitation technology. We describe a sensitive and specific assay that combines the binding of cultured cell and tumor extracts to [3H]all-trans-retinoic acid or [3H]9-cis-retinoic acid with immunoprecipitation of the hormone-receptor complexes by the subtype-specific antibodies to determine the levels of functional retinoid receptor subtype proteins that are present. We also report the use of a hormone-binding assay that uses RAR- and RXR-selective compounds as competitors of the tritiated retinoids to ascertain the RAR and RXR subfamily profiles of these cells. HeLa cells contain all six retinoid receptor proteins ranging in concentration from 9 fmol/mg total protein for RAR beta and RXR gamma to 50 fmol/mg for RXR alpha. Hep G2 and HL60 cells express RAR alpha and RXR alpha proteins at approximately 20-60 fmol receptor/mg protein, and RAR beta is expressed at lower levels (approximately 5 fmol/mg) in Hep G2 cells. MCF-7 cells in culture express RAR alpha (approximately 32 fmol/mg), RAR gamma (approximately 35 fmol/mg), and RXR alpha (approximately 60 fmol/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed2004

Retinoids and receptor interacting protein 140 (RIP140) in gene regulation.

Retinoids exert pleiotropic effects in various biological processes by binding to their nuclear receptors, the retinoic acid receptors (RARs) and retinoid X receptors (RXRs), to regulate gene transcription. Apo-RARs and RXRs repress target gene expression by recruiting corepressors to the target DNA, triggering chromatin condensation by the action of histone deacetylases present in the corepressor complexes. In contrast, holo-RARs and RXRs recruit coactivators, some known to encode histone acetyl transferases, which trigger histone hyperacetylation, chromatin decondensation, and ultimately gene activation. Receptor interacting protein 140 (RIP140) represents a novel RAR/RXR coregulator that suppresses vitamin A-regulated gene expression in a retinoid- dependent manner. This review addresses the action of different retinoid ligands on gene expression, the molecular mechanisms underlying RAR/RXR-mediated gene regulation, and the unique properties of RIP140 as a novel retinoid hormone-dependent negative coregulator for RAR- and RXR-mediated gene regulation.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Receptor specificity of retinoid-induced epidermal hyperplasia: effect of RXR-selective agonists and correlation with topical irritation.

Retinoid induction of epidermal hyperplasia was investigated in hairless mice with synthetic ligands for the retinoic acid (RAR) and retinoid X (RXR) nuclear receptors. Induction of hyperplasia by all-trans retinoic acid and the RAR-specific retinoids TTNPB, tazarotene and AGN 190121 varied over a wide range (ED50 = 0.2-100 nmol/animal in three daily applications). Potency of induction was not directly correlated to receptor-binding affinity, but specificity of action could be demonstrated by inhibition with the high-affinity antagonist of the RARs, AGN 193109. Although RAR is functionally complexed with RXR in vivo, RXR-selective compounds have only weak potency in induction of hyperplasia. The ED50 value of the RXR-selective AGN 191701 was 600 nmol/animal compared with an ED50 value of 0.2 nmol for the structurally similar RAR-selective TTNPB. SR11237 and SR11217, also RXR-selective, each have an ED50 value of >1000 nmol. Unlike RAR-specific retinoids, RXR-selective retinoids cause only very mild skin flaking at high doses. Relative potencies for cumulative topical irritation (flaking and abrasion) of both RAR and RXR ligands were well correlated with epidermal hyperplasia. These data are consistent with RXR as a silent partner in the RAR-RXR heterodimer in skin.

Administration, Topical↗

PubMed1998

Effects of retinoid treatment of rats on hepatic microsomal metabolism and cytochromes P450. Correlation between retinoic acid receptor/retinoid x receptor selectivity and effects on metabolic enzymes.

Retinoids are compounds that bind to and activate one or more retinoid receptors to elicit various physiological responses. There are two families of retinoid receptors, i.e. retinoic acid receptors (RAR) and retinoid X receptors (RXR), for which the various synthetic and naturally occurring retinoids have differing selectivities. The synthetic analogs LG100268 and LGD1069 (Targretin) are RXR-selective, whereas ALRT1550 is highly RAR-selective. Naturally occurring all-trans-retinoic acid (Tretinoin) has a degree of selectivity for RAR, whereas ALRT1057 (9-cis-retinoic acid, Panretin) is equally active at RAR and RXR (i. e. a pan-agonist). To evaluate the effects of these compounds on metabolic enzymes, male Sprague-Dawley rats received daily oral doses for 4 days, and liver microsomes were prepared on day 5. As a class, these ligands exerted profound effects on hepatic microsomal metabolic enzyme levels. Those with RAR activity decreased hepatic cytochrome P450 (CYP or P450) levels and in vitro metabolism of the compound of pretreatment, whereas those exerting predominantly RXR activity increased these parameters. A similar relationship was observed when glucuronidation was examined. Hepatic CYP2B1/2 was unaffected and CYP3A was decreased by RAR-selective ALRT1550, whereas both were induced by ligands selective for RXR. However, both RAR- and RXR-selective ligands decreased CYP1A2, whereas they induced CYP4A. Although the mechanisms underlying these effects are not known, these results suggest that RAR- and RXR-binding ligands exert distinct effects on hepatic metabolism, and they indicate the potential for drug-drug interactions, especially involving CYP3A. The nature of such interactions would depend on the RAR/RXR selectivity of the ligand and the P450 isozymes responsible for the metabolism of coadministered drugs.

Animals↗

PubMed1999

Synthetic retinoid CD437 induces S-phase arrest and apoptosis in human prostate cancer cells LNCaP and PC-3.

BACKGROUND: Exposure of prostate carcinoma cell lines to retinoids, which function through the classical retinoic acid nuclear receptor, (RARs) or retinoid X receptors (RXRs), results in minimal cytostatic inhibition of cell proliferation. METHODS: Growth inhibition and various regulatory responses were investigated in two human prostate carcinoma cell lines (LNCaP and PC-3) treated with or without a synthetic retinoid, CD 437. RESULTS: Incubation of prostate carcinoma cell lines with a novel retinoid CD437 resulted in the marked inhibition of proliferation. LNCaP and PC-3 possessed IC50 values for CD437 of 375 nM and 550 nM, respectively. Incubation with 1 microM CD437 for 24 hr resulted in 100% and 60% inhibition of growth in LNCaP and PC-3 cells, respectively. Simultaneously, cell flow cytometric analyses revealed a dramatic increase of the cell population in S phase, in both LNCaP (from 38.6% up to 86.7%) and PC-3 (27.9% to 55.7%), and a decreased proportion of cells in G2 phase, in LNCaP (from 23.7% down to 1.2%) and PC-3 (14.9% to 2.2%), indicating a significant S-phase arrest. The cell growth inhibition and S-phase arrest in these cells were followed by apoptosis, as revealed by the acquisition of the characteristic cell morphology including the appearance of apoptotic bodies, and further confirmed by cellular DNA fragmentation. CD437-induced-S phase arrest was associated with upregulated mRNA levels of p21waf1/cip1/sdi1 in both LNCaP (p53+/+) and PC-3 (53-/-) cells. CONCLUSIONS: CD437 represents a unique retinoid that induces S-phase arrest and apoptosis in both androgen-dependent (LNCaP) and -independent (PC-3) human prostate cancer cells, suggesting a potential role of CD437 in the treatment of human prostate cancer.

Antineoplastic Agents↗

PubMed2000

Identification of a unique binding protein specific for a novel retinoid inducing cellular apoptosis.

The retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN, CD437) induces apoptosis in a variety of cell types, many of which are cancer cells that resist the antiproliferative and/or differentiating effects of retinoids. While the retinoids exert their effects by binding to the retinoic acid nuclear receptors (RARs) or retinoid X receptors (RXRs), AHPN (CD437) binds to another protein with different ligand specificity. In nuclear extracts from HL-60R cells the binding of AHPN (CD437) was only minimally competed by either retinoic acid (tRA)or 9-cis-retinoic acid (9-cis-RA), the natural ligands for the RARs and RXRs, respectively. Moreover, AHPN (CD437) was unable to compete with either tRA or 9-cis-RA for binding to endogenous retinoid receptors in nuclear extracts from the MDA-MB-468 breast carcinoma cell line. Size exclusion chromatography revealed AHPN binding to a 95 kDa protein(s) which is neither an RAR or RXR. Our results suggest that apoptosis induction by AHPN (CD437) may occur through interaction with another protein and is independent of the RAR/RXR-signaling pathways.

Antineoplastic Agents↗

PubMed1985

Modulation of carcinogenesis in the urinary bladder by retinoids.

Bladder cancer has a 70% recurrence rate within five years and a high associated mortality. It commonly occurs in one or both of two predominant growth/behaviour patterns: either well-differentiated, relatively benign exophytic papillary lesions, or flat, poorly differentiated invasive carcinoma usually arising from carcinoma-in-situ. We have used the F344 rat treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as a model for the papillary disease, and the BBN-treated B6D2F1 mouse for flat, invasive bladder carcinoma. In the rat, carcinogenesis is a multistage process and several retinoids will delay or even halt the development of bladder cancer. Inhibition of carcinogenesis is not complete, but there is a consistent reduction in the time-related incidence of papillomas and carcinomas and a concomitant improvement in the overall differentiation of the urothelium. In the BBN/mouse model, retinoids also have anticarcinogenic activity but interpretation of the results is more complicated. Unlike the F344 rat, the B6D2F1 mouse has a non-uniform response to BBN; not all mice develop bladder cancer even after treatment with very high doses of BBN and in those that do, more than one mechanism of carcinogenesis may be involved. Individual retinoids differ markedly in their ability to modulate bladder carcinogenesis in rodents; the behaviour of one analogue cannot be predicted automatically from data obtained with another. Combined data from rodent trials in this and other laboratories have identified N-(4-hydroxyphenyl)retinamide (HPR) as the most anticarcinogenic retinoid tested so far for the rodent bladder. It is also less toxic in rodents and better tolerated in humans than either 13-cis-retinoic acid or etretinate, two retinoids currently used in dermatological practice. A prophylactic chemopreventive trial of HPR in bladder cancer patients starting in 1985 will be centered on the Middlesex Hospital, London.

Animals↗

PubMed1985

Retinoids and the control of pattern in regenerating limbs.

It has recently been discovered that, as well as having effects on cell division and differentiation, retinoids induce dramatic changes in the development of pattern in limbs. Local application of retinoic acid to the anterior side of chick limb buds causes anteroposterior mirror-imaging such that the limb has six digits instead of three. In Rana limb buds retinoids induce changes in both the anteroposterior and proximodistal axes. In regenerating axolotl limbs their effect is primarily on the proximodistal axis. These proximodistal effects result in the regeneration of a complete limb from distal amputation levels. Concentration effects, time effects and the relative efficacy of various retinoids have been established. Cellular changes observed include a stimulation of epidermal mucopolysaccharide production, inhibition of cell division, induction of cartilage matrix breakdown and a stimulation of fibronectin production by mesodermal cells. The relevance of each of these changes to pattern effects has been determined. Initial experiments on the cellular location of radiolabelled retinoic acid are described. It thus seems that retinoids can change the determination of developing cells, and once we know the molecular basis of retinoid action then we should also know how developing cells become specified to form particular cell types.

Ambystoma↗

PubMed2005

Congenital diaphragmatic hernia: a retinoid-signaling pathway disruption during lung development?

Congenital diaphragmatic hernia (CDH) usually occurs sporadically. The prognosis remains poor, with a 50% perinatal mortality rate. Most deaths result from hypoxemia due to lung hypoplasia and abnormal development of pulmonary vasculature that results in persistent pulmonary hypertension. Our current understanding of the pathogenesis of CDH is based on an assumption linking herniation of abdominal viscera into the thorax with compression of the developing lung. Pulmonary hypoplasia, however, can also result from reduced distension of the developing lung secondary to impaired fetal breathing movements. Moreover, a nitrofen-induced CDH model shows that lung hypoplasia precedes the diaphragmatic defect, leading to a "dual-hit hypothesis." Recent data reveal the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH. We describe the clinical and epidemiological aspects of human CDH, the metabolic and molecular aspects of the retinoid-signaling pathway, and the implications of retinoids in the development of the diaphragm and the lung. Finally, we highlight the existing links between CDH and disruption of the retinoid-signaling pathway, which may suggest an eventual use of retinoids in the treatment of CDH.

Animals↗

PubMed1996

Pharmacokinetics of retinoids in women after meal consumption or vitamin A supplementation.

These studies were conducted to evaluate the pharmacokinetics of several retinoids after meal consumption or vitamin A supplementation to establish a reference for future assessment of teratogenic risks of retinoid therapeutic agents. In the first study, 36 healthy young female volunteers consumed single meals containing vitamin A amounts ranging from 1,305 to 169,474 IU. In the second study, 24 other female volunteers took vitamin A supplements at a dose level of 5,000, 10,000, or 25,000 IU/day for 60 days. Plasma concentrations of tretinoin, isotretinoin, 4-oxo-tretinoin, and 4-oxo-isotretinoin in samples collected during the studies were analyzed using a high-performance liquid chromatography method with ultraviolet detection. Pharmacokinetic parameters for the retinoids were calculated using model-independent methods. Plasma concentrations of tretinoin were not altered by meal consumption or vitamin A supplementation. Plasma levels of 4-oxo-tretinoin were below the assay detection limit (0.3 ng/mL) in the majority of samples collected throughout the studies. Linear relationships between dose and maximum concentration (Cmax) and dose and area under the concentration-time curve (AUC) for isotretinoin and 4-oxo-isotretinoin were derived from data from the meal study. For the most bioavailable formulation used in the supplement study, daily ingestion of 5,000 IU of vitamin A caused increases of 141 +/- 53% and 171 +/- 77% from baseline in the 24-hour AUCs of isotretinoin and 4-oxo-isotretinoin, respectively. Dose-related increases in systemic exposure to retinoids were observed after ingestion of vitamin A by means of a meal or a supplement. Findings from these studies can be used as a basis for future safety evaluations of retinoid compounds.

Adult↗

PubMed2003

Differential regulation of protein expression, growth and apoptosis by natural and synthetic retinoids.

All-trans retinoic acid (ATRA) can down regulate the anti-apoptotic protein Bcl-2 and the cell cycle proteins cyclin D1 and cdk2 in estrogen receptor-positive breast cancer cells. We show here that retinoids can also reduce expression of the inhibitor of apoptosis protein, survivin. Here we have compared the regulation of these proteins in MCF-7 and ZR-75 breast cancer cells by natural and synthetic retinoids selective for the RA receptors (RARs) alpha, beta, and gamma then correlated these with growth inhibition, induction of apoptosis and chemosensitization to Taxol. In both cell lines ATRA and 9-cis RA induced the most profound decreases in cyclin D1 and cdk2 expression and also mediated the largest growth inhibition. The RARalpha agonist, Ro 40-6055 also strongly downregulated these proteins although did not produce an equivalent decrease in S-phase cells. Only ATRA induced RARbeta expression. ATRA, 9-cis RA and 4-HPR initiated the highest level of apoptosis as determined by mitochondrial Bax translocation, while only ATRA and 9-cis RA strongly reduced Bcl-2 and survivin protein expression. Enumeration of dead cells over 96 h correlated well with downregulation of both survivin and Bcl-2. Simultaneous retinoid-mediated reduction of both these proteins also predicted optimal Taxol sensitization. 4-HPR was much weaker than the natural retinoids with respect to Taxol sensitization, consistent with the proposed requirement for reduced Bcl-2 in this synergy. Neither the extent of cell cycle protein regulation nor AP-1 inhibition fully predicted the antiproliferative effect of the synthetic retinoids suggesting that growth inhibition requires regulation of a spectrum of RAR-regulated gene products in addition even to pivotal cell cycle proteins.

Apoptosis↗