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Retinoid metabolism is important for many physiological functions, such as differenciation, growth, and vision. In the visual context, after the absorption of light in rod photoreceptors by the visual pigment rhodopsin, 11-cis retinal is isomerized to all-trons retinal. This retinoid subsequently undergoes a series of modifications during the visual cycle through a cascade of reactions occurring in photoreceptors and in the retinal pigment epithelium. Retinol dehydrogenases (RDHs) are enzymes responsible for crucial steps of this visual cycle. They belong to a large family of proteins designated as short-chain dehydrogenases/reductases. The structure of these RDHs has been predicted using modern bioinformatics tools, which allowed to propose models with similar structures including a common Rossman fold. These enzymes undergo oxidoreduction reactions, whose direction is dictated by the preference and concentration of their individual cofactor (NAD(H)/NADP(H)). This review presents the current state of knowledge on functional and structural features of RDHs involved in the visual cycle as well as knockout models. RDHs are described as integral or peripheral enzymes. A topology model of the membrane binding of these RDHs via their N- and (or) C-terminal domain has been proposed on the basis of their individual properties. Membrane binding is a crucial issue for these enzymes because of the high hydrophobicity of their retinoid substrates. Key words: RDH, visual cycle, photoreceptor, retinal pigment epithelium, oxidoreduction, membrane. Les retinol deshydrogenases (RDHs) sont des enzymes qui contiennent des sequences concensus caracteristiques de la famille des SDRs (short-chain dehydrogenases/reductases) dont elles font partie. On retrouve les RDHs principalement dans le systeme visuel. En effet, plusieurs RDHs ont ete localisees au niveau de la retine, notamment dans les photorecepteurs et l'epithelium pigmentaire retinien. Ces enzymes jouent donc un role majeur dans le cycle visuel des retinoides qui prend place dans ces deux types cellulaires. Elles permettent la regeneration du pigment visuel des photorecepteurs. Cette revue presente l'etat des connaissances sur la structure de ces RDHs, leur liaison membranaire, leurs interactions avec d'autres proteines et leurs fonctions. La prediction de la structure de ces enzymes par des methodes bio-informatiques a permis de proposer des modeles montrant qu'elles adoptent des conformations similaires, incluant le repliement de Rossmann, en consequence de leurs sequences communes et necessaries pour leurs fonctions. Ces enzymes accomplissent des reactions d'oxydoreduction de differents retinoides qui sont generalement reversibles in vitro. La preference et les concentrations en cofacteur (NAD(H)/NADP(H)) dictent en grande partie le sens de l'oxydoreduction in vivo. Plusieurs types de souris knockout ont ete produits pour comprendre le role de ces RDHs. Toutefois cette approche est limitee par le redondance de l'activite enzymatique des RDHs. Enfin, cette revue propose aussi une topologie membranaire pour ces RDHs sur la base de leurs proprietes individuelles. Leur liaison membranaire joue un role crucial car leurs substrats, les retinoides, sont des molecules tres hydrophobes. Mots-cles: RDH, cycle visuel, photorecepteur, epithelium pigmentaire retinien, oxydoreduction, membrane., Plain language summary This review provides the current state of knowledge of the properties and functions of enzymes denominated 'retinol dehydrogenases' (RDHs), which are members of a larger family of [...]

ABSTRACT Modalities for the treatment of atrophic facial acne scars have been studied extensively. One, an erbium:yttrium-aluminum garnet (Er:YAG) laser device that generates both short, ablative pulses of high fluence [...]

ABSTRACT Patients at high risk for the development of multiple non-melanoma skin cancers, especially those receiving immunosuppressive medications following solid organ transplantation, are candidates for chemoprophylaxis. In patients where photo-protection [...]

Fluorescent bisretinoids, such as A2E and all-trans-retinal dimer, form as a by-product of vitamin A cycling in retina and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin pigments. These pigments are implicated in pathological mechanisms involved in several vision-threatening diseases including age-related macular degeneration. Efforts to understand damaging events initiated by these bisretinoids have revealed that photoexcitation of A2E by wavelengths in the visible spectrum leads to singlet oxygen production and photooxidation of A2E. Here we have employed liquid chromatography coupled to electrospray ionization mass spectrometry together with tandem mass spectrometry (MS/MS), to demonstrate that A2E also undergoes photooxidation-induced degradation and we have elucidated the structures of some of the aldehyde-bearing cleavage products. Studies in which A2E was incubated with a singlet oxygen generator yielded results consistent with a mechanism involving bisretinoid photocleavage at sites of singlet molecular oxygen addition. We provide evidence that one of the products released by A2E photodegradation is methylglyoxal, a Iow molecular weight reactive dicarbonyl with the capacity to form advanced glycation end products. Methylglyoxal is already known to be generated by carbohydrate and lipid oxidation; this is the first report of its production via bisretinoid photocleavage. It is significant that AGE-modified proteins are detected in deposits (drusen) that accumulate below RPE cells in vivo; drusen have been linked to age-related macular degeneration pathogenesis. Whereas various processes play a role in drusen formation, these findings are indicative of a contribution from lipofuscin photooxidation in RPE. advanced glycation end products | lipofuscin | photofragmentation | photooxidation | retinal pigment epithelial cells doi /10.1073/pnas.0913112107

Retinoids are absolutely required for normal growth and development during the postnatal period. We studied the delivery of retinoids to milk, availing of mouse models modified for proteins thought to be essential for this process. Milk retinyl esters were markedly altered in mice lacking the enzyme lecithin:retinol acyltransferase ([Lrat.sup.-/-] ), indicating that this enzyme is normally responsible for the majority of retinyl esters incorporated into milk and not an acyl-CoA dependent enzyme, as proposed in the literature. Unlike wild-type milk, much of the retinoid in [Lrat.sup.-/-] milk is unesterified retinol, not retinyl ester. The composition of the residual retinyl ester present in [Lrat.sup.-/-] milk was altered from predominantly retinyl palmitate and stearate to retinyl oleate and medium chain retinyl esters. This was accompanied by increased palmitate and decreased oleate in [Lrat.sup.-/-] milk triglycerides. In other studies, we investigated the role of retinol-binding protein in retinoid delivery for milk formation. We found that [Rbp.sup.-/-] mice main-rain milk retinoid concentrations similar to those in matched wild-type mice. This appears to arise due to greater postprandial delivery of retinoid, a lipoprotein lipase (LPL)-dependent pathway. Importantly, LPL also acts to assure delivery of long-chain fatty acids (LCFA) to milk. The fatty acid transporter CD36 also facilitated LCFA but not retinoid incorporation into milk. Our data show that compensatory pathways for the delivery of retinoids ensure their optimal delivery and that LRAT is the most important enzyme for milk retinyl ester formation. fatty acid; lactation; vitamin A doi: 10.1152/ajpendo.00491.2009.

ABSTRACT Keratoacanthomas represent approximately 1% of skin malignancies treated in a Mohs practice in Houston, TX. The authors compared the age of onset, sex, location and month of prevalence of [...]

The discovery of new small molecules and their testing in rational combination poses an ongoing problem for rare diseases, in particular, for pediatric cancers such as neuroblastoma. Despite maximal cytotoxic therapy with double autologous stem cell transplantation, outcome remains poor for children with high-stage disease. Because differentiation is aberrant in this malignancy, compounds that modulate transcription, such as histone deacetylase (HDAC) inhibitors, are of particular interest. However, as single agents, HDAC inhibitors have had limited efficacy. In the present study, we use an HDAC inhibitor as an enhancer to screen a small-molecule library for compounds inducing neuroblastoma maturation. To quantify differentiation, we use an enabling gene expression-based screening strategy. The top hit identified in the screen was all-trans-retinoic acid. Secondary assays confirmed greater neuroblastoma differentiation with the combination of an HDAC inhibitor and a retinoid versus either alone. Furthermore, effects of combination therapy were synergistic with respect to inhibition of cellular viability and induction of apoptosis. In a xenograft model of neuroblastoma, animals treated with combination therapy had the longest survival. This work suggests that testing of an HDAC inhibitor and retinoid in combination is warranted for children with neuroblastoma and demonstrates the success of a signature-based screening approach to prioritize compound combinations for testing in rare diseases. chemical genomics | small molecule screening

Gtyceroneogenesis is an important metabolic pathway for fatty acid reesterification in adipose tissue, thereby reducing fatty acid release. Glyceroneogenesis and cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), which is the key enzyme in this pathway, are both regulated by a series of hormones and nutrients, among which all-trans retinoic acid (all-trans RA) is a transcriptional inducer of the PEPCK-C gene (Pckl). All-trans RA binds to the retinoic acid receptor (RAR) and activates it, whereas its stereoisomer 9-cis retinoic acid (9-cis RA) is a ligand for the 9-cis RA receptor (RXR). Three RXR-binding elements [retinoic acid response element (RARE)I/PCK1, RARE2, and RARE3/PCK2] were previously located in the promoter of Pck 1. Using 3T3-F442A adipocytes, we demonstrated that Pck 1 expression was 10-fold more sensitive to 9-cis RA ([EC.sub.50]: 10 nmol/L) than to all-trans RA. We then analyzed the respective involvement of RARE1/PCK1, RARE2, and RAR E3/PC K2 in the response of Pck I to 9-cis RA and all-trans RA in adipocytes. The response to 9-cis RA mainly involved the RARE1/PCK1 element, whereas RARE2 was mainly responsive to all-trans RA. In contrast, the full response to both RA isomers involved these 2 elements and included RARE3/PCK2 as well. Furthermore, 9-cis RA, but not all-trans RA, selectively induced PCK1 in ex-vivo-treated human adipose tissue explants, with a concomitant induction of glyceroneogenesis monitored by [1-[sup.14]C]-pyruvate incorporation into neutral lipids. The concomitant 9-cis RA-induced reduction in fatty acid output indicates an important role for this RA stereoisomer in lipid homeostasis through stimulation of PEPCK-C and glyceroneogenesis in adipose tissue.

Byline: Sandra Montedonico (1), Nana Nakazawa (1), Prem Puri (1) Keywords: Retinoic acid; Retinoids; Lung development; Congenital diaphragmatic hernia; Nitrofen rat model; Lung hypoplasia Abstract: There is increasing evidence to suggest that the retinoid pathway is involved in the pathogenesis of congenital diaphragmatic hernia (CDH). We hypothesised that retinoids are involved in the pathogenesis of associated pulmonary hypoplasia in CDH and therefore designed this study to investigate the effects of retinoid acid on nitrofen-induced hypoplastic lungs. Pregnant rats were exposed to either olive oil or 100 mg nitrofen on day 9.5 of gestation. Foetal lungs were harvested on embryonic day 13.5 and were cultured for 96 h with or without exogenous retinoic acid (RA) (1 uM) added daily to the culture medium. Lungs were divided into four study groups: control (n=31) control + RA (n=19) nitrofen (n=19) and nitrofen + RA (n=12). Lung growth was assessed in each group by measuring branching morphogenesis, total DNA content and the proportion of proliferating cells stained by immunohistochemistry. One-way ANOVA test was used for statistical analysis. Retinoic acid significantly increased the growth of nitrofen-induced hypoplastic lungs, whilst growth of control lungs did not change. The number of lung buds and lung area of nitrofen-exposed hypoplastic lungs after 96 h of culture significantly increased after the addition of RA compared to the non-treated hypoplastic lungs (25.75+-6.47 vs 15.11+-3.29 and 0.98+-0.18 mm.sup.2 vs 0.65+-0.13 mm.sup.2, respectively P&lt 0.0001). Lung perimeter was also higher when RA was added to hypoplastic lungs compared to the non-treated ones, although it did not reach significance (12.51+-2.53 mm vs 11.19+-2.56 mm P=0.17). Conversely, the addition of RA to control lungs did not affect the number of lung buds, lung area or lung perimeter after 96 h in culture compared to the non-treated ones (31.28+-4.66 vs 31.81+-6.67 1.29+-0.18.sup.2 vs 1.29+-0.23 mm.sup.2 and 18.47+-3.47 mm vs 17.89+-2.94 mm, respectively P=NS). Retinoic acid also increased the total DNA content and the proportion of proliferating cells in hypoplastic lungs compared to the non-treated ones (2.59+-0.58 ug vs 1.96+-0.31 ug and 57.89+-9.46% vs 36.76+-8.15%, respectively P&lt 0.001). The addition of RA did not affect either total DNA content or the proportion of proliferating cells in control lungs compared to the non-treated ones (4.04+-0.64 ug vs 3.79+-0.85 ug and 58.67+-11.23% vs 56.03+-10.36%, respectively P=NS). This study demonstrates for the first time that RA rescues lung hypoplasia in nitrofen-induced hypoplastic lungs. These results suggest that retinoid pathway may be involved in the pathogenesis of associated pulmonary hypoplasia in CDH. Author Affiliation: (1) Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland Article History: Registration Date: 14/10/2005 Online Date: 12/11/2005

Vitamin A signals play critical roles during embryonic development. In particular, heart morphogenesis depends on vitamin A signals mediated by the retinoid X receptor [alpha] (RXR [alpha]), as the systemic mutation of this receptor results in thinning of the myocardium and embryonic lethality. However, the molecular and cellular mechanisms controlled by RXR [alpha] signaling in this process are unclear, because a myocardium-restricted RXR [alpha] mutation does not perturb heart morphogenesis. Here, we analyze a series of tissue-restricted mutations of the RXR [alpha] gene in the cardiac neural crest, endothelial, and epicardial lineages, and we show that RXR [alpha] signaling in the epicardium is required for proper cardiac morphogenesis. Moreover, we detect an additional phenotype of defective coronary arteriogenesis associated with RXR [alpha] deficiency and identify a retinoid-dependent Wnt signaling pathway that cooperates in epicardial epithelial-to-mesenchymal transformation. coronary vessels | epicardium | retinoids | wnt | FGF

Numerous reports have indicated that the biological activity of all-trans retinoyl [beta]-glucuronide (RAG) is similar to that of all-trans-retinoic acid (RA), but without the toxic side effects of RA. In the present series of studies, we report new findings that support the contention that RAG can function as a nontoxic substitute for RA in a variety of clinic settings. One study on the effects of sc injected graded doses of RA and RAG (20-480 [micro]mol/kg BW) into pregnant Sprague-Dawley rats showed that any differences between RAG and RA could be observed only at the highest dose levels of 360 and 420 [micro]mol/kg BW, with RAG being much less toxic than RA. Similarly, daily topical application of RAG (0.16-1.6%) and RA (0.1-0.5%) to shaved swine dorsal skin for six mo resulted in redness and scabbing in RA-treated patches, and to a lesser extent in 1.6% RAG-treated, but not in other RAG-treated patches. Histological scores were significantly higher in the dermis and epidermis of RA-treated pigs than in RAG-treated pigs. Studies to document the pharmacokinetics of chronically administered RAG in mice indicated that, unlike RA, sustained blood levels of parent retinoid (RAG) can be achieved during at least 2 mo of daily administration. Another investigation to study the effects of RAG on the development and growth in nude mice of tumors derived from the human neuroblastoma cell line LA-N-5 showed that sc injection of RAG (30 [micro]mol/kg BW) reduced tumor formation when the retinoid was first administered 3 d before tumor injection and continued daily for 30 d thereafter. In established tumors, RAG was shown to inhibit progressive tumor growth, the antitumor effects of RAG being comparable with RA. However, with RAG, as opposed to RA, there were no significant adverse physical side effects. Based on the results of these series of studies along with ample published reports over the last 15 y, we conclude that RAG may be a safe and effective alternative to RA and some other retinoids that are presently being utilized in the clinic. KEY WORDS: * retinoyl glucuronide * retinoic acid * neuroblastoma * pharmacology * toxicity

Retinoids have been demonstrated to have pharmacological application in the areas of dermatology and oncology. In addition to the natural retinoids such as all-trans-retinoic acid and 9-cis-retinoic acid, many new potential retinoid drugs have been synthesized, including retinoic acid receptor (RAR)-subtype selective agonists, retinoid X receptor (RXR)-selective agonists, RAR-selective antagonists, anti-AP1-specific retinoids and retinoids that induce apoptosis. Recent studies demonstrate that some retinoids, in addition to modulating the RAR/RXR pathway, are also capable at pharmacological concentrations of binding to aryl hydrocarbon receptor (AhR) and activating the AhR/AhR nuclear translocator pathway. Future studies are necessary to ascertain the consequences, if any, of activation of the AhR signaling pathway by pharmacological doses of specific retinoids. KEY WORDS: * aryl hydrocarbon receptor * AhR nuclear translocator * retinoic acid receptor * retinoids * retinoid X receptor

Many agents that exhibit chemopreventive activity are able to mediate a differentiation response in premalignant and malignant tissues. One of the most widely studied classes of tumor differentiation agents is the retinoids. There is rapidly evolving evidence for beneficial retinoid actions in the prevention or treatment of clinical tumors. However, the use of retinoids in the clinic is limited by acquired resistance and toxicity, especially when administered chronically in preventive strategies. Although retinoids are known to regulate gene transcription by activating retinoid receptors, the identity of the target genes that mediate the beneficial effects of retinoids are largely unknown. Here we review a useful model of retinoid-induced tumor cell differentiation: human embryonal carcinoma. The pluripotent nature and ease of use make human embryonal carcinoma cells a valuable and practical complement to human embryonic stem cells as an in vitro model of early human development. In addition, retinoid treatment of human embryonal carcinoma is an important model of induced tumor cell differentiation because retinoids cause the reversal of the malignant phenotype coincident with terminal neuronal differentiation. We have used both de novo and candidate approaches with this system in an effort to uncover critical downstream targets of retinoid receptors during differentiation induction. KEY WORDS: * retinoic acid * embryonal carcinoma * chemoprevention * microarray * differentiation

The drug alitretinoin appears to be effective in treating a complication of AIDS called Kaposi's sarcoma, according to a study of 268 AIDS patients. This drug is a form of retinoic acid, which is effective in treating many other skin diseases.

Retinoids, synthetic and natural analogs of retinoic acid, exhibit potent growth inhibitory and cell differentiation activities that account for their beneficial effects in treating hyperproliferative diseases such as psoriasis, actinic keratosis, and certain neoplasias. Tazarotene is a synthetic retinoid that is used in the clinic for the treatment of psoriasis. To better understand the mechanism of retinoid action in the treatment of hyperproliferative diseases, we used a long-range differential display-PCR to isolate retinoid-responsive genes from primary human keratinocytes. We have identified a cDNA, tazarotene-induced gene 3 (TIG3; Retinoic Acid Receptor Responder 3) showing significant homology to the class II tumor suppressor gene, H-rev 107. Tazarotene treatment increases TIG3 expression in primary human keratinocytes and in vivo in psoriatic lesions. Increased TIG3 expression is correlated with decreased proliferation. TIG3 is expressed in a number of tissues, and expression is reduced in cancer cell lines and some primary tumors. In breast cancer cell lines, retinoid-dependent TIG3 induction is observed in lines that are growth suppressed by retinoids but not in nonresponsive lines. Transient over-expression of TIG3 in T47D or Chinese hamster ovary cells inhibits colony expansion. Finally, studies in 293 cells expressing TIG3 linked to an inducible promoter demonstrated decreased proliferation with increased TIG3 levels. These studies suggest that TIG3 may be a growth regulator that mediates some of the growth suppressive effects of retinoids.

Byline: J. D. Radcliffe (1), D. M. Czajka-Narins (2) Keywords: Hypertriglyceridemia; Protein; Rat; Retinoid; Soy Abstract: Previous research carried out in an animal model of retinoid-induced hypertriglyceridemia -- rats fet a 13-cis retinoic acid (13cRA)-containing diet having casein as the protein source -- has demonstrated that the complete replacement of dietary casein with soy protein isolate (SPI) can decrease the severity of this condition. In this study, the effect of partially replacing dietary casein with SPI was investigated. Five groups of male Fischer 344 rats were used in a 14-day study, with two groups being fed diets having casein as the protein source, without or with 13cRA (groups A and B, respectively), and three groups being fed 13cRA-containing diets in which SPI was used to bring about the isonitrogenous replacement of 25, 50, or 100% of the casein in the formula for the diet used for group B (groups C-E, respectively). Serum triglyceride concentration for group B was significantly different ( p &lt 0.05) from that of groups A, D, and E (5.41 vs 2.62, 4.04, and 2.66 mmol/l, respectively). Serum cholesterol concentrations for groups D and E were significantly lower ( p &lt 0.05) than for groups A and B (1.63 and 1.60 vs 2.00 and 2.14 mmol/l, respectively). Thus, the isonitrogenous replacement of 50% of dietary casein with SPI can reduce the severity of retinoid-induced hypertriglyceridemia while decreasing the serum concentration of cholesterol. Author Affiliation: (1) Department of Nutrition and Food Sciences, Texas Woman's University, Houston, TX, 77030 (2) Department of Nutrition and Food Sciences, Texas Woman's University, Denton, TX, 76204 Article History: Registration Date: 14/10/2004

Use of retinoyl beta-glucuronide may replace use of retinoic acid as a safer and equally effective treatment of skin disorders and some cancers. Retinoyl beta-glucuronide is a metabolite of vitamin A and a by-product of retinoic acid. It is as biologically active as retinoic acid without the toxicity. Unlike retinoic acid or retinoyl beta-glucose, retinoyl beta-glucuronide has not been shown to be teratogenic.

The synthetic retinoid CD437 displays strong dose-dependent therapeutic effects against human malignant melanoma cells. The synthetic retinoid activates and upregulates the transcription factor AP-1 on mRNA and protein levels leading eventually to programmed cell death of MeWo melanoma cells. Moreover, treatment with CD437 significantly reduced the growth of melanoma cells in a xenograft model.

ABSTRACT Malignant acanthosis nigricans (MAN) with oral florid papillomatosis is a rare paraneoplastic condition affecting the skin and mucocutaneous tissues associated with an underlying malignancy. It is characterized by proliferation [...]

N-(4-hydroxyphenyl)retinamide (HPR) reduces serum retinol concentrations in rats with normal vitamin A status. The mean transit times for retinol and retinol-binding protein (RBP) are in the same range for HPR-treated and normal rats, which means there is no accelerated removal of retinol or RBP from the circulation due to HPR treatment. Liquid chromatography of radioactive samples showed decreased secretion of the retinol-RBP complex secretion from hepatic and extrahepatic tissues. Thus, decreased plasma retinol level following HPR treatment is due to reduced input into plasma.

ABSTRACT Background: Up to 50% of patients undergoing allogenic stem cell transplantation or bone marrow transplantation (BMT) can develop acute or chronic graft versus host disease (GVHD) as a severe [...]

Retinoids are chemical derivatives of vitamin A that are used in the treatment of various skin problems, including acne and conditions associated with aging. Previous studies have documented the toxic effects of these compounds in humans. Recently, a new group of retinoids, called arotinoids, were developed. These compounds have been reported to be a thousand times more potent than previously available retinoids. The teratogenic effects (ability to cause birth defects) of 13 different arotinoid compounds were determined in pregnant mice at days 8 and 9 of gestation. Previous studies have shown that the mouse embryo is most susceptible to the toxic effects of retinoids between days eight and nine of gestation. The toxic effect of arotinoids on mouse embryos was related to the chemical structure of the particular arotinoid being tested and to the dose of the drug. When mouse embryo cells were grown in culture, the arotinoids prevented the development of, and were toxic to, cells that are required for normal bone development (chondrocytes). The doses of arotinoids that were toxic to the developing embryo were directly related to the doses that inhibited bone cell growth in culture. Further studies are required to determine the tissue distribution (where the chemical goes in the body) and metabolism of these compounds. (Consumer Summary produced by Reliance Medical Information, Inc.)

Retinoids are used for treating dermatological disorders. Isotretinoin has been marketed for treating severe acne, and etretinate for treating psoriasis. However, retinoids have been shown to be embryotoxic and teratogenic (causing abnormal development) in animals and humans. Recently, a new class of retinoids, called arotinoids, was developed with the hope that they would be less toxic. The arotinoids were reported to be 1,000 times more active than retinoic acid. Therefore, a study was performed to compare the potential toxicity of three arotinoids, Ro 13-7410, Ro 13-6298 and Ro 15-1570, with retinoic acid in female rats. The rats were treated orally with arotinoids on day 9 or 13 of gestation (pregnancy). Treatment on day 9 resulted in malformations of the head and trunk (upper body), whereas treatment on day 13 resulted limb malformations. Ro 13-7410 and Ro 13-6298 were about 1,000 times more embryotoxic and teratogenic than retinoic acid. In contrast, Ro 15-1570 was active at the same doses as retinoic acid, but did not produce the head and trunk malformations produced by the other two arotinoids. Ro 15-1570 did produce limb malformations at day 13 of gestation, but showed no signs of bone toxicity in adult rats. It is concluded that Ro 13-7410 and Ro 13-6298 are more teratogenic than Ro 15-1570, and that Ro 15-1570 produced teratogenic effects similar to those observed with retinoic acid. (Consumer Summary produced by Reliance Medical Information, Inc.)