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H Nau

Publications and source records attributed to H Nau.

At least 55 records · Page 3Linked to original sources
PubMed1998

Studies on the teratogen pharmacophore of valproic acid analogues: evidence of interactions at a hydrophobic centre.

Propyl-4-yn-valproic acid (2-propyl-4-pentynoic acid), an analogue of valproic acid with a triple bond in one alkyl side chain, potently induces exencephaly in mice. Given that propyl-4-yn-valproic acid is a branched chain carboxylic acid, we synthesized a series of analogues with n-alkyl side chains of increasing length and correlated their potential to induce neural tube defects and to inhibit proliferation and induce differentiation in cells of neural origin, the latter being crucial to the orderly structuring of the embryo. All analogues significantly increased the incidence of neural tube defects in the embryos of dams exposed to a single dose of 1.25 mmol/kg on day 8 of gestation. This effect occurred in a dose-dependent manner and the rate of exencephaly increased with the progressive increase in n-alkyl side chain length. Moreover, increasing chain length resulted in a dose-dependent inhibition of C6 glioma proliferation rate over a concentration range of 0-3 mM and this was independent of the cell type employed and mode of estimating proliferative rate. The antiproliferative action of these analogues was associated with profound shape change in neuro-2A neuroblastoma involving extensive neuritogenesis and an associated increase in neural cell adhesion molecule (NCAM) prevalence at points of cell-cell contact, the latter exhibiting a dose-dependent increase when the n-alkyl chain was extended to five carbon units. These results suggest an interaction with a specific site in which the n-alkyl side is proposed to serve as an 'anchor' within a hydrophobic pocket to facilitate the ionic and/or H-bonding of the carboxylic acid and high electron density of the carbon-carbon triple bond.

Animals↗
PubMed1998

Cell motility is inhibited by the antiepileptic compound, valproic acid and its teratogenic analogues.

Valproic acid (VPA) is an established human teratogen that causes neural tube defects in 1-2% of human foetuses exposed to the drug during early pregnancy. In this study, individual cell motility was evaluated using short- and long-term time-lapse video-recording and computer assisted image analysis, and it was found that VPA and selected VPA-analogues inhibited individual cell motility of L-cells in a dose-dependent manner. The compounds caused a decrease in the root-mean-square speed, S, and in the rate of diffusion, R, but an increase in the time of persistence in direction, P. Using short-term recordings and measurements of mean-cell speed, the reduction in the motile behaviour was shown to correlate with the teratogenic potency of the tested compounds. The observed effects of VPA on cell motility was independent of the employed L-cell clone, and could be reproduced in cells containing the neuronal marker NCAM and in the neuronal cell line N2a. Furthermore, the observed effect was independent of culture substratum, being observed for L-cells grown on fibronectin as well as on plastic. Immunofluorescence microscopy revealed that VPA-treatment of mouse L-cells caused a redistribution of F-actin and of a series of focal adhesion proteins, indicating that the effect of VPA on cell motility may be causally related to increased cell-substratum interactions or to alterations in the organisation or dynamics of the actin cytoskeleton.

Animals↗
PubMed1998

[Recommendations for blood studies and clinical monitoring in early detection of valproate-associated liver failure. Results of a consensus conferences 9 May - 11 May 1997 in Berlin].

Valproate is a frequently used antiepileptic drug. It is associated with rare but serious adverse effects like liver failure. The first symptom is impairment of the patient's well being. Isolated changes of standard laboratory liver parameters are not reliable early indicators. Thus, according to the knowledge of today, prophylactic blood screening cannot predict complications. On the contrary, clinical symptoms are the most relevant indicators of impending complications, eventually supported by laboratory findings. An abrupt withdrawal of valproate and administering carnitin in parallel can interrupt the otherwise fatal course of the complication and induce a subsequent recovery. At a Consensus Conference the current knowledge about early detection and therapy of the valproate-induced serious hepatotoxicity was discussed. The results regarding recommended laboratory screening, as well as diagnostic and therapeutic strategies are reported.

Adolescent↗
PubMed1998

Radial astrocytes: toxic effects induced by antiepileptic drug in the developing rat hippocampus in vitro.

Neuron-glia relationships are crucial for differentiation of both glial and neuronal cells. Interference with these intricate cell interactions could affect regular neuroembryogenesis. In order to analyse potential developmental neurotoxic effects of therapeutically administered antiepileptics such as valproate, we employed organotypic cultures of the rat hippocampus. In these cultures thin tissue slices were continuously rotated between the gas and medium phases, which greatly improved oxygen and nutrient accessibility. This resulted in long-term preservation of the native cytoarchitecture. Exposure of organotypically cultured hippocampi to valproate hampered, in a dose-dependent manner, regular formation of the pyramidal cell layer. Most interestingly, radial astrocytes, which comprise a transient cell population during distinct developmental periods, were selectively affected even by low doses of valproate, but not by structurally related non-teratogenic isomer 2-ethyl-4-methyl-pentanoic acid. The xenobiotic effect did not represent a general gliotoxic insult, since neither the glutathione quotient as determined by HPLC, nor the DNA content, nor the total amount of glial fibrillary acidic protein evaluated by ELISA were significantly altered. Instead, the morphology of astrocytes proved to be the most sensitive index of intoxication with the orientation of radial astrocytes being most affected as revealed by immunofluorescence. In contrast to radial astrocytes, other astrocytic populations proved to be fairly resistent. The data indicate that developmentally regulated cell polarity of astrocytes is a target of therapeutically relevant xenobiotics. This could in turn disturb neuronal differentiation and normal histogenesis.

Animals↗
PubMed1998

Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid.

The teratogenic properties of valproic acid (VPA) and its analogues depend to a great extent on their chemical structure. We investigated the structure-teratogenicity relationships of VPA, its structural isomer, valnoctic acid (VCA), and their two amide analogues, valpromide (VPD) and valnoctamide (VCD), respectively. Each substance was injected (3 mmol/kg) in NMRI-mice on the morning of day 8 of gestation. Embryolethality, fetal weight and exencephaly rates were recorded on day 18 of gestation. VPA caused 53% exencephaly, VPD induced 6%, VCA and VCD produced only 1% exencephaly (control values between 0 and 1%). VPA-treated mice also had increased embryolethality rates (52%). There was no significant change of embryolethality in the other treatment groups. Pharmacokinetic studies showed that VCD was eliminated from plasma at a slower rate than VPA. Also, the residual teratogenic activity of VPD was not accounted for by the relatively small amounts of its hydrolysis product VPA. This study indicates that VPD, VCA and VCD were distinctly less teratogenic than VPA. Apparently the amidation of the free carboxylic group and/or methyl-substitution at the beta-position of the carbon chain greatly decreased the teratogenic activity of VPA.

Abnormalities, Drug-Induced↗
PubMed1998

The human sebocyte culture model provides new insights into development and management of seborrhoea and acne.

Seborrhoea and acne are exclusively human diseases and sebaceous gland differentiation is species specific. Therefore, fundamental research on human sebaceous cell function and control requires human in vitro models. The human sebocyte culture model, introduced in 1989, has been used in several studies to elucidate sebaceous gland activity and its regulation at the cellular level. Cultured human sebocytes have been shown to preserve important sebocytic characteristics, although they undergo an incomplete terminal differentiation in vitro. In vitro synthesis of free fatty acids without bacterial involvement and marked interleukin 1 alpha expression at the mRNA and protein levels with no further induction by lipopolysaccharides lead to the assumption that human sebocytes may initiate acne lesions by an intrinsic mechanism. Androgens affected sebocyte activity in vitro in a manner dependent on the localization of the sebaceous glands. In vitro stimulation of sebocyte proliferation by androgens could be completely abolished by spironolactone. Cultured sebocytes strongly expressed type 1 5 alpha-reductase and metabolized testosterone to androstenedione, 5 alpha-androstanedione, 5 alpha-dihydrotestosterone, androsterone and 5 alpha-androstanediol, whereas the levels of 5 alpha-reductase activity were probably not feedback regulated. 4,7 beta-Dimethyl-4-aza-5 alpha-cholestan-3-one, a type 1 5 alpha-reductase inhibitor, induced an early, marked down-regulation of 5 alpha-reductase activity in human sebocytes in vitro, while hydrofinasteride, a type 2 inhibitor, required 10(3)-fold higher concentrations to induce similar effects. Stimulation of sebocyte proliferation by insulin, thyroid-stimulating hormone and hydrocortisone indicates that the hormonal control of the sebaceous gland could be a complex mechanism. Retinoids inhibited sebocyte proliferation in a dose-dependent manner and down-regulated lipid synthesis and sebocyte differentiation in vitro. Isotretinoin was the most potent compound. On the other hand, vitamin A was found essential for sebocyte activity and differentiation in vitro and could be partially substituted by synthetic retinoids. The inhibitory effect of isotretinoin on sebocyte proliferation was barely affected by the presence of vitamin A. The low persistent isotretinoin levels or, more likely, the considerably elevated tretinoin concentrations detected in human sebocytes after treatment with isotretinoin in vitro may be responsible for the inhibitory effect of this compound on sebocyte activity.

Acne Vulgaris↗
PubMed1998

VPA-induced neural tube defects in mice. I. Altered metabolism of sulfur amino acids and glutathione.

Valproate (VPA) has been shown to induce neural tube defects (NTDs) in humans and mice, but the mechanism of action has not been elucidated. Folate supplementation has been reported to prevent the defect. It was the aim of our experiment to reveal effects of VPA and of folate coadministration on amino acid metabolism in an NTD mouse model. After treating pregnant mice intraperitoneally with 2.1 mmol VPA/kg body weight, plasma homocysteine concentrations were found to be increased. Coadministration of 4 mg/kg folate decreased this level. Plasma methionine levels were reduced under both experimental conditions. Fifteen min after treating mice with 3 mmol VPA/kg body weight, hepatic levels of both S-adenosylmethionine (SAM) and S-adenosylhomocysteine were found to be increased by +175% and +348%, respectively; but the levels had normalized again 30 min after VPA injection. Simultaneously, plasma methionine and serine levels had decreased by -43% and -51%, respectively, while homocysteine and cysteine increased by +71% and +81%, respectively. Reduced glutathione (GSH) decreased by -45%, but total glutathione did not change. These changes were statistically significant, and they occurred dose-dependently. We proposed that VPA induces methionine deficiency inhibition of folate metabolism and homocysteine remethylation, increase in aminothiols, and suppression of the GSH system in maternal blood within 1 h after application. These changes may be responsible for the teratogenic potential of VPA. Folate may prevent NTDs by changing homocysteine catabolism.

Abnormalities, Drug-Induced↗
PubMed1997

Prediction of teratogenic potency of valproate analogues using cerebellar aggregation cultures.

The aim of this study was to develop a novel in vitro system suitable for preclinical testing for developmental toxicity of drugs. An assay system consisting of primary cultures of dissociated cerebella from 6-day-old mice was chosen, since it allowed quantification of neuronal aggregation and fasciculated neurites. A human teratogen, the antiepileptic drug valproic acid (VPA), as well as its structural analogues, ( +/- )-4-en-VPA and E-2-en-VPA, with varying teratogenic activities, were tested and found to affect aggregation and fiber formation of cerebellar neurons. Based on a dose-response study, the concentrations of compounds causing 50%, inhibition (IC50) of formation of thick and thin fibers were determined. The lowest IC50 values were found for VPA (52 +/- 7 and 86 +/- 11 microM for thick and thin fibers, respectively), which in vivo caused the highest rate of exencephaly among the three compounds tested, ( +/- )-4-en-VPA exhibited intermediate values (150 +/- 30 and 300 +/- 40 microM), whereas the highest IC50 values were found for E-2-en-VPA (260 +/- 42 and 430 +/- 40 microM). The latter compound does not induce neural tube defects, but has been shown to have neurobehavioral effects in prenatally exposed animals. Subsequently, the purified S- and R-enantiomers of 4-yn-VPA (teratogenic and non-teratogenic, respectively) were tested for their effects on aggregation and fiber formation of the cerebellar neurons. Treatment with S-4-yn-VPA resulted in pronounced changes in numbers of aggregates and fasciculated processes compared to the cultures treated with R-4-yn-VPA, indicating that the intrinsic stereoselective potency of the enantiomers may be correlated to the difference in their effects on cerebellar neurons in vitro. Thus, the teratogenic potency of VPA and its analogues correlated with their effects on aggregation of neural cells and formation of fasciculated neurites in primary cultures of dissociated cerebella, indicating that the in vitro assay system employed may be used as a pre-screening test for prediction of teratogenic potency of drugs.

Animals↗
PubMed1997

Stereoselective dysmorphogenicity of the enantiomers of the valproic acid analogue 2-N-propyl-4-pentynoic acid (4-yn-VPA): cross-species evaluation in whole embryo culture.

We previously reported the in vitro differential stereoselective dysmorphogenic potential of the R(+) and S(-) enantiomers of 2n-propyl-4-pentynoic acid (4-yn-VPA) in mice. To determine whether this stereoselectivity is species specific, we evaluated the dysmorphogenic potential of these isomers as well as valproic acid (VPA) to gestational day 9 rat embryos using whole embryo culture (WEC). Aqueous solutions of the sodium salts of R-4-yn-VPA, S-4-yn-VPA, 50%R/ 50%S-4-yn-VPA or VPA were added to the culture medium to give 0, 0.075, 0.15, 0.3, 0.6, or 1.2 mmol/L and embryos were evaluated 48 hr later. The S-4-yn-VPA enantiomer gave clear concentration-dependent dysmorphology as well as effects on developmental score, somite number, crown rump length, and head length. Effects on rotation and defects of the neural tube, somites and heart were observed. Embryolethality was observed only at 1.2 mmol/L concentration. The R-4-yn-VPA enantiomer was neither embryo toxic nor dysmorphogenic at any concentration. VPA significantly reduced all parameters and was dysmorphogenic at the highest concentration but was not embryo lethal. The 50/50 mixture of R- and S-isomers appeared to elicit a degree of embryolethality and dysmorphology similar to VPA. The potency order for the four chemicals was S(-) > S(-)/R(+) = VPA > > > R(+), comparable to that observed in mice by either in vivo or in vitro exposure. These data demonstrate that the stereoselective dysmorphology for these enantiomers can be observed across species and is not related to maternal metabolism.

Abnormalities, Drug-Induced↗
PubMed1997

The area under the concentration-time curve of all-trans-retinoic acid is the most suitable pharmacokinetic correlate to the embryotoxicity of this retinoid in the rat.

Earlier studies with etretinate and its metabolite acitretin suggested that area under the concentration-time curve (AUC) is the most suitable pharmacokinetic correlate to etretinate-induced teratogenesis. In an attempt to test this hypothesis with respect to the embryotoxic effects of all-trans-retinoic acid (all-trans-RA), we determined the embryotoxicity and plasma pharmacokinetics of all-trans-RA and its metabolites following administration of all-trans-RA to Wistar rats on Gestational Day (GD) 9, either subcutaneously (sc; dose levels 1, 3, or 5 mg/kg body mass) or orally (po; 5 mg/kg body mass). The 5 mg/kg dose of all-trans-RA was not embryotoxic when administered orally but led to high rates of embryolethality and skeletal defects following sc treatment. Determination of retinoids by HPLC showed that all-trans-RA reached similar maximum plasma concentrations (C(max)) after both dosing regimens, but its plasma AUC was ca. threefold higher after sc injection than po administration due to the slower uptake rate of the drug and its limited detoxification via beta-glucuronidation following sc injection. Furthermore, retinoid analysis in rat tissues (liver, kidney, duodenum, and jejunum), collected 1 hr after sc or po administration of 5 mg all-trans-RA/kg body mass on GD 9, confirmed that formation of all-trans-retinoyl-beta-glucuronide was much more extensive after po than after sc administration. Finally, linear regression analysis of either C(max). or AUC values of all-trans-RA in rat plasma and fetal abnormality rates showed that AUC values are better correlated with the embryotoxic outcome than C(max) [AUC-based correlation coefficient (r) > 0.90; C(max)-based r < 0.43]. Our findings establish the relevance of the AUC of all-trans-RA, and not its C(max), as the most appropriate pharmacokinetic marker of embryonic exposure and embryotoxic potency of all-trans-RA and stress the importance of the duration of exposure as a major determinant of embryotoxic outcome for retinoids.

Abnormalities, Drug-Induced↗
PubMed1997

RARalpha-mediated teratogenicity in mice is potentiated by an RXR agonist and reduced by an RAR antagonist: dissection of retinoid receptor-induced pathways.

To dissect the complex pattern of retinoid-induced developmental defects, an RXR-selective agonist (AGN191701, an arylpropenyl-thiophene-carboxylic acid derivative) was coadministered with an RARalpha-selective agonist (Am580, an arylcarboxamidobenzoic acid derivative) to NMRI mice on Day 8.25 of gestation. AGN191701 was neither fetotoxic nor teratogenic at the doses used, but potentiated Am580-induced resorptions, spina bifida aperta, micrognathia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, tail malformations, fused ribs, and fetal weight retardation. These effects were generally reduced by coadministration of an RAR-selective antagonist (CD2366, an adamantyl-methoxyphenyl-heptatrienoic acid derivative). The incidence of other defects induced by an RARalpha-selective agonist such as exencephaly or cleft palate was neither greatly affected by the RXR-selective agonist nor by the antagonist. These results suggest that some malformations such as the posterior neural tube defect spina bifida as well as urogenital defects may be mediated via liganded RARalpha-RXR heterodimerization, while other defects such as the anterior neural tube defect exencephaly as well as cleft palate are induced by different mechanisms.

Abnormalities, Drug-Induced↗
PubMed1997

Effects of all-trans-retinoyl-beta-D-glucuronide and all-trans-retinoic acid on chondrogenesis and retinoid metabolism in mouse limb bud mesenchymal cells in vitro.

Retinoids, derivatives of vitamin A, are essential for many vertebrate functions. Furthermore, several drugs of this class of compounds are valuable in the treatment of certain forms of skin disorders and cancer. However, the therapeutic application of retinoids is limited by their teratogenic potency. The limbs are important sites of retinoid-induced malformations in rodents. Therefore, organoid cultures of limb bud mesenchymal cells have been established for screening of the teratogenic potency of retinoids. We have now applied this system to compare the effects of all-trans-retinoyl-beta-D-glucuronide (all-trans-RAG) with those of all-trans-retinoic acid (all-trans-RA) on chondrogenesis, as assessed by the Alcian blue binding assay and by electron microscopic evaluation including quantitative morphometric analysis. First data of retinoid toxicokinetics in the culture media as well as retinoid concentrations in the cultured mesenchymal limb bud cells were established. While all-trans-RA inhibited chondrogenesis at 10(-7) M by ca. 50%, tenfold higher concentrations of all-trans-RAG were necessary to obtain the same effect. This difference reflects the ratio of RA isomers which were found in the medium after incubation with either all-trans-RAG or all-trans-RA. A pulse experiment (10(-5) M all-trans-RAG or all-trans-RA for the first 2 h of a 6-day incubation period) demonstrated inhibition of chondrogenesis with all-trans-RA, but not with all-trans-RAG. The data indicate that RAG inhibits chondrogenesis upon hydrolysis to RA. Surprisingly, the rather polar RAG isoforms were extensively accumulated in the limb bud mesenchymal cells when compared to the medium. Both all-trans-RAG and all-trans-RA also induced a large increase of retinyl ester concentrations in the chondrocytes compared to vehicle-treated cells. This finding further supports a recent suggestion that RA regulates retinol metabolism via feedback inhibition of retinol oxidation and stimulation of the esterification of retinol.

Alcian Blue↗
PubMed1997

Correlation of in vitro anti-proliferative potential with in vivo teratogenicity in a series of valproate analogues.

The prediction that an anti-proliferative effect coupled with a pro-differentiative action will detect a neural tube teratogen has been validated by comparison of these in vitro endpoints with in vivo teratogenicity in a series of closely allied valproate structural analogues. The majority of the compounds significantly inhibited C6 glioma proliferation, the most potent compounds being ranked as octanoic acid > 2-propylhexanoic acid > or = 2-ethylhexanoic acid > or = valproic acid. The anti-proliferative potency of these compounds did not correlate strictly to their relative in vivo teratogenic potential. Valproic acid exhibited an anti-proliferative IC50 of 1.45 mM, whereas 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid were virtually indistinguishable, exhibiting significantly lower IC50 values of 2.5 and 2.55 mM, respectively. The concanavalin A lectin affinity assay was employed to establish whether an anti-proliferative action was coupled with an increased state of cell differentiation. In this lectin affinity assay, the most potent analogues to significantly attenuate the affinity of exposed C6 glioma cells for concanavalin A lectin-coated plastic included 2-butylhexanoic acid, 2-propyl-4-pentenoic acid, 2-propylhexanoic acid and 2-ethylhexanoic acid in a manner which can be related to their relative teratogenic potencies in vivo. All compounds screened positive in both the anti-proliferative and pro-differentiative assays exhibited in vivo exencephalic rates of 5-44%. These included valproic acid, 2-ethylhexanoic acid, 2-propylhexanoic acid and 2-butylhexanoic acid. It would appear that combined anti-proliferative and pro-differentiative screens provide a promising detection system for teratogenic status in a series of valproate analogues.

Abnormalities, Drug-Induced↗
PubMed1996

Identification of 14-hydroxy-4,14-retro-retinol as an in vivo metabolite of vitamin A.

Retinol (vitamin A alcohol) undergoes extensive metabolism in vertebrates. We report here (i) the identification of a yet undescribed in vivo metabolite of retinol as 14-hydroxy-4,14-retro-retinol in pregnant mice, rats and rabbits following dosing with vitamin A, and (ii) the preferential accumulation of 14-hydroxy-4,14-retro-retinol in maternal and embryonic tissues, rather than in material plasma.

Animals↗
PubMed1996

Binding of a valproate metabolite to the trifunctional protein of fatty acid oxidation.

The anti-convulsant drug valproate causes hepatic failure in a small percentage of patients. We now report that the valproate metabolite 2,4-dien-valproate binds (IC50 = 42 microM) to the alpha-subunit of the trifunctional protein responsible for the second and third steps in the mitochondrial beta-oxidation of fatty acids. Binding of valproate itself, or of the metabolites 2-envalproate, 4-en-valproate or 3-hydroxy-4-en-valproate, is considerably weaker. We conclude that valproate-induced hepatotoxicity may be due in part to the reversible binding of the valproate metabolite 2,4-dien-valproate or its CoA ester to the alpha-subunit of the trifunctional protein with consequent inhibition of fatty acid oxidation.

Animals↗
PubMed1996

Fully automated determination of selective retinoic acid receptor ligands in mouse plasma and tissue by reversed-phase liquid chromatography coupled on-line with solid-phase extraction.

A fully automated reversed-phase HPLC method was developed for the quantitative assay of three retinoids (Am-580, CD-2019 and CD-437) which selectively activate the retinoic acid receptors RAR alpha, RAR beta and RAR gamma, respectively. Mouse plasma, embryo and maternal tissues were prepared for injection by on-line solid-phase extraction (SPE) and valve-switching techniques. Following automatic injection, the sample was loaded on preconditioned disposable cartridges, cleaned-up and then transferred onto the analytical column to be eluted in the backflush mode, separated by gradient elution and detected by UV, while a new cartridge was concomitantly conditioned. The overall recovery was quantitative allowing for external standardization. The calibration curves were linear in all biological samples tested so far, with a correlation coefficient (r) >0.99. The intra-day precision was < or = 7.8% (n = 5-6) and the inter-day variability was < or = 9.4% (n = 3). The lower limit of detection was 2.5 ng/ml or ng/g for CD-2019 and CD-437, and 5 ng/ml for Am-580 with a S/N ratio of 5 using a sample weight of 25 microliters or mg. The method is now in routine use in our laboratory for the assessment of the pharmacokinetic profiles of these retinoids. The small sample size required, the simple sample preparation and the rapid analysis with high degree of automation make this method convenient for microanalysis of biological samples both in animal and human studies.

Animals↗
PubMed1996

Pattern of retinoid-induced teratogenic effects: possible relationship with relative selectivity for nuclear retinoid receptors RAR alpha, RAR beta, and RAR gamma.

Retinoic acid, an oxidative metabolite of vitamin A, is involved in the control of many biological processes including embryonic development. Excess as well as deficiency of retinoids were 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 RAR's and RXR's, which exhibit a specific temporal and spatial expression during development. The significance of the retinoid receptors was investigated here by studying the teratogenic effects of retinoid ligands with relative selectivity for binding and transactivation of the retinoic acid receptors RAR alpha, RAR beta and RAR gamma. Pregnant NMRI mice were administered 5 or 15 mg/kg of CD 336 (Am 580) (alpha-ligand), CD 2019 (beta-ligand), CD 437 (gamma-ligand) or 37.5 mg/kg all-trans-retinoic acid in 25% Cremophor EL on day 8.25 or day 11 of gestation by gastric intubation. External, visceral and skeletal malformations were observed on day 18 of gestation. The order of teratogenic potency was: alpha-ligand > beta-ligand > gamma-ligand. In addition, these retinoids also produced a different spectrum of defects. The alpha-ligand induced the most varied defects including severe ear, mandible, and limb malformations. The beta-ligand induced defects of the urinary system and liver in greater frequency than expected from its relative potency. The gamma-ligand preferentially induced ossification deficiencies and defects of the sternebrae and vertebral body. Our results show that these three retinoids, which were previously demonstrated to exhibit retinoid-like activities in several systems, exert differing teratogenic activities, in regard to both potency and regioselectivity: we hypothesize that the relative selectivity for binding and transactivation of the three retinoic acid receptors could possibly be related to the differences of teratogenic effects observed in this study. The low potency of the gamma-ligand may lead the way to interesting new retinoids with improved therapeutic ratio.

Abnormalities, Drug-Induced↗