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001-es BibID:	BIBFORM036665
Első szerző:	Elmazar, Mohamed M. A.
Cím:	RARalpha-Mediated Teratogenicity in Mice Is Potentiated by an RXR Agonist and Reduced by an RAR Antagonist : dissection of Retinoid Receptor-Induced Pathways / Elmazar M. M., Rühl R., Reichert U., Shroot B., Nau H.
Dátum:	1997
ISSN:	0041-008X
Megjegyzések:	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.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Toxicology And Applied Pharmacology. - 146 : 1 (1997), p. 21-28. -
További szerzők:	Rühl, Ralph (1969-) (vegyész) Reichert, Uwe Shroot, B. Nau, Heinz
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM036662
Első szerző:	Elmazar, Mohamed M. A.
Cím:	Synergistic teratogenic effects induced by retinoids in mice by coadministration of a RARalpha- or RARgamma-selective agonist with a RXR-selective agonist / Elmazar M. M., Rühl R., Nau H.
Dátum:	2001
ISSN:	0041-008X
Megjegyzések:	To study the interaction of retinoid-induced limb defects and cleft palate on day 11 of gestation, a RXR-selective agonist (AGN191701, an arylpropenyl-thiophene-carboxylic acid derivative, 20 mg/kg orally) was coadministered with a RARalpha-agonist (Am580, an arylcarboxamidobenzoic acid derivative, 5 mg/kg orally) to NMRI mice. AGN191701 was neither fetotoxic nor teratogenic at the dose used but potentiated Am580-induced limb defects and cleft palate and prevented Am580-induced fetal weight retardation. These results suggest that Am580-induced limb defects and probably cleft palate on day 11 of gestation may be mediated via RARalpha-RXR heterodimerization, particularly in the absence of toxicokinetic interactions. AGN191701 was also coadministered with a RARgamma-agonist (CD437, an adamantyl-hydroxyphenyl naphthoic acid derivative, 15 mg/kg orally) on days 8 and 11 of gestation to investigate which CD437-induced defects are mediated via RARgamma-RXR heterodimerization. On day 8 of gestation, AGN191701 potentiated CD437-induced embryolethality, exencephaly, spina bifida aperta, cleft palate, and tail defects, as well as visceral and skeletal defects, but not micrognathia. On day 11 of gestation, the incidence of CD437-induced cleft palate and limb defects was also potentiated when coadministered with the RXR agonist. These results suggest that synergistic teratogenic effects can be induced by coadministration of two receptor-selective retinoids, indicating the importance of RARalpha-RXR and RARgamma-RXR heterodimers in producing structural defects during organogenesis.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Toxicology And Applied Pharmacology. - 170 : 1 (2001), p. 2-9. -
További szerzők:	Rühl, Ralph (1969-) (vegyész) Nau, Heinz
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM037319
Első szerző:	Nau, Heinz
Cím:	All-trans-retinoyl-beta-glucuronide is a potent teratogen in the mouse because of extensive metabolism to all-trans-retinoic acid / Nau, H., Elmazar, M. M. A., Rühl, R., Thiel, R., Sass, J.
Dátum:	1996
Megjegyzések:	All-trans-retinoyl-beta-D-glucuronide (all-trans-RAG) is a water-soluble derivative of all-trans-retinoic acid (all-trans-RA) and has been characterized as an endogenous metabolite of vitamin A in rat bile and kidney. All-trans-RAG was previously demonstrated to be a major metabolite after application of all-trans-RA in several species (mouse, rat, rabbit, monkey); all-trans-RAG was described in these experiments to exhibit a very low placental transfer to the embryo. Because retinoid-like activity has been found after application of all-trans-RAG in vivo as well as in several in vitro systems, and because of its low placental transfer, this glycoconjugate appeared to be an interesting retinoid with possible therapeutic activity, but reduced teratogenicity. Here we investigated the teratogenic activity of all-trans-RAG in comparison to all-trans-RA in mice, and performed accompanying pharmacokinetic studies. Surprisingly, all-trans-RAG was more teratogenic than equimolar doses of all-trans-RA following subcutaneous application on day 11 of gestation in the mouse (20 mumol/kg body weight). Pharmacokinetic studies revealed that all-trans-RAG was extensively hydrolyzed to all-trans-RA and that the plasma area under the concentration-time curve (AUC) of all-trans-RA following all-trans-RAG application exceeded the plasma AUC value of all-trans-RA following application of all-trans-RA. Extensive hydrolysis of all-trans-RAG was also observed after intravenous application of this glycoconjugate. Transfer of all-trans-RAG to the embryo was low, but transfer was high to maternal organs such as the liver and kidney. These in vivo studies suggest that all-trans-RAG serves as a precursor of all-trans-RA by the intravenous and subcutaneous routes, and application of all-trans-RAG results in high and teratogenic in vivo exposure to all-trans-RA.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Teratology. - 54 : 3 (1996), p. 150-156. -
További szerzők:	Elmazar, Mohamed M. A. Rühl, Ralph (1969-) (vegyész) Thiel, Renate Sass, Jörn
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM036660
Első szerző:	Rühl, Ralph (vegyész)
Cím:	Embryonic subcellular distribution of 13-cis- and all-trans-retinoic acid indicates differential cytosolic/nuclear localization / Ralph Rühl, Claudia Plum, Mohamed M. A. Elmazar, Heinz Nau
Dátum:	2001
Megjegyzések:	Isotretinoin (13-cis-retinoic acid [13CRA], Accutane) is used for the treatment of dermatological diseases. Isotretinoin is, however, teratogenic in animals and humans. The mechanism of action of its teratogenicity is still not clearly identified. It has little or no binding properties to cytosolic retinoid-binding proteins or nuclear retinoid receptors (RAR, RXR). One hypothesis is that the teratogenicity of 2 approximately equipotent teratogenic doses of 13CRA and all-trans-retinoic acids (ATRA) could mainly be correlated to ATRA in the nuclei, where the retinoic acid receptors (RARs) are located. To test this hypothesis, female mice at gestational day 11 were treated with approximately equipotent teratogenic doses of 13-cis-retinoic acid (100 mg/kg orally) or all-trans-retinoic acid (10 mg/kg orally) and sacrificed 1 h and 4 h after administration. Embryos were homogenized and centrifuged into 4 fractions, and the purity of the fractions was tested by quantification of marker constituents for various cell compartments. We analyzed, by RP-HPLC, nuclear, mitochondrial, microsomal, and cytosolic fractions, as well as embryo homogenate and maternal plasma. After treatment with 13-cis-retinoic acid, this substance was mainly located in the nuclear fraction of the embryo (approximately 82%), whereas all-trans-retinoic acid, after ATRA treatment, was mainly located in the cytosolic supernatant (approximately 64%). The binding to cellular retinoid-binding protein (CRABP) may limit the access of ATRA to the nucleus, in contrast to 13CRA, which does not bind to CRABP. The concentration of ATRA in the nuclear fraction was similar after administration of either 13CRA or ATRA. The teratogenic activity of 13-cis-retinoic acid could therefore be explained by its access to the nucleus and its possible conversion to all-trans-retinoic acids, which will interact with the nuclear retinoid receptors.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Toxicological Sciences. - 63 : 1 (2001), p. 82-89. -
További szerzők:	Plum, Claudia Elmazar, Mohamed M. A. Nau, Heinz
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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