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001-es BibID:	BIBFORM036663
Első szerző:	Krätke, Renate
Cím:	All- trans -retinoic acid and all- trans -retinoyl-beta-d -glucuronide alter the development of axolotl embryos ( Ambystoma mexicanum ) in vitro / Renate Krätke, Ralph Rühl, Frank Kirschbaum, Heinz Nau
Dátum:	2000
ISSN:	0340-5761
Megjegyzések:	Retinoids are involved in several physiological processes and are used in the treatment of various skin disorders. Therapy with retinoids during pregnancy may induce severe embryotoxic effects like craniofacial and cardiovascular malformations in the developing embryo. We investigated the effects of all-trans-retinoic acid (ATRA) and all-trans-retinoyl-β-D-glucuronide (ATRAG) in an amphibian embryotoxicity assay with Ambystoma mexicanum (axolotl) as an alternative in vitro method. Embryos were exposed to various concentrations of ATRA or ATRAG for 48 h beginning with the blastula stage. Kinetic investigations in the embryonic tissue were performed during the exposure period. Both retinoids interfered with the development of the axolotl embryos. Dose-dependent effects observed included growth retardation, craniofacial and cardiovascular malformations, as well as neural tube defects. In the axolotl, ATRA induced slightly more pronounced embryotoxic effects than ATRAG. All-trans-retinal was shown to be a major endogenous retinoid in this species. Endogenous levels of all-trans-retinaldehyde were increased during exposure to both ATRA and ATRAG. The glucuronide, however, was only detected in small amounts after ATRAG exposure. The embryotoxic potential of ATRAG could be explained by deglucuronidation to ATRA.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Archives Of Toxicology. - 74 : 3 (2000), p. 173-180. -
További szerzők:	Rühl, Ralph (1969-) (vegyész) Kirschbaum, Frank Nau, Heinz
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM036658
Első szerző:	Rühl, Ralph (vegyész)
Cím:	Effects of all-trans-retinoic acid and all-trans-retinoyl glucuronide in two in vitro systems of distinct biological complexity / Ruhl Ralph, Sass Jörn, Nau Heinz, Klug Stephan
Dátum:	2001
ISSN:	0340-5761
Megjegyzések:	In vitro systems are widely used to evaluate the embryotoxic potential of retinoids. The effective concentrations of these retinoids, however, are not consistent in the various in vitro systems used in evaluating embryotoxicity. This may be explained by the different level of complexity for each individual system, which may lead to different concentrations of the substances in the target tissues. To verify this hypothesis we have compared two in vitro systems of distinct biological complexity: the rat whole embryo culture system, and the mouse limb bud organ culture system. The lipid soluble, teratogenic retinoid all-trans-retinoic acid (ATRA), and all-trans-retinoyl-beta-D-glucuronide (ATRAG), an endogenous, water-soluble and biologically active retinoid with limited placental transfer, were compared with regard to their embryotoxic potential in vitro. In both in vitro systems, ATRAG showed a lower degree of embryotoxicity than ATRA. In the limb bud organ culture, ATRAG revealed only slightly less toxicity than ATRA, whereas the effective concentrations of the two compounds in the whole embryo culture system differed by almost two orders of magnitude. During incubation with ATRAG, ATRA is generated by hydrolysis and is found in culture media and exposed tissues. The presence of membrane barriers around the developing embryo in the whole embryo culture system possibly prevents the transfer of ATRAG to the embryo and, therefore, its exposure to the active hydrolysis product ATRA. From these results we conclude that analysis of retinoid concentrations in the culture media and in the exposed tissues is essential for the interpretation of results obtained from in vitro toxicity testing.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Archives Of Toxicology. - 75 : 8 (2001), p. 497-504. -
További szerzők:	Sass, Jörn Nau, Heinz Klug, Stephan
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM036666
Első szerző:	Sass, Jörn
Cím:	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 / Sass, J. O., Zimmermann, Bernd, Rühl, Ralph, Nau, Heinz
Dátum:	1997
ISSN:	0340-5761
Megjegyzések:	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-β-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.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Archives Of Toxicology. - 71 : 3 (1997), p. 142-150. -
További szerzők:	Zimmermann, Bernd Rühl, Ralph (1969-) (vegyész) Nau, Heinz
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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