Induction of RAR-β2 Gene Expression in Embryos and RAR-β2 Transactivation by the Synthetic Retinoid Ro 13-6307 Correlates with Its High Teratogenic Potency
| Autor: | Michael Gyda, Dianne Robert Soprano, H. Jiang, D.C. Harnish, Kenneth J. Soprano, D. M. Kochhar, Nikolaos Tairis |
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| Rok vydání: | 1993 |
| Předmět: |
Transcriptional Activation
Gene isoform medicine.medical_specialty animal structures Transcription Genetic Receptors Retinoic Acid medicine.drug_class Retinoic acid Tretinoin Biology Toxicology Mice chemistry.chemical_compound Transactivation Pregnancy Internal medicine medicine Animals RNA Messenger Retinoid Receptor Pharmacology Reporter gene Retinoid X receptor alpha Stereoisomerism Embryo Mammalian Teratogens Endocrinology Gene Expression Regulation chemistry embryonic structures Fatty Acids Unsaturated Female Retinoid X receptor beta Carrier Proteins |
| Zdroj: | Toxicology and Applied Pharmacology. 122:159-163 |
| ISSN: | 0041-008X |
| DOI: | 10.1006/taap.1993.1183 |
| Popis: | Vitamin A (retinol), its metabolite all-trans retinoic acid (RA), and many synthetic analogs (retinoids) express variable potencies as teratogens. Although biological activities of retinoids are mediated by nuclear RA receptors (RARs) and retinoid X receptors (RXRs), it is not known if any of these receptors mediate teratogenicity, and if the potency also depends on the nature of the ligand-receptor interactions. Previous evidence has implicated that one specific isoform, RAR-beta 2, does play a role in mediating retinoid teratogenicity. Here, we employed an aromatic retinoid with a triene side chain, Ro 13-6307, to study its interactions with RAR-beta 2 since its teratogenicity is much higher and its accessibility to the embryo is much lower than RA. A fully teratogenic dose of Ro 13-6307 (10 mg-kg) given to pregnant mice preferentially elevated the level of RAR-beta 2 mRNA in susceptible embryonic regions (maximal induction, 10- to 12-fold above control in limb buds) in a manner comparable to a fully teratogenic dose of all-trans RA (100 mg-kg). Using the RAR-beta 2 promoter linked to a reporter gene in cotransfection experiments, the efficacy of Ro 13-6307 and RAR-beta 2 in transcription transactivation was found to be 30-40 times greater than all-trans RA. Since the teratogenic potency of Ro 13-6307 is estimated from a previous study to be 44-fold greater than all-trans RA, we suggest that the teratogenicity of this synthetic retinoid is generally proportional to its ability to enhance receptor function. |
| Databáze: | OpenAIRE |
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