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Retinoids Vitamin A and its derivatives

Retinoids Vitamin A and its derivatives. Retinoids. I mportant for cell growth, apoptosis and differenciation. N ecessary for vision. Development of embryonic, epithelial cells ( gastrointestinal tract, skin , bones ). A ntioxidative agent. C oenzyme Q biosynthesis.

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Retinoids Vitamin A and its derivatives

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  1. RetinoidsVitamin A and its derivatives

  2. Retinoids Important forcell growth, apoptosis and differenciation Necessary for vision Development of embryonic, epithelial cells (gastrointestinal tract, skin, bones) Antioxidative agent Coenzyme Q biosynthesis Suppressive effects in cancer development

  3. Retinoids -karoten Bond cleavage Retinol (vitamin A) Retinoic Acid

  4. Exprese genů Mode of action • Nuclear receptors RAR a RXR

  5. Mode of action • Isoforms of RAR a RXR • Both have isoforms a,b and g, each of them several subtypes • Formation of homo- and heterodimers • 48 possible RAR-RXR heterodimers =>sensitive regulation of gene expression • RXR – heterodimers even with other receptors like VDR, TR, PPAR

  6. Retinoic acid • 3 basic subtypes • all-trans-, 9-cis- and 13-cis-retinoic acid • All-trans RA binds selectively to RAR • Cis RA bind to both receptor types • RA may be isomerized inside cells 13-cis-retinoic acid

  7. Retinoid-binding proteins • CRBP – cellular retinol binding protein • - binding of retinol, immediate decrease of retinol concentration • CRBAP – cellular retinoic acid binding protein • Controlling ratio free retinol/free retinoic acid and so retinoid signalling

  8. RE: Retinol-Ester R: Retinol RBP: Retinol Binding Protien (LMW) TTR: Transthyrethin (HMW)

  9. RAL - Retinal

  10. Disruption of retinoid signalling by xenobiotics • Relatively little is known • Possible modes of action: • Metabolization of retinoids by detoxication enzymes • Disruption of binding retinoids to retinoid binding proteins • Retinoids as antioxidants may be consumed cause of oxidative stress caused by xenobiotics • Interference of chemicals (binding to RAR/RXR)

  11. Consequences of retinoid signalling disruption - Decreased retinoid levels in organisms - Downregulation of growth factors - Xerophtalmia, night blindness - Embryotoxicity, developmental abnormalities X - Increased ATRA concentration – teratogenic effect Change may cause severe developmental anomalies

  12. Disruption of retinoid signalling by xenobiotics • - Most studies focused on effects of PCBs, PCDDFs • Exposure to these chemicals leads to: • Increased serum concentrations of retinol and RA • Mobilization of hepatic storage forms • In kidney, concentration of all forms elevated

  13. In vivo teststo assess retinoid signalling disruption • - Mostly derived from classical toxicity tests, particularly of developmental toxicity • Direct measurements of various retinoid forms in living organisms (laboratory and wildlife)

  14. Mostly epithelial cell lines (keratinocytes) • Mouse embryonic cell lines P19 • pluripotent cells • differentiation dependent on circumstances • dif. triggered by ATRA - Other cell lines – rainbow trout gonads, human salivary gland, breast or prostatic carcinomas etc. In vitro tests

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