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Retinoids
Vitamin A and its derivatives
Suppressive effects in
cancer development
Retinoids
Necessary for vision Important for cell growth,
apoptosis and
differenciation
Development of embryonic,
epithelial cells (gastrointestinal
tract, skin, bones)
Antioxidative
agent
Coenzyme Q
biosynthesis
Retinoids
Retinol (vitamin A)
OH
CH3CH3CH3
CH3
CH3
OH
CH3CH3CH3
CH3
CH3
O
CH3CH3CH3
CH3
CH3 CH3 CH3 CH3
CH3
CH3
Bond cleavage
Retinoic Acid
-karoten
Mode of action
- Nuclear receptors RAR a RXR
RAR
RXR
RAR RXR
RARERXRE
Retinoidy
Exprese genů
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Mode of action
- Isoforms of RAR a RXR
- Both have isoforms ,  and , 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
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
OH
CH3CH3CH3
CH3
CH3
O
13-cis-retinoic acid
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
RE: Retinol-Ester
R: Retinol
RBP: Retinol Binding
Protien (LMW)
TTR: Transthyrethin
(HMW)
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RAL - Retinal
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)
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
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
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In vivo tests to 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)
In vitro tests
- 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.