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Copy of Biosyntéza a degradace steroidních hormonů

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by

Marek Hilser

on 19 September 2016

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Transcript of Copy of Biosyntéza a degradace steroidních hormonů

Definition of hormone?
Synthesis of steroid
hormones

Clinical and Patological Aspects of Steroid Hormones Synthesis
Biosynthesis and Biodegradation of Steroid Hormones , Mechanisms of Their Action
HO
Pregnenolone C21
Cholesterol C27
O
Progesterone C21
CH
3
O
HO
CH
2
Deoxycorticosterone C21
HO
Corticosterone C21
C
H
O
Aldosterone C21
P450 SCC ?
Aldosterone
Kortisol
Dihydrotestosterone
Estriol
Pregnenolone
Deoxykortikosterone
Progesterone
Cholesterol
Kortikosterone
Hydroxypregnenolone
Hydroxyprogesterone
Deoxycortisol
DHEA
Androstendione
Testosterone
Estradiol
Estron
21 - hydroxyláza
18 - hydroxylase
18 - hydroxydehydrogenase
11b - hydroxylase
C27
C21
C19
C18
C18
5a - reduktase
P450 Scc
17,20- Lyase
17a-hydroxylase
P450c17
mitochondria
endoplasmic reticulum
Classification of hormones
oblast účinku
chemical composition
solubility
location of receptors
HYDROFOBIC
HYDROFILIC
chem. character?
transport?
biological half-life?
receptor?
mediator of action?

Classification of hormones
Transport of steroid hormones
corticosteroid - binding globulin (transkortin)
CBG
SHBG
sex hormone-binding globulin
Albumin
Cortizol
Aldosteron
Testosteron
Estradiol
Progesteron
2x
3*
2*
2*
5*
Dihydrotestosteron
1*
K (nmol/l)
d
HSP
Receptors of steroid hormones
HRE
HRE
hormon responsive elements
GRE
PRE
MRE
ARE
ERE
...
GGTACA nnnTGTTCT
AGGTCA---TGA/TCCT
transactivation domain
ligand binding domain
domain for interaction with DNA
HSP binding domain
Map of SH synthesis
Aldosterone
Cortisol
Dihydrotestosterone
Estriol
Deoxykorticosterone
Progesterone
Cholesterol
Corticosterone
Hydroxypregnenolone
Hydroxyprogesterone
Deoxycortisol
Androstendione
Testosterone
21 - hydroxylase
18 - hydroxylase
18 - hydroxydehydrogenase
AROMATASE
11b - hydroxylase
C27
5a - reductse
P450 Scc
Pregnenolone
DHEA
Estrone
Estradiol
What do you see in the picture A and what is the cause of this disease?
Example of chemical modification of cholesterole molecule in the proces of SH synthesis mineralocorticoid pathway
ACTH, LH, FSH
P450 scc
3b hydroxysteroid dehydrogenase
and other enzymes
Endoplasmic reticulum
StAR
Iniciation of SH synthesis
Mitochondrion
Blood circulatory system
What is their significance for clinical medicine?
Antagonists of steroid receptors
Inhibitors of aromatase
Syntéza 1,25 (OH) -D
2
3
Vitamine D3 -cholecaciferol
isomerisation
liver
25 - hydroxylase
OH
Kidney
1a - hydroxylase
Calcitriol
OH
OH
24 - hydroxylase
OH
HO
non reactive metabolite
Population groups at risk of calcitrol deficiency?
Sucklings
Seniors
Pacients with kidney disease (dialysis)
Prevention of calcitriol deficiency
Prevention ?
solar light
fish oil
Vitamin D
3
20 min. a day
steroidogenic acute regulatory protein
transport of cholesterol to the inner mitochondrial membrane
Inactivation and elimination of steroid hormones
hydrofobic
hydrofilic
Phase I
hydroxylation
Phase II
glucuronidation
sulfonation
liver
kidney
bile/urine
Hormonal therapy
The End
*
C = 10 - 10
-15
-9
Concentration of hormones in extracelular fluid
mol/l
Other similar molecules
C = 10 - 10
-5
-3
mol/l
transkripce specifických genů
dimerization domain
heat shock protein
C21
C21
C21
C21
C21
C21
C21
C21
C19
C19
C19
C18
Inhibitors 5a-reductase
Aldosteron
Kortisol
Estriol
Pregnenolon
Deoxykortikosteron
Progesteron
Cholesterol
Kortikosteron
Hydroxypregnenolon
Hydroxyprogesteron
Deoxykortisol
DHEA
Androstendion
Testosteron
Estradiol
Estron
21 - hydroxyláza
18 - hydroxyláza
18 - hydroxydehydrogenáza
AROMATÁZA
11b - hydroxyláza
C27
C21
C19
C18
C18
P450 Scc
17,20- Lyáza
17a-hydroxyláza
P450c17
mitochondrie
endoplazmatické retikulum
Map of SH synthesis
C21
C21
C21
C21
C21
C21
C21
C21
C19
C19
C18
AROMATÁZA
Fetal liver
DHEAS
C19
DHEAS
C19
16a-DHEAS
C19
16a-DHEA
C19
16a - hydroxy...
16a - hydroxy...
Esterase
R-C-O
AROMATASE
PTH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Receptors for:
Glucocorticoids - type I (mineralocorticoids)
- type II
Estrogens
Androgens
Progesterone



Fetoplacental unit
Apparent mineralocorticoid excess syndrome
GR type II
in vitro
GR type I
"mineralocorticoid receptor"
Cortisol
Aldosteron
afinity
=
Concentration of cortizol in ECF cca 100x higher ten concntration of aldosteron
*
*
*
???
11b - hydroxysteroid dehydrogenase
Aldosteron responsive tissues
carbenoxolone
liquorice
mutace
O
-
-
Fetal adrenal glands
Placenta
Placenta
non active
active
active
active
Tamoxifen
Spironolacton
Adrenogenital syndrome
liver: 25 - hydroxylase
kidney: 1a - hydroxylase
Ca
2+
+
-
+
Full transcript