Glomerulonefritis Membranoproliferativa (GNMP). Correlaciones ...
Kortikosteroidi - cfgbc.mf.uni-lj.sicfgbc.mf.uni-lj.si/people/damjana/teaching/steroidi_3.pdf ·...
Transcript of Kortikosteroidi - cfgbc.mf.uni-lj.sicfgbc.mf.uni-lj.si/people/damjana/teaching/steroidi_3.pdf ·...
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Kortikosteroidi
glukokortikoidi C21 (OH ali O skupina na C11, OH na C17) kortizol, kortizon
vpliv na metabolizem ogljikovih hidratov in proteinov, zmanjšujejo imunskiodziv, vnetne in alergijske reakcije
mineralokortikoidi C21 (CHO na C18)aldosteron
regulirajo reabsorbcijo Na+ ionov v ledvicah, zadrževanje vode v organizmu, vplivajona krvni tlak
C
H2COH
O
O
OHHO
C
H2COH
O
O
HO
C
H2COH
O
O
OHO
C
H2COH
O
O
HOCH
O
kortizol kortizon kortikosteron
aldosteron kortikosteron
C
H2COH
O
O
HO
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So skupina steroidnih hormonov, ki nastajajo v skorji nadledvične žleze
Vpleteni so v številne fiziološke mehanizme, kot na primer odziv na stres, imunski odziv in uravnavanje vnetja, presnovo ogljikovih hidratov in beljakovin, uravnavanje elektrolitov v krvi in vedenje
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glukokortikoidi, kot na primer kortizol, uravnavajo presnovo ogljikovih hidratov, lipidov in beljakovin ter z zaviranjem sproščanja fosfolipidov ter dejavnosti eozinofilcev delujejo protivnetno.
mineralokortikoidi, kot je aldosteron, nadzirajo raven vode in elektrolitov, predvsem tako, da spodbujajo reabsorbcijo natrija v ledvicah.
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KORTIZOL
Vpliv kortizola na metabolizem ogljikovih hidratov1. vpliv na glukoneogenezo2. zmanjšuje izkoriščanje glukoze v celicah3. poveča količino glukoze v krvi – adrenalni
(steroidni) diabetes
Vpliv kortizola na metabolizem beljakovinVpliv kortizola na metabolizem maščob
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Kortizol in stres
vsaka oblika stresa povzroči izločanje ACTH, to pa izločanje kortizolastresne situacije : travma, infekcija, huda vročina ali mraz, kirurški posegi
Protivnetno delovanje kortizola
v celicah stabilizira lizosomne mebrane↓ permeabilnost kapilar, zaradi česar se zmanjša izguba plazme v okolico↓ migracijo levkocitov v vnetno okolico in fagocitozo uničenih celic -verjetno posledica blokade prostaglandinov in levkotrienov ↓ število levkocitov↓ telesno temperaturo - ↓ izločanje IL1 iz levkocitov.
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Če se je vnetje že razvilo, dajanje kortizola lahko zmanjša stopnjo vnetja
ta učinek uporabljamo pri zdravljenju nekaterih vnetnih bolezni: revmatoidni artritis, akutni glomerulonefritis
Zaradi znižanja eozinofilcev in limfocitov v krvi, se zmanjša obrambna sposobnost telesa in lahko vderejo v telo razni patogeni s posledičnimi hudimi vnetji ( npr. TBC)
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CUSHINGov SINDROM (CS)
CS ali hiperkortisolism je endokrina motnja in jo povzroča prekomerna raven kortikoidnega hormona kortizola
Lahko jo sproži tudi zdravljenje drugih bolezni s kortikosteroidi
Sorazmerno redka in prizadene navadno odrasle stare od 20-50
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ADDISONOVA BOLEZEN (AB)
Hipo-kortikoizem
Redka endokrina ali hormonska motnja (1 do 2/ 100 000 ljudi)
Prizadene lahko ljudi vseh starosti, moške in ženske
SIMPTOMI:
Izguba teže, mišična oslabelost, utrujenost
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Sekundarna adrenalna insuficiencaJe bolj pogosta kot primarnaPovzroči jo pomanjkanje ACTHTako se produkcija kortizola zmanjša, ne pa produkcija aldosterona
Lahko se pojavi pri ljudeh, ki so prejemali glukokortikoidne hormone dalj časa in nenadoma prenehali jesti zdravila
Drug razlog je tudi kirurško odstranjen benigen, ACTH izdelovalen tumor hipofize (CS) in tako je vir ACTH odstranjen
Manj pogosto se pojavi, če se hipofiza zmanjša ali preneha proizvajati ACTH
To je lahko posledica: tumor, premalo prekrvavljena hipofiza kirurške odstranitve dela hipofize
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MINERALOKORTIKOIDI
95 % aldosteron, deoksikortikosteron, kortikosteron
Uravnavanje K+ v ECT
Delovanje na ledvice
Zadrževanje Na+ in vode
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Mehanizem delovanja steroidnih hormonov
• potujejo do tarčnih tkiv s pomočjo prenašalnih proteinov
• difundirajo preko membrane
• vezava na ustrezni receptor v celici
• vezava na specifično zaporedje DNA (HRE)
• omogočajo transkripcijo določenih genov
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Dinamične spremembe v subcelularni lokalizaciji mineralokortikoidnega receptorja (MR-YFP) v živih celicah
COS celice
Hipokampični nevron
Nishi M. et al., Mol. Endo. 15, 1077-1092 (2001)
-910 M kortikosteron
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10-6M
-910 M
kortikosteron GRGR--CFPCFP
MRMR--YFPYFP
GRGR--CFPCFP
MRMR--YFPYFP
Hitrost jedrne lokalizacije GR in MR poučinkovanju kortikosteronaje odvisna od:
-koncentracije kortikosterona-vrste celic
Nishi M. et al., Mol. Endo. 15, 1077-1092 (2001)COS-1
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Kogenitalna adrenalna hiperplazija
Okvara v 21-steroidni hidroksilazi CYP21
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Cholesterol is converted into side chain oxysterols by three different enzymes. Two of these (cholesterol 24-hydroxylase and sterol 27-hydroxylase) are cytochrome P-450 (CYP) enzymes, while a third (cholesterol 25-hydroxylase) is a member of a family of proteins that contain diiron cofactors
OKSISTEROLI
CYP24
CYP24
Non CYP......
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Stranske verige oksisterolov in njihova vloga v metabolizmu lipidov. Strukture treh naravnih oksisterolov in njihove predvidene funkcije
OKSISTEROLI
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Oxysterols:- regulate expression of genes involved in lipid and sterol biosynthesis through the sterol regulatory element binding protein (SREBP) pathway (25-hydroxy-cholesterol)
-are substrates for the formation of bile acids (24, 25 and 27-oxysterols)
-24-hydroxy-cholesterol is a potent ligand of the liver X receptor LXR.
-are involved in the reverse cholesterol transport from the periphery to the liver (27-hydroxy cholesterol)
- Mutations in CYP27A1 gene lead to sterol storage disorder cerebrotendinous xanthomatosis (CTX) which is characterized by abnormal deposition of cholesterol
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Žolčne kislineStrukturne značilnostiC24, A/B obroča cis, OH skupine v položaji alfa,amfipatičnost - delujejo kot detergenti, aktivirajo lipaze
primarne žolčne kisline: holna, henodeoksiholna kislina(biosinteza v jetrih iz holesterola)
sekundarne žolčne kisline: deoksiholna, litoholna kislina(rezultat bakterijske dehidroksilacije na položaju C7)
konjugirane žolčne kisline: glikoholna, tauroholna, glikodeoksiholna, taurodeoksiholna kislina...
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Povezava med obročema A in B pri steroidih
R
H
R
H
• cis - 5 b H atom - žolčne kisline
• trans - 5a H atom - steroli, steroidni hormoni
C19
C19
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henodeoksiholna k. tauroholna k.
Struktura žolčnih kislin
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HOH
COOHOH
OH
HOH
COOHOH
HOH
COOH
OH
HOH
COOH
holna kislina(3a,7a,12a-trihidroksiholanska k.)
deoksiholna kislina(3a,12a-dihidroksiholanska k.)
henodeoksiholna kislina(3a,7a-dihidroksiholanska k.)
litoholna kislina(3a-hidroksiholanska k.)
H2N-CH2-CH2-SO3- H2N-CH2-COOH
taurin glicin
Žolčne kisline
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Tvorba micela pri raztapljanju maščob
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Bile acids are physiological agents important for absorption and transport of lipid soluble vitamins,steroids and xenobiotics.
Over 50% of excess cholesterol in the body is eliminated by thebile acid pathway.
Bile acids are ligands for the FXR (BAR) and PXR receptors.
PXR is a lithocholic acid receptor that controls the biosynthesis and metabolism of bile acids.
FXR and PXR cooperate to control biliary and urinary bile acid excretion, suggesting that potent PXR and FXR ligands may
offer a new approach to the treatment of cholestaticliver disease
Importance of bile acids
PXR – pregnana X receptor
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LXRα
Acetat
Holesterol
CYP7A1
Oxysteroli
Žolčne kisline
reciklizacija
SREBP
FXR
FXR
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Vitamin D
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http://www.mja.com.au/public/issues/177_03_050802/now10763_fig.jpg
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http://www7.nationalacademies.org/germanbeyonddiscovery/VitaminD_8-2.jpg
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http://www.healingtherapies.info/VitDmetabolism.jpg
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http://www.uku.fi/biokem/kuvat/kuva1sv.gif
Vitamin D posreduje svojo biološko vlogo preko receptorja VDR
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Dermatol Nurs. 2006 Feb;18(1):40-3, 49.
Psoriasis: disease management with a brief review of new biologics.Khachemoune A, Guillen S.SUNY Downstate Medical Center, Brooklyn, NY, USA.
Psoriasis is a chronic inflammatory dermatosis that affects 0.6% to 4.8% of the population and is seen in all ages.
The disease is characterized by a well-demarcated, salmon-colored plaque surmounted by silver-white scales.
Given the chronic nature of the disease, goal of treatment is to induce and maintain remission, with minimal short and long-term side effects from therapy. Most agents can be used alone or in combination with other treatment modalities.
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Vitamin D in metabolizem kalcija
http://hopkins-gi.nts.jhu.edu/images/shared/buildAPage/bap_71_BS-01.jpg
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J Clin Invest. 2006 Apr;116(4):892-904. Epub 2006 Mar 9
Identification and characterization of noncalcemic, tissue-selective, nonsecosteroidal vitamin D receptor modulators.
Ma Y, et al., Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Vitamin D receptor (VDR) ligands are therapeutic agents for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism.
VDR ligands also show immense potential as therapeutic agents for autoimmune diseases and cancers of skin, prostate, colon, and breast as well as leukemia.
However, the major side effect of VDR ligands that limits their expanded use and clinical development is hypercalcemia that develops as a result of the action of these compounds mainly on intestine.
The nonsecosteroidal VDRMs were less calcemic in vivo, and LY2108491 exhibited more than 270-fold improved therapeutic index over the naturally occurring VDRligand 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in an in vivo preclinical surrogate model of psoriasis
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Steroidi in rak
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Rak na dojki
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Hormonski vplivi pri nastanku raka na dojki
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http://breast-cancer-research.com/content/figures/bcr601-1.jpg
Mehanizem delovanja steroidov
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http://images.webmd.com/images/hw/media67/medical/hw/n5551878.jpg
Rak na ustju materničnega vratu
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http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/8655.jpg
Rak na jajčnikih
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http://www.dfwovarian.org/images/Slide8.jpg
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http://medicineworld.org/images/blogs/8-2007/prostate-cancer-2960.jpg
Rak na prostati
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http://www.cdc.gov/cancer/00_images/prostate/pros_chart2.gif
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http://www.cartoonstock.com/lowres/dcr0575l.jpg
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Ponovitev struktur steroidov
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HOH
COOHOH
OH
HOH
COOHOH
HOH
COOH
OH
HOH
COOH
holna kislina(3a,7a,12a-trihidroksiholanska k.)
deoksiholna kislina(3a,12a-dihidroksiholanska k.)
henodeoksiholna kislina(3a,7a-dihidroksiholanska k.)
litoholna kislina(3a-hidroksiholanska k.)
H2N-CH2-CH2-SO3- H2N-CH2-COOH
taurin glicin
Žolčne kisline
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Kortikosteroidi
glukokortikoidi C21 (OH ali O skupina na C11, OH na C17) kortizol, kortizon
vpliv na metabolizem ogljikovih hidratov in proteinov, zmanjšujejo imunskiodziv, vnetne in alergijske reakcije
mineralokortikoidi C21 (CHO na C18)aldosteron
regulirajo reabsorbcijo Na+ ionov v ledvicah, zadrževanje vode v organizmu, vplivajo na krvni tlak
C
H2COH
O
O
OHHO
C
H2COH
O
O
HO
C
H2COH
O
O
OHO
C
H2COH
O
O
HOCH
O
kortizol kortizon kortikosteron
aldosteron kortikosteron
C
H2COH
O
O
HO
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Spolni hormoni
androgeni (C19, OH ali O skupina na C17) testosteron, androstendionuravnavajo razvoj moških sekundarnih spolnihznakov, anabolno delovanje
estrogeni (C18, aromatski obroč A, OH na C3) estradiol, estronuravnavajo razvoj ženskih sekundarnih spolnih znakov
gestagen (C21, O skupina na C20) progesteronregulacija ženskega reproduktivnega cikla
C
CH
O3
O
HO
OH
O
OH
HO
O
O
O
testosteron androstendion
estradiol estron
progesteron