Kortikosteroidi. glukokortikoidi C21 (OH ali O skupina na C11, OH na C17) kortizol, kortizon. mineralokortikoidi C21 (CHO na C18) aldosteron
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1 regulirajo reabsorbcijo Na + ionov v ledvicah, zadrževanje vode v organizmu, vplivajo na krvni tlak Kortikosteroidi glukokortikoidi C21 (OH ali O skupina na C11, OH na C17) kortizol, kortizon H 2 COH H 2 COH C O C O OH OH HO O HO H 2 COH C O O kortizol kortizon kortikosteron O O vpliv na metabolizem ogljikovih hidratov in proteinov, zmanjšujejo imunski odziv, vnetne in alergijske reakcije mineralokortikoidi C21 (CHO na C18) aldosteron HO O H 2 COH C O CH HO H 2 COH C O O O aldosteron kortikosteron
2 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
3 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.
4 KORTIZOL Vpliv kortizola na metabolizem ogljikovih hidratov 1. vpliv na glukoneogenezo 2. zmanjšuje izkoriščanje glukoze v celicah 3. poveča količino glukoze v krvi adrenalni (steroidni) diabetes Vpliv kortizola na metabolizem beljakovin Vpliv kortizola na metabolizem maščob
5 Kortizol in stres vsaka oblika stresa povzroči izločanje ACTH, to pa izločanje kortizola stresne 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.
6 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)
7 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
8 ADDISONOVA BOLEZEN (AB) Hipo-kortikoizem Redka endokrina ali hormonska motnja (1 do 2/ ljudi) Prizadene lahko ljudi vseh starosti, moške in ženske SIMPTOMI: Izguba teže, mišična oslabelost, utrujenost
9 Sekundarna adrenalna insuficienca Je bolj pogosta kot primarna Povzroči jo pomanjkanje ACTH Tako 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
10 MINERALOKORTIKOIDI 95 % aldosteron, deoksikortikosteron, kortikosteron Uravnavanje K+ v ECT Delovanje na ledvice Zadrževanje Na+ in vode
11 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
12 Dinamične spremembe v subcelularni lokalizaciji mineralokortikoidnega receptorja (MR-YFP) v živih celicah M kortikosteron COS celice Hipokampični nevron Nishi M. et al., Mol. Endo. 15, (2001)
13 kortikosteron 10-6 M GR-CFP MR-YFP 10-9M MR-YFP GR-CFP Hitrost jedrne lokalizacije GR in MR po učinkovanju kortikosteronaje odvisna od: -koncentracije kortikosterona -vrste celic COS-1 Nishi M. et al., Mol. Endo. 15, (2001)
14 Kogenitalna adrenalna hiperplazija Okvara v 21-steroidni hidroksilazi CYP21
15 OKSISTEROLI CYP24 Non CYP... CYP24 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
16 OKSISTEROLI Stranske verige oksisterolov in njihova vloga v metabolizmu lipidov. Strukture treh naravnih oksisterolov in njihove predvidene funkcije
17 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
18 Žolčne kisline Strukturne značilnosti C24, 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...
19 Povezava med obročema A in B pri steroidih trans - 5a H atom - steroli, steroidni hormoni R C19 H cis - 5 b H atom - žolčne kisline R C19 H
20 Struktura žolčnih kislin henodeoksiholna k. tauroholna k.
21 Žolčne kisline OH COOH COOH HO H OH HO H OH holna kislina (3a,7a,12a-trihidroksiholanska k.) henodeoksiholna kislina (3a,7a-dihidroksiholanska k.) OH COOH COOH HO H HO H deoksiholna kislina (3a,12a-dihidroksiholanska k.) H 2 N-CH 2 -CH 2 -SO 3 - taurin litoholna kislina (3a-hidroksiholanska k.) H 2 N-CH 2 -COOH glicin
22 Tvorba micela pri raztapljanju maščob
23 Importance of bile acids 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 the bile 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 cholestatic liver disease PXR pregnana X receptor
24 SREBP Acetat Holesterol LXRα CYP7A1 Oxysteroli FXR Žolčne kisline reciklizacija FXR
25 Vitamin D
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29 Vitamin D posreduje svojo biološko vlogo preko receptorja VDR
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31 Dermatol Nurs 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.
32 Vitamin D in metabolizem kalcija
33 J Clin Invest Apr;116(4): 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 LY exhibited more than 270-fold improved therapeutic index over the naturally occurring VDR ligand 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in an in vivo preclinical surrogate model of psoriasis
34 Steroidi in rak
35 Rak na dojki
36 Hormonski vplivi pri nastanku raka na dojki
37 Mehanizem delovanja steroidov
38 Rak na ustju materničnega vratu
39 Rak na jajčnikih
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41 Rak na prostati
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45 Ponovitev struktur steroidov
46 Žolčne kisline OH COOH COOH HO H OH HO H OH holna kislina (3a,7a,12a-trihidroksiholanska k.) henodeoksiholna kislina (3a,7a-dihidroksiholanska k.) OH COOH COOH HO H HO H deoksiholna kislina (3a,12a-dihidroksiholanska k.) H 2 N-CH 2 -CH 2 -SO 3 - taurin litoholna kislina (3a-hidroksiholanska k.) H 2 N-CH 2 -COOH glicin
47 regulirajo reabsorbcijo Na + ionov v ledvicah, zadrževanje vode v organizmu, vplivajo na krvni tlak Kortikosteroidi glukokortikoidi C21 (OH ali O skupina na C11, OH na C17) kortizol, kortizon H 2 COH H H 2 COH 2 COH C O C O C OH OH HO O HO O O kortizol kortizon kortikosteron O O vpliv na metabolizem ogljikovih hidratov in proteinov, zmanjšujejo imunski odziv, vnetne in alergijske reakcije mineralokortikoidi C21 (CHO na C18) aldosteron HO O CH H 2 COH C O HO H 2 COH C O O O aldosteron kortikosteron
48 Spolni hormoni androgeni (C19, OH ali O skupina na C17) testosteron, androstendion uravnavajo razvoj moških sekundarnih spolnih znakov, anabolno delovanje OH O estrogeni (C18, aromatski obroč A, OH na C3) estradiol, estron uravnavajo razvoj ženskih sekundarnih spolnih znakov O OH testosteron O O androstendion HO estradiol gestagen (C21, O skupina na C20) progesteron regulacija ženskega reproduktivnega cikla HO estron O CH 3 C O progesteron
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