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Steroid hormons

Steroid hormons

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Steroid hormons

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  1. Steroid hormons

  2. are chemicals released by cells Endocrine glands Higher stability chemical messenger that transports a signal from one cell to another Paracrine Autocrine Hormons

  3. Hormonal cascade – amplification of signal • CNS è target cell • Stimuli • Action potential • Chemical signal • Limbic system • Hypothalamus • Pituitary gland • Target cell - hormon

  4. Hormonal cascade – feed back • t, noise, trauma • Limbic system – hypocampus • ng hypothalamic releasing hormon (corticotropin releasing hormone) • Pituitary gland receptor • Adrenocorticotrope hormon mg • (ACTH és β-lipotropin) t1/2 is longer, as t1/2 (CRH) • Adrenal cortex – zona fasciculata – receptor – cortisol - mg

  5. Various types of receptors Receptors: Peptid hormons Growth factors Aminoacid derivatives Hormons (epinephrine) Hypothetical cell Steroid hormons + receptors Nucleus Thyroid hormons + receptors Cell membrane Cytoplasm Steroid hormons Steroid receptors

  6. Biochemistry of steroid hormones • Autoradiography of Madhabananda Sar and Walter E. Stumpf • Guinea pig endometrium + radioactivly labelled progesterone (15’)

  7. Classification of steroid hormons • Sex & progestagen hormons

  8. Classification of steroid hormons • Sex & progestagen hormons

  9. Classification of steroid hormons • Sex & progestagen hormons • Hormons of adrenal cortex

  10. Cross sectional view of adrenal cortex • Cortex • Zona glomerulosa: • mineralocorticoids • Zona fasciculata: • glucocorticoids + androgens • Zona reticularis: • glucocorticoids + androgens

  11. Carbon skeleton • Cyclopentano- perhydrophenanthrene skeleton • A, B, C, D - four fused rings

  12. A koleszterin • 1.) transz, szék elnyújtott szalagszerű felépítés • 1) 3-b-OH membrán / H2O határ • 3.) 18/19 CH3, váz tömör • 4.) gátolja membrán fluiditását, gátolja a membrán befagyását • 5.) a lipoproteinek alkotórésze, szérum koncentráció – rizikótényező “A koleszterin a biológia leginkább dekorált molekulája. 13 Nobel-díjjal tüntették ki ama tudósokat, akik munkásságuk nagy részét a koleszterinnek áldozták. 1784 óta, amikor először izolálták epekövekből, szinte hipnotikus hatást gyakorolt a tudomány különböző területein dolgozó tudósokra. A koleszterin Janus-arcú molekula. Vízben való oldhatatlansága, mely hasznos a sejtmembránokban, halálhozóvá is teszi.” Michael Brown L Joseph Goldstein: Nobel Lettures 1985

  13. Stereochemistry of steroid hormons

  14. Via - D5-pregnenolonone …

  15. Reduction glucuronidization Inactivation of steroind hormones

  16. Steroid hormons - Progesterones

  17. Steroid hormons – 17ß-estradiol

  18. Steroid hormonsk – Testosteron

  19. Steroid hormons – Dehydroepiadrosteron

  20. Steroid hormons – Cortisol

  21. Steroid hormons – Aldosteron

  22. 1,25-dihydroxy vitamine D3

  23. Classification: # of C atoms • C27 • 1,25(OH)2D3 • C21 • progesteron, cortizol, aldosteron • C19 • testosteron & dehydroepiandrosteron • C18 • 17β-estradiol

  24. Steroid hormons Cholesterol C27 Pregnenolon C21

  25. Characteristic substituents • Glucocorticoids, mineralocorticoids • C11 • OH, O • Estrogens • Lack of C19 methyl groups • Ring „A” is aromatic • Steroid receptors • Estradiol Ring „A” - Rings B–C–D • Other steroid hormons other than female hormones • Ring „A” is coplanar to rings B–C–D

  26. Sterical positions of ring „A” and rings „B-C-D”

  27. Sterical positions of ring „A” and rings „B-C-D”

  28. Receptors of steroidal hormones • Hydrophobic molecules • Plasma proteins • Free diffusion • „Target cells”: receptors: in cytoplasm / nucleus

  29. Receptors of steroidal hormones • intracellular • non-steroid component • thyroid hormons • Retinoic acid • Vitamine D3 • Steroids • cytoplasmic • glucocorticoid receptors • aldosteron • nucleus – chromatin assotiated form • Other receptors

  30. Steroid Receptor Gene Superfamily

  31. Kcortisol/receptor 109 M−1 Kcortosol/CBG 107 M−1 Cortisol receptor–complex (~ 300 kDa) dimer 90 kDA heat shock protein heat shock Masking DNS-binding domain Hormon – receptor interaction - activation Hydrolysis of proteins, + charge aminoacids – DNA Ligand receptor complex translocation DNS binding site – HSE hormone response element Regulation of gen transcription Enhancement of transcription – mRNA – protein Repression – in given cases Steroid hormon receptors

  32. Biochemistry of steroidal hormones • The hormon receptor complex: • Receptor • Homodimer formation • DNS hormone response elements • Glucocortikoid RE: • 5’AGAACAnnnTGTTCT3’ • 3’TCTTGTnnnACAAGA5’ • Transcription factor: • gens

  33. Biosynthesis of steroid hormones • [cAMP]intracellulará • [Ca2+] intracellulará • [cAMP] intracellulará • Acute • Mobilisation of cholesterol – mit. membrane • Chronic • Steroidogen enzyme transcription á

  34. [cAMP]intracellulará • Cholesterol – pregnenolone • Cytochrom P450 SCC (side chain cleavage) enzyme • NADPH + H+; O2 C27 22 OH - cholesterol 22,20 diOH - cholesterol Cyt450 SCC C22

  35. [cAMP]intracellulárisá • Protein inductionStAR (Steroidogenic acut regulatory protein) • 30 kD, phosphoprotein • testis • ovary

  36. [cAMP]intracellulará • Protein induction • StAR (Steroidogenic acut regulatory protein) • Defective / non-functional StAR • Lipoid congenital adrenal hyperplasia (LCAH) • Steroid synthesis of adrenals and gonadsis lowered • Lipid deposition