Steroid Hormones and Vitamin D Flashcards
Synthesis of steroid hormones
-Involves shortening the hydrocarbon chain of cholesterol and hydroxylating the steroid nucleus
Rate limiting step in steroid hormone synthesis
- Conversion of cholesterol to 21C pregnenolone
- Catalyzed by the cholesterol side chain cleavage enzyme (desmolase, CPY11A, P450SCC)
- Requires NADPH and O2
CPY11A
- Cytochrome p450 oxidase in inner mitochondrial membrane
- Coverts cholesterol to pregnenolone
- Requiers NADPH and O2
StAR
- Steroidogenic acute regulatory protein
- Moves cholesterol from the outer mitochondrial matrix to the inner mitochondrial matrix
Congenital adrenal hyperplasias
-Defect at any step in steroid hormone synthesis
3-B-Hydroxysteroid dehydrogenase deficiency
- Prevents conversion from pregnenolone to progesterone
- Reduction in all steroid hormones (glucocorticoids, mineralcorticoids,active androgens, estrogens)
- Salt excretion in urine
- Female like genitalia
17-alpha Hydroxylase Deficiency
- Prevents conversion from progesterone to 17-alpha hydroxyprogesterone
- Virtually no sex hormones or cortisol
- Increased production of mineralcorticoids
- Fluid and sodium retention leads to hypertension
- Female like genitalia
21-alpha Hydroxylase Deficiency
- Prevents conversion from progesterone to 11 deoxycorticosterone and prevents conversion from 17-alpha hydroxyprogesterone to 11 deoxycortisol
- Most common of congenital adrenal hyperplasias
- Mineralcorticoids and glucocorticoids virtually absent
- Overproduction of androgens
11-B1 Hydroxylase Deficiency
- Prevents conversion of 11-deoxycorticosterone to corticosterone and conversion of 11-deoxycortisol to cortisol
- Decrease in serum cortisol, aldosterone, and corticosterone
- Increased production of 11-deoxycortiosterone causes fluid retention (suppresses renin-angiotensin system)
- Overproduction of androgens
Location of cortisol production
-Middle layer, zona fasiculata of adrenal cortex
Cortisol synthesis
- Binds G protein coupled receptor
- Increased cAMP
- Activated PKA
- PKA activates the lipase that converts cholesterol ester to cholesterol and the StAR protein
- Cholesterol moves to IMM and converted to pregnenolone
- Pregnenolone returned to the cytosol and converted to progesterone
- Progesterone converted to 11-deoxycortisol (CPY17 & CPY21)
- 11-deoxycortisol returned to IMM and converted to cortisol by CPY11B1
Aldosterone physiological functions
- Produced in zona glomerulosa, outer layer of adrenal cortex
- Production stimulated by decrease in plasma Na/K ratio and by angiotensin II
- Angiotensin II binds a G coupled surface receptor and acts through the phosphatidylinositol 4,5 bisphosphate pathway
- Works primarily on kidney tubules to enhance Na and water uptake and K efflux
- Increases blood pressure
- ACE inhibitors used to treat renin-dependent hypertension
Androgens production
- Produced by zona reticularis (inner layer) and middle layer
- Adrenal androgens (androsterone and androstenedione) converted to testosterone and estrogen in peripheral tissues
- Estrogen produced from androstenedione and then testosterone using aromatase
Action of steroid hormone at molecular level
- Bind receptors inside of cell that enters the nucleus
- Dimerization and coactivator proteins
- Binds a hormone response element
- HRE is in the promoter or enhancer element for genes that are responsive to steroid hormones
- Binding of ligand exposes a DNA binding domain that allows the complex to associate with DNA through a zinc finger motif
Metabolism and excretion of steroid hormones
- Conjugated with glucuronic acid or sulfate to make them more water soluble (in liver)
- Some secreted into bile and feces, the rest in the urine
- NO protein carriers needed because they are water soluble
Active vitamin D molecule
- 1,25-dihydroxycholecalciferol (1,25-diOH-D3, calcitrol)
- Regulates plasma levels of calcium and phosphorus
Sources of vitamin D
- Exogenous: ergocalciferol (D2, in plants), cholecalciferol (D3, in animal tissues)
- Endogenous: 7-dehydrocholesterol is converted to cholecalciferol in dermis and epidermis when exposed to sunlight
Converting inactive vitamin D to active vitamin D
- Two sequential hydroxylation reactions
- First occurs in liver by 25 hydroxylase: yields 25-hydroxycholecalciferol (25-OH-D3, calcidiol)
- Further hydroxylation in the kidney by 25-hydroxycholecalciferol 1 hydroxylase to form 1,25-diOH-D3 (calcitrol)
- Both hydroxylases are cytochrom p450 proteins
Regulation of 25-hydroxycholecalciferol 1-hydroxylase
- Activity increased directly by low plasma phosphate
- Activity increased indirectly by low plasma calcium
- Low calcium triggers PTH which upregulates the 25-hydroxycholecalciferol 1-hydroxylase
- Elevated 1,25-diOH-D3 inhibits the activity and expression of PTH
Vitamin D receptor interaction in intestinal calcium absortion
- 1,25-DiOH-D3 stimulates intestinal absorption of calcium
- Enters cells and binds to ligand binding domain within the vitamin D receptor (VDR) within the cytoplasm
- VDR complex enters the nucleus and forms a heterodimer with RXR and binds coactivator proteins
- Complex recognizes a DNA sequence or Vitamin D response element (VDRE)
Calbindin-D9k
-Mediates the transport of calcium across the enterocytes from the apical side
TRPV5
-Allows entry of calcium into the epithelial cell
