Vitamin D and steroids (19) Flashcards
What is cholesterol the precursor for?
- glucocorticoids - cortisol
- mineralcorticoides - aldosterone
- sex hormones - androgens, estrogens, progestins
Where is the receptor for a steroid ?
cytoplasm or nucleus
What is the rate limiting step in steroid synthesis?
conversion of cholesterol to 21 C pregenolone
-cyt P450SCC or desmolase
Where is p450 SCC located?
on the inner mitochondrial membrane
What protein mediates the movement of cholesterol from the outer mito membrane to the inner?
StAR
What happens when there is a defect of 3-B-hydroxysteroid dehydrogenase?
-build up of pregnenolone
-no synthesis of any steroids:
glucocorticoids
mineralcorticoids
androgens
estrogens
- female like genitalia
What happens if there is a defect in 17-alpha-hydroxylase?
- build up of progesterone
- no sex hormones or cortisol
-inc production of mineralcorticoids
Na+ fluid retention –> HTN
-female like genitalia
What happens if there is a 21-alpha-hydroxylase deficiency?
-no synthesis of: minercorticoids & glucocorticoids
overproduction of androgens:
masculization of external genitalia in females
early virilization in males
What happens in a 11-B hydroxylase defiency?
decrease in cortisol, aldosterone, corticosterone
fluid retention
overproduction of androgens
What deficiency is the most common?
21-alpha-hydroxylase
Where is cortisol produced?
zona fasiculata of the adrenal cortex
Describe the pathway leading to the release of cortisol?
- CRH by hypothalamus in response to stress
- anterior pituitar releases ACTH
- cortisol secreted by adrenal cortex
How does ACTH lead to production of cortisol?
- G protein receptor - inc cAMP, activated PKA
- activation of lipase
- converts cholesterol esters to cholesterol - activation of StAR
- cholesterol moves to inner mit membrane - cholesterol–> pregnenolone
- moves to cytosol - pregnenolone –> progesterone
- progesterone –> 11 -deoxycortisol
- 11-deoxycortisol –> cortisol
Which enzymes catalyze the conversion of progesterone –> 11-deoxycortisol?
CYP17, CYP21
Which enzyme catalyzes the B-hydroxylation at C21 of 11-deoxycortisol to convert it to cortisol?
CYP11B1
Where is aldosterone produced?
outer layer of the adrenal cortex: zona glomerulosa
What stimulates the production of aldosterone?
decrease in plasma Na+/K+
angiotensin II
What converts angiotensinogen to angiotensin I?
Renin secreted by kidneys
What converts angio I –> angio II?
ACE
What are ACE inhibitors used to treat?
renin dependent BP
What are androgens produced by?
inner and middle layers of adrenal cortex
zona reticularis
What stimulates the release of LH and FSH from the anterior pituitary?
GRH from the hypothalamus
What is the function of LH?
causes testes to produce testoerone, ovaries to produce estrogen and progesterone
What is the function of FSH?
regulates growth of ovarian follicles
regulates spermatogenesis
What enzyme catalyzes the conversion of androstenedione to estrogen?
aromatase
What are aromatase inhibitors used to treat?
hormone (+) breast cancer
What motif does the hormone response element associate with in the DNA?
zinc finger
Where are steroid hormones converted into inactive excretion products?
in the liver
How does the liver make the steroid hormones water soluble?
conjugation with glucoronic acid or sulfate
What are the sources of vit D?
- endogenous - 7-dehydrocholesterol
- exogenous:
ergocalciferol - D2 - plants
cholecalciferol -D3 - animals
What is 7-dehydrocholesterol converted to and where?
cholecalciferol in dermis and epidermis with sun
-transported to liver with binding protein
What form of vit D is measured by clinical labs to see if someone is deficient?
25-OH-D3 or calcidiol
-major form in the plasma
What are the two steps that activate cholecalciferol? Name the enzymes, products, and locations
- Liver:
enzyme: 25 hydroxylase
product: 25-OH-D3 (calcidiol) - Kidney
enzyme: 25-hydroxycholecaliferol 1 hydroxylase
product: 1,25-diOH-D3 (calcitriol)
Is 25-hydroxycholecaliferol 1 hydroxylase mediated directly or indirectly by phosphorous and calcium?
Phosphorous - directly
-low P stimulates enzyme
calcium - indirectly
- low ca2+ causes PTH which stimulates enzyme
What does the vitamin D receptor form a heterodimer with in the nucleus?
RXR - retinoid x receptor
What proteins are upregulated in response to RXR-VDR binding to the VDRE?
calbindin - allows transport of ca2+ across enterocyte
TRPV5 - entry of ca2+ apically
Low plasma calcium has what effects?
inc ca2+ absorption and bone resorption
demineralization
High plasma calcium has what effects?
inhibits bone resorption, inc excretion
mineralization
conversion of 25-OH-D3 to 24,25-DiOH-D3
inc expression of calcitonin
What level is considered vit D deficient?
<30
Above What level of vit D , is considered to have adverse effects?
> 125
What level is considered adequate vit D?
50-125
What two diseases does demineralization cause in kids and adults?
rickets in kids and osteomalacia in adults
What is renal osteodystrophy?
chronic kidney disease
dec vitamin D , inc retention of P
What does hyperthyroidism cause?
lack of PTH
hypocalcemia and hyperphosphatemia
