L18 - Adrenal steroidogenesis

Question 1

Why is the study of adrenal steroidogenesis of major biological interest?

Answer 1

1) Regulation at level of synthesis rather than secretion

2) Enzymatic defect –> Congenital Adrenal Hyperplasia (CAH)

Question 2

Receptors of Steroids vs Peptide/protein?

Answer 2

Steroid: Cytosolic/nuclear

Peptide/protein: in plasma membrane

Question 3

What does 5b-HSD convert?

Answer 3

Testosterone –> DHT

Question 4

What does CYP11A do? What is it stimulated by?

Answer 4

Cholesterol –> Pregnenolone

Stimulated by ACTH

Question 5

Which enzyme is not a CYP enzyme in the steroid biosynthesis pathway?

Answer 5

3B-HSD
Converts:
1) Pregnenolone –> Progesterone
2) 17-hydroxypregnenolone –> 17-hydroxyprogesterone
3) DHEA –> Androstenedione (androgen precursor)

Question 6

What are the enzymes required for production of cortisol? (@Max I know you’re good enough to name the intermediates too :D)

Answer 6

CYP11A –> 3b-HSD –> CYP17 –> CYP21–> CYP11B1

Question 7

What are the enzymes required for production of aldosterone? (@Max I know you’re good enough to name the intermediates too :D)

Answer 7

CYP11A –> CYP17 –> CYP21 –> CYP11B1 –> CYP11B2

Question 8

Where are cytochrome P450 present in?

Answer 8

Mitochondria and microsomes (ER)

Question 9

How does Cytochrome P450 oxidize?

Answer 9

RH + O2 + NADPH + H –> ROH + H2O + NADP

Question 10

What do multiprotein complexes consist of?

Answer 10

1) Cytochrome P450

2) Electron-donating system

Question 11

Which cytochromes are in mitochondria and which are in microsome?

Answer 11

Mitochondria: CYP11 or SCC
Microsome: CYP17 or CYP21 (+3b-HSD - but this is not cytochrome)

Question 12

How are cytochromes different in mitochondria than in microsomes?

Answer 12

They have an adrenodoxin/iron-sulfur protein

Question 13

Which 3 reactions are catalyzed by CYP11?

Answer 13

20alpha-hydroxylation, 22-hydroxylation and cleavage of cholesterol side chain at C20-22

Question 14

Which tissues are CYP11, 17 expressed in?

Answer 14

In all primary steroidogenic tissues: Adrenal cortex, ovary, testicular Leydig cells and placenta
n.B. CYP17 expressed in Zona Fasciculata and Reticularis (cortisol!)

Question 15

Which tissues are 3b-HSD expressed in?

Answer 15

Primary steroidogenic tissues + breast, prostate, liver, skin

Question 16

Which tissues are CYP21 expressed in?

Answer 16

Only in adrenal cortex (production of cortisol/aldosterone)

Question 17

Difference between CYP11B1 and CYP11B2

Answer 17

CYP11B1: Production of cortisol, expressed in Fasciculata + Reticularis
CYP11B2: Production of aldosterone, expressed in Glomerulosa

G = 11B2 
FR = 11B1

Question 18

Factors controlling release of CRH

Answer 18

+: Diurnal, Stress

-: Glucocorticoid

Question 19

Which layers of the adrenal cortex do ACTH, Ang II and K+ bind to?

Answer 19

Glomerulosa: Ang II + K + ACTH

Fasciculata/Reticularis: Only ACTH

Question 20

3 forms of Congenital Adrenal Hyperplasia

Answer 20

1) Salt-losing (67% of classic): Decreased or total lack of cortisol (glucocorticoid) and aldosterone production
2) Simple virilizing (33% of classic): Musculinization of external genitalia in females or early sex development in males [ANDROGEN PRODUCTION]
3) Late-onset (non-classic): ONLY IN FEMALES

Question 21

Which cytochrome does CAH lack?

Answer 21

CYP21

Question 22

How does CAH cause short stature?

Answer 22

Decreased glucocorticoid/cortisol –> Increased ACTH –> bind to adrenal cortex, increased pregnenolone –> progesterone –> 17-alpha hydroxyprogesterone –> increased in androgen –> virilization –> accelerated bone growth and early maturation –> short stature

Question 23

How does CAH cause shock?

Answer 23

Decreased aldosterone –> persistent loss of sodium ions in urine –> dehydration and hypotension –> shock and sudden death

Question 24

How does CYP21P (pseudogene) cause CYP21 mutation?

Answer 24

1) Unequal crossing over –> gene deletion (increased risk by tandem arrangement)
2) Gene conversion