BCM - Steroid Biosynthesis Flashcards
How does the body respond to short term stress?
Sympathetic stimulation of the adrenal medulla, causing secretion of epinephrine and norepinephrine
How does the body respond to long term stress?
Glucocorticoid and Mineralocorticoid secretion from the adrenal cortex
What is PXR?
Xenobiotic nuclear receptor
It is an adopted orphan receptor (we used to not know what the receptor did, now we do)
What does activation of PXR do and what is its ligand?
PXR promotes the CYP3A4 gene after St. John’s wart activates the receptor
CYP3A4 is an enzyme that metabolizes 60% of all prescribed drugs
What happens to the CYP3A4 metabolized drugs?
They get excreted in the bile
What are steroid hormones derived from?
Cholesterol
What is desmolase?
Desmolase (aka CYP 450scc) is an enzyme that converts Cholesterol into Pregnenolone, the first step and rate-limiting step in synthesis of steroid hormones
Desmolase is positively regulated by ACTH
What happens in the process of steroid synthesis after pregnenolone is made?
Pregnenolone is converted to Progesterone
Then progesterone can either be converted into corticosteroids (aldosterone/cortisol) or sex hormones (testosterone/estradiol)
Where is desmolase found?
Desmolase enzyme can be found in all the steroid producing tissues (adrenal, ovaries, testes, placenta)
How is cortisol secretion regulated?
Cortisol provides negative feedback to the anterior pituitary (inhibiting ACTH secretion) and the Hypothalamus (inhibiting CRH secretion)
What are the SHORT TERM actions of ACTH?
SHORT TERM = seconds
Stimulates lipoprotein uptake into cortical cells and increases bioavailability of cholesterol in adrenal cortex
What are the LONG TERM actions of ACTH?
LONG TERM = hours
Stimulates transcription of key enzymes needed for steroid hormone synthesis, including:
- CYP450scc (Desmolase)
- Steroid 11(beta)-hydroxylase
- Associated electron transfer proteins
What happens in a adrenal cortex cell if it is cancerous?
PKA is constitutively active, causing cell proliferation and cortisol synthesis
What is the enzyme responsible for the conversion of Pregnenolone to Progesterone?
3(beta) - Hydroxysteroid Dehydrogenase
AKA 3(beta)-HSD
What does cortisol do?
Increases blood pressure, anti-inflammatory, promotes gluconeogenesis, immunosuppression
What is Infant Respiratory Distress syndrome?
Process of surfactant production is defective due to lack of glucocorticoids
With children of normal term births, the infant recieves a burst of glucocorticoids during delivery, altering the lung structure so that it can produce surfactant, allowing the lung to expand
What are classical presentations of Congenital Adrenal Hyperplasia?
CAH classical presentations include ambiguous genitalia in females, and salt wasting (resulting in dehydration, vomiting, diarrhea)
Which genes are typically affected in Congenital ADrenal hyperplasia?
CAH involves mutation of the 21-hydroxylase enzyme 90-95% of the time
5% involves mutation of 11(beta)-hydroxylase enzyme
What happens when 11-beta-hydroxylase enzyme is mutated?
11 beta hydroxylase enzyme is required in the pathway for Aldosterone synthesis and the pathway for Cortisol synthesis
Mutation in this enzyme causes buildup of precursors
Results in excess androgen production (male sex hormones
Results in 11-deoxycorticosterone accumulation (which is a mineralocorticoid receptor agonist; promotes sodium and water rentention as aldosterone normally would HYPERTNSION!!)
What happens with 21 hydroxylase mutation form of CAH?
Accumulation of Progesterone and 17 alpha hydroxypregnenalone and 17 alpha progesterone
Lack of aldosterone causes salt wasting and females have obvious genital ambiguity
