Exam 5: Adrenocorticoids Flashcards
What is a steroid?
An organic molecule containing in its chemical nucleus the tetrahydrocyclopentanophenanthrene ring system
How do you number a steroid molecule?
What is the difference between a and b designation?
a is below the plane of the carbocycle
b is above the plane
What is the designation between a and e?
Axial and equatorial groups
What is a cholestane?
A steroid with 27 carbons that include a 8 carbon side chain
What type of process converts cholesterol to pregnenolone?
Oxidative cleavage and NADPH in the adrenal glands
What is pregnenolone?
Biosynthetic precursor of adrenocorticoids
What initiates the biotransformation of cholesterol?
CYP 450 enzyme complex
What enzymes of are in CYP450 enzyme complex?
Cyp11A1, adrenodoxin, and adrenodoxin reductase
What occurs due to defects in CYP11A1?
Lack of glucocorticoids, feminization and hypertension
What is another name for pregnenolone biosynthesis?
Desmolase activity (breaking of C-C bonds)
Describe the 3 oxidative processes of pregnenolone biosynthesis?
All reactions require NADPH and O2
1. Addition of a hydroxl forming a diol
2. Addition of hydroxyl forming a triol
3. Cleavage of isocaproic side chain synthesizing pregnenolone
What are examples of pregnenole isomers at C21?
- Pregnane
- Pregesterone
- Hydrocortisone
- Corticosterone
- Aldosterone
What are pregnenole isomers that yield C19 steroids?
- Androstane
- Testosterone
- Dihydrotestosterone
What are pregnenole isomers that yield C18 steroids through oxidative aromatization?
Estrane
Estradiol
What is the on/off switch between hydrocortisone and cortisone?
11b-hydroxysteroid dehydrogenase
What are isoforms of 11bHSD?
1 and 2
What is the difference between 11bHSD isoforms?
1: liver isozyme
2: kidney isozyme
What is the difference between hydrocortisone and cortisone?
H: active
C: inactive
What reaction does 11b-HSD initiate?
C-11 keto-enol isomerization
What reaction does 3a-HSD and 5b-reductase initiate?
Ring A reduction
What enzyme initiates C-17 oxidation?
C-17 oxidase
What are the enzymatic steps of adrenocorticoid biosynthesis to hydrocortisone?
a. Side chain cleavage from cholesterol to pregnenolone
b. pregnenolone to 17a-hydroxypregnelone by 17 a-hydroxylase (CYP17)
c. 17a-hydroxypregnelone to 17a-hydroxyprogesterone by 5-ene-3b-hydroxysteroid dehydrogenase
d. 3-oxosteroid-4,5-isomerase
e. 17a-hydroxyprogesterone to 11-deoxycortisol by 21-hydroxylase (CYP21)
f. 11-deoxycortisol to hydrocortisone by 11b-hydroxylase (CYP11B2)
What are the enzymatic steps of adrenocorticoid biosynthesis to aldosterone?
a. Side chain cleavage from cholesterol to pregnenolone
c. pregnelone to progesterone by 5-ene-3b-hydroxysteroid dehydrogenase
d. 3-oxosteroid-4,5-isomerase
e. progesterone to 21-hydroxyprogesterone by 21-hydroxylase (CYP21)
f. 21-hydroxyprogesterone to corticosterone by 11b-hydroxylase (CYP11B2)
g. corticosterone to aldosterone by 18-hydroxylase
What do all biologically active adrenocorticoids contain?
Ketone at the 3-posistion and a double bond at the 4,5 position (ene-one)
How are 5b metabolites formed?
4,5 double bond is reduced by 5b-reductase
What enzymes reduce 3-ketone of an adrenocorticoids?
- 3a-hydroxysteroid dehydrogenase provides the 3a-hydroxyl configuration
- 3β-hydroxysteroid dehydrogenase provides the 3β-hydroxyl configuration
What is the biomarker for determining the level of HPA suppression and adrenal insufficiency?
Formation of 6b-hydroxyhydrocortisone
What other steroid metabolisms can occur other than 3,4,5 ene-one?
- 20 ketone reduction
- Oxidation of 17-ketol to carboxylic acid
- 6b-hydroxylation
Is prednisone active or inactive?
Inactive
Describe prednisone metabolism into active and inactive metabolites?
- Prednisone to prednisolone (active) by 11b-hydroxysteroid dehydrogenase
- Prednisolone to 6b or 16a-hydroxyprednisolone (active) by CYP450
- Prednisolone to 20a/b-hydroxyprednisolone (inactive) by 20a/b-hydroxyprednisolone dehydrogenase
Describe the SAR of steroid receptor binding?
- H-bond with 3-ketone and Arg or Gln
- H-bond with 11 and 19 OH and Asn
- H-bond with 18C=O and Thr
- H-bond with 17 OH and Gln
What is the SAR of steroid structures?
- The 3-keto and the 4,5-double bond are essential for both MC and GC activity
- 11-hydroxyl on the C ring is required for GC activity, not for MC activity
- A C21-hydroxyl is required for MC activity, not for GC activity (some exceptions)
- For optimum potency, GC have a 17-hydroxyl group on the D ring (ester or acetonide)
- A 1,2-double bond enhances the ratio of GC to MC potency
- An all trans backbone configuration in the polycyclic ring system is essential for activity
- Conformation of the A ring can dramatically effect activity
What is the therapeutic use for cortisone?
Corticosteroid of choice for replacement therapy in patients with adrenocortical insufficiency
How is cortisone administered?
Orally or IM as the 21-acetate
Describe the metabolism of cortisone?
- Hydro and cortisone are rapidly deacetylated by first-pass metabolism
- Oral cortisone is inactivated by oxidative metabolism before hydrocortisone conversion
What is the difference between cortisone acetate and hydrocortisone acetate?
C: slow absorption after IM (24-48hr)
H: complete absorption with 1-2hr half life (95% bioavailability)
What is this drug?
Cortisone