11.22.17 Introduction to Steroids

Question 1

Cholesterol is transported from the ____ by transporter proteins that dock to the outer _____ membrane.

Answer 1

Cholesterol is transported from the cytoplasm by transporter proteins that dock to the outer mitochondrial membrane.

Question 2

The rate limiting step in steroid biosynthesis lies with the _______, which facilitates cholesterol crossing the aqueous inner membrane space.

Answer 2

The rate limiting step in steroid biosynthesis lies with the steroidogenic acute regulatory protein (StAR), which facilitates cholesterol crossing the aqueous inner membrane space.

Question 3

Once transferred to the inner membrane, conversion of cholesterol to ______ occurs by the membrane-bound cytochrome p450scc.

Answer 3

Once transferred to the inner membrane, conversion of cholesterol to pregnenolone occurs by the membrane-bound cytochrome p450scc.

Question 4

The adrenal _____ have no 17a-hydroxylase.

Answer 4

The adrenal zona glomerulosa have no 17a-hydroxylase.

Question 5

Leydig cells are missing the enzymes _____, ______, and ______.

Answer 5

Leydig cells are missing 11b-hydroxylase, 21a-hydroxylase, and aromatase.

Question 6

Name and briefly describe the four steroid transport proteins.

Answer 6

• corticosteroid-binding globulin (CBG, “transcortin”): transport corticosteroids, aldosterone, progesterone.
• sex hormone-binding globulin (SHBG): transport estradiol, testosterone
• androgen-binding protein (ABP): testosterone
• serum albumin: corticosteroids, estradiol, tetosterone. Low affinity, but available in high concentration.

Question 7

Ways in which steroid metabolism is mediated:

• Steroids are inactivated by ____ in the liver.
• Converted to less active steroid. (eg. estradiol–>estrone)
• altered to have ___ or ____ (eg. testosterone–>DHT)

Answer 7

Ways in which steroid metabolism is mediated:

• Steroids are inactivated by glucuronide conjugation in the liver.
• Converted to less active steroid. (eg. estradiol–>estrone)
• altered to have increased affinity or altered specificity (eg. testosterone–>DHT)

Question 8

Steroid hormones interact with _____ receptors of the _____ super family. These receptors are different than membrane receptors in that they are _____ factors.

Answer 8

Steroid hormones interact with intracellular receptors of the nuclear receptor super family. These receptors are different than membrane receptors in that they are transcription factors.

Question 9

Steroids directly activate _____ without activating a kinase cascade. Nuclear hormone receptors ____ and ____ to the nucleus after binding their ligands.

Answer 9

Steroids directly activate gene transcription without activating a kinase cascade. Nuclear hormone receptors dimerize and translocate to the nucleus after binding their ligands.

Question 10

There are several modes of nuclear receptor DNA-binding, describe (4):

Answer 10

• Steroid receptor (eg. GR, MR, PR, AR, ER)
• RXR heterodimers (eg. PPAR, TR, VDR)
• Monomeric orphan receptors
• Dimeric orphan receptors

Question 11

Agonists can induce a ______ that favors ______ binding. Endogenous ligands normally ______ gene expression.

Answer 11

Agonists can induce a receptor conformation (eg. H12 shift down on ER) that favors coactivator binding. Endogenous ligands normally upregulates gene expression.

Question 12

Antagonists can block endogenous ligand effects by _____ binding. They can also induce a conformation of the receptor that prevents _____ binding and promotes _____ binding. No effect on transcription in the absence of endogenous ligand.

Answer 12

Antagonists can block endogenous ligand effects by competitive binding. They can also induce a conformation of the receptor that prevents coactivator binding and promotes corepressor binding. No effect on transcription in the absence of endogenous ligand.

Question 13

Inverse agonists reduce ____ level of activity.

Answer 13

Inverse agonists reduce basal level of activity.

Question 14

Selective receptor modulators (SRMs) have ____ or _____ response. They work by promoting a conformation of the receptor that is closely balanced.

• Coactivators abundant = SRM behaves as _____
• Corepressors abundant = SRM behaves as _____

Answer 14

Selective receptor modulators (SRMs) have agonist or antagonist response. They work by promoting a conformation of the receptor that is closely balanced.

• Coactivators abundant = SRM behaves as agonist
• Corepressors abundant = SRM behaves as antagonist

Question 15

Therapeutic use of antagonists/agonists include replacement therapy. Give two examples:

Answer 15

• adrenal steroids: Addison’s

- estrogen/progesterone: menopause

Question 16

Therapeutic use of antagonists/agonists include pharmacologic use. Give four examples:

Answer 16

– glucocorticoids as anti-inflammatory agents
– estrogen/progesterone for contraception
– androgens for increased muscle mass
– mifepristone (RU486) for pregnancy termination

Question 17

Therapeutic use of antagonists/agonists include use for cancer. GIve two examples:

Answer 17

• tamoxifen: breast CA

- flutamide/bicalutamide: prostate CA