corticosteroids and steroid receptors - 2 Flashcards by Emily Liu

what are 2 uses for glucocorticoids in non-endocrine disease

anti-inflammatory/immunosuppressive therapy
and
neoplastic disease

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what causes asthma

narrowing of airway due to inflammatory response

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what are 2 neoplastic diseases that glucocorticoids can treat

acute lymphocytic leukemia and cerebral edema

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how can glucocorticoids treat acute lymphocytic leukemia

suppression of the number of lymphocytes

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how can glucocorticoids treat cerebral edema

symptomatic relief for patients with brain tumors

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why can glucocorticoids treat symptoms for cerebral edema

it causes vasoconstriction to help relieve headaches

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what is metyrapone used for

cushings disease and test for ACTH production

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what test metyrapone test for and why

test for ACTH production because it stops cortisol pathway so there should be a loss of negative feedback to ACTH production

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what is metyrapone

11-β hydroxylase inhibitor

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which drug is a 11-β hydroxylase inhibitor

metyrapone

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what are 2 major adverse effects of metyrapone and how

salt + water retention (increase deoxycorticosterone)

hirsutism (increase androgen)

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what does aminoglutethimide do

inhibits the conversion of cholesterol to pregnenolone

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what drug inhibits the conversion of cholesterol to pregnenolone

aminoglutethimide

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what are 2 uses for aminoglutethimide

cushings syndrome (with ketoconazole)

- breast carcinoma (decrease estrogen production)

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what does ketoconazole do

inhibits 17α-hydroxylase

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what drug inhibits 17α-hydroxylase

ketoconazole

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what are the side effects of ketoconazole

increase in levels of ACTH progesterone and aldosterone

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what 2 drugs are often combined for cushings syndrome

aminoglutethimide and ketoconazole

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why does ketoconazole increase ACTH

because less cortisol is made

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what does trilostane do

inhibits 3β dehydrogenase

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what 2 disorders is trilostane used for

cushings syndrome and primary hyperaldosteronism

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which pathway is 3β dehydrogenase used in (mineralocorticoid or glucocorticoid or sex steroid pathway)

all of them

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what does mifepristone do

antagonist at glucocorticoid and progesterone receptors (prevents activation_

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when is mifepristone used (what conditions)

inoperable patients with ectopic ACTH secretion or adrenal carcinoma

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what family are the glucocorticoid receptors (GR)

STRO/ nuclear receptor family

what are 3 types of glucocorticoid receptors

GRα GRβ GRγ

what are the binding affinities of aldosterone, sex steroids, cortisol, dexamethasone to GRα

dexamethasone>> cortisol>> aldosterone, sex steroids

can GRβ bind glucocorticoids

what cant GRβ bind

glucocorticoids

where are GRβ found

nucleus

what is the endogenous ligand to GRβ

its unknown

what does GRβ do to GRα

inhibits the activity of GRα via the formation of transcriptionally impaired GRα-GRβ heterodimers

what kind of disorder has an upregulation in GRβ

asthma

what happns with glucocorticoid receptors with asthma

upregulated GRβ

what does GRγ bind to and how strong

glucocorticoids but weak

what is the transcriptional activity of GRγ

less active than GRα

what is GRγ expression associated with

glucocorticoid resistance in corticotrope adenomas

which GR is associated with corticotrope adenomas

GRγ

does GRγ bind to glucocorticoids

yes

does GRα bind to glucocorticoids

yes

which GR doesnt bind to glucocorticoids

GRβ

what are the binding affinities of aldosterone, progesterone, cortisol to MR

all the same

are MR or GR more selective

what is the role of corticosteroid binding globulin (what % does it bind)

binds 80% of circulating cortisol

do synthetic cortisols bind t oCBG

is CBG in the brain

where and what is MDR-P-glycoprotein

a transporter protein expressed in the apical membranes of endothelial cells in the BBB

what does MDR-P-glycoprotein do

extrude steroids from cells

what does MDR-P-glycoprotein do to brain

limits access of natural and synthetic glucocorticoids to the brain

does MDR-P-glycoprotein increase or decrease glucocorticoids in the brain

decrease

what does 11β-hydroxysteroid dehydrogenase (11-βHSD1) do + how

amplify local concentrations of glucocorticoids | converts cortisone to cortisol

how does 11β-hydroxysteroid dehydrogenase (11-βHSD1) work

low affinity enzyme that converts cortisone to cortisol

what affinity is 11β-hydroxysteroid dehydrogenase (11-βHSD1)

low affinity enzyme

where is 11β-hydroxysteroid dehydrogenase (11-βHSD1)

widespread distribution, including hippocampus

what does 11β-hydroxysteroid dehydrogenase (11-βHSD2) do

converts cortisol into cortisone

what affinity is 11β-hydroxysteroid dehydrogenase (11-βHSD2)

high affinity enzyme that converts to cortisol into cortisone

what is the binding affinity of cortisone to MR

low

where is 11β-hydroxysteroid dehydrogenase (11-βHSD2)

kidney, sweat glands, parotid gland, colon, CNS (salt appetite, volume regulation, autonomic control)

is 11β-hydroxysteroid dehydrogenase (11-βHSD2) in hippocampus

is 11β-hydroxysteroid dehydrogenase (11-βHSD1) in hippocampus

yes

which 11β-hydroxysteroid dehydrogenase is in the hippocampus

which 11β-hydroxysteroid dehydrogenase is a low affinity enzyme

which 11β-hydroxysteroid dehydrogenase is a high affinity enzyme

which 11β-hydroxysteroid dehydrogenase converts cortisol/corticosterone into cortisone

which 11β-hydroxysteroid dehydrogenase converts cortisone to cortisol or corticosterone

how do steroid hormones get into the cell

diffusion

what are steroid receptors associated with

a complex of chaperone proteins which compromise heat shock proteins 70 and 90

what are 2 roles of chaperone proteins

help other proteins avoid misfolding | maintain receptors in an inactive form with high affinity for steroid

what keeps steroid receptors in the unactivated state

Heat shock proteins / chaperones

what is nuclear hormone response element

short sequence of DNA bind to a specific hormone receptor complex and regulate transcription

how do GR MR androgen or progesterone receptors bind to the nuclear hormone response element

as dimers

what does nuclear hormone response element do (2 words)

initiate transcription

what is transrepression

repression of gene transcription activated by other transcriptional factors

what activates repression of gene transcription (transrepression)

transcription factors

which transcription factor do glucocorticoids suppresss

the activity of the pro-inflammatory TF

what 2 things can happen with initiation of transcription from nuclear hormone response element

- interaction with the consensus nucleotide sequence of the HRE and transcription initiation complex - inhibition of target gene via binding to negative HRE in promotor region

how does the nuclear hormone response element cause transcription

-interaction with the consensus nucleotide sequence of the HRE and transcription initiation complex

how does the nuclear hormone response element cause inhibition

-inhibition of target gene via binding to negative HRE in promotor region

what two things work together to do transrepression

the TF and the glucocorticoid receptor (protein protein interactions)

which 2 protein protein interactions cause transrepression

the TF and the glucocorticoid receptor

what kind of interactions occur and with what things happen in transrepression

protein-protein interactions between TF and GR

what cant the blocked TF bind to

transcription factor elements

do you require dimerization of receptors for transrepression

it may not be required

what happens to gene transcription when theres the TF GR protein protein interaction + WHY

there is a reduction | because the TF cant bind to the transcription factor elements

what are 3 molecular mechanisms of corticosteroids on gene expression

- homodimerization/transactivation - transrepression - heterodimerization

what is homodimerization/transactivation

when GR MR androgen or progesterone receptors bind as dimers to a common nuclear hormone response element

where do the homodimerization/transactivation dimers bind to

a common nuclear hormone response element

what is heterodimerization

formation of heterodimers between different steroid receptors

what do the heterodimers do

bind to hormone response element or unknown DNA elements to affect the rate of gene transcription

what are 3 different mechanisms/ classes of non-genomic action of steroids

- steroid receptors on plasma - cytosolic steroid receptors - non-specific interactions of steroids with cellular membranes

what happens with binding of steroids to cytosolic receptors

dissociation of the different Hsps and other cofactors, then the other Hsps/cofactors are available for other cellular processes

what are 2 non-specific interactions of steroids with cellular membranes

steroids intercalate into plasma and mitochondrial membranes and influence their biophysical properties and the function and activity of membrane associated proteins ugh

corticosteroids and steroid receptors - 2 Flashcards

(92 cards)