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PMCOL 343 > corticosteroids and steroid receptors - 2 > Flashcards

corticosteroids and steroid receptors - 2 Flashcards

1
Q

what are 2 uses for glucocorticoids in non-endocrine disease

A

anti-inflammatory/immunosuppressive therapy
and
neoplastic disease

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2
Q

what causes asthma

A

narrowing of airway due to inflammatory response

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3
Q

what are 2 neoplastic diseases that glucocorticoids can treat

A

acute lymphocytic leukemia and cerebral edema

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4
Q

how can glucocorticoids treat acute lymphocytic leukemia

A

suppression of the number of lymphocytes

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5
Q

how can glucocorticoids treat cerebral edema

A

symptomatic relief for patients with brain tumors

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6
Q

why can glucocorticoids treat symptoms for cerebral edema

A

it causes vasoconstriction to help relieve headaches

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7
Q

what is metyrapone used for

A

cushings disease and test for ACTH production

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8
Q

what test metyrapone test for and why

A

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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9
Q

what is metyrapone

A

11-β hydroxylase inhibitor

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10
Q

which drug is a 11-β hydroxylase inhibitor

A

metyrapone

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11
Q

what are 2 major adverse effects of metyrapone and how

A

salt + water retention (increase deoxycorticosterone)

hirsutism (increase androgen)

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12
Q

what does aminoglutethimide do

A

inhibits the conversion of cholesterol to pregnenolone

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13
Q

what drug inhibits the conversion of cholesterol to pregnenolone

A

aminoglutethimide

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14
Q

what are 2 uses for aminoglutethimide

A
  • cushings syndrome (with ketoconazole)

- breast carcinoma (decrease estrogen production)

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15
Q

what does ketoconazole do

A

inhibits 17α-hydroxylase

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16
Q

what drug inhibits 17α-hydroxylase

A

ketoconazole

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17
Q

what are the side effects of ketoconazole

A

increase in levels of ACTH progesterone and aldosterone

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18
Q

what 2 drugs are often combined for cushings syndrome

A

aminoglutethimide and ketoconazole

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19
Q

why does ketoconazole increase ACTH

A

because less cortisol is made

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20
Q

what does trilostane do

A

inhibits 3β dehydrogenase

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21
Q

what 2 disorders is trilostane used for

A

cushings syndrome and primary hyperaldosteronism

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22
Q

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

A

all of them

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23
Q

what does mifepristone do

A

antagonist at glucocorticoid and progesterone receptors (prevents activation_

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24
Q

when is mifepristone used (what conditions)

A

inoperable patients with ectopic ACTH secretion or adrenal carcinoma

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25
Q

what family are the glucocorticoid receptors (GR)

A

STRO/ nuclear receptor family

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26
Q

what are 3 types of glucocorticoid receptors

A

GRα
GRβ
GRγ

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27
Q

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

A

dexamethasone» cortisol» aldosterone, sex steroids

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28
Q

can GRβ bind glucocorticoids

A

no

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29
Q

what cant GRβ bind

A

glucocorticoids

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30
Q

where are GRβ found

A

nucleus

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31
Q

what is the endogenous ligand to GRβ

A

its unknown

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32
Q

what does GRβ do to GRα

A

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

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33
Q

what kind of disorder has an upregulation in GRβ

A

asthma

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34
Q

what happns with glucocorticoid receptors with asthma

A

upregulated GRβ

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35
Q

what does GRγ bind to and how strong

A

glucocorticoids but weak

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36
Q

what is the transcriptional activity of GRγ

A

less active than GRα

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37
Q

what is GRγ expression associated with

A

glucocorticoid resistance in corticotrope adenomas

38
Q

which GR is associated with corticotrope adenomas

A

GRγ

39
Q

does GRγ bind to glucocorticoids

A

yes

40
Q

does GRα bind to glucocorticoids

A

yes

41
Q

which GR doesnt bind to glucocorticoids

A

GRβ

42
Q

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

A

all the same

43
Q

are MR or GR more selective

A

GR

44
Q

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

A

binds 80% of circulating cortisol

45
Q

do synthetic cortisols bind t oCBG

A

no

46
Q

is CBG in the brain

A

no

47
Q

where and what is MDR-P-glycoprotein

A

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

48
Q

what does MDR-P-glycoprotein do

A

extrude steroids from cells

49
Q

what does MDR-P-glycoprotein do to brain

A

limits access of natural and synthetic glucocorticoids to the brain

50
Q

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

A

decrease

51
Q

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

A

amplify local concentrations of glucocorticoids

converts cortisone to cortisol

52
Q

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

A

low affinity enzyme that converts cortisone to cortisol

53
Q

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

A

low affinity enzyme

54
Q

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

A

widespread distribution, including hippocampus

55
Q

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

A

converts cortisol into cortisone

56
Q

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

A

high affinity enzyme that converts to cortisol into cortisone

57
Q

what is the binding affinity of cortisone to MR

A

low

58
Q

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

A

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

59
Q

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

A

no

60
Q

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

A

yes

61
Q

which 11β-hydroxysteroid dehydrogenase is in the hippocampus

A

1

62
Q

which 11β-hydroxysteroid dehydrogenase is a low affinity enzyme

A

1

63
Q

which 11β-hydroxysteroid dehydrogenase is a high affinity enzyme

A

2

64
Q

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

A

2

65
Q

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

A

1

66
Q

how do steroid hormones get into the cell

A

diffusion

67
Q

what are steroid receptors associated with

A

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

68
Q

what are 2 roles of chaperone proteins

A

help other proteins avoid misfolding

maintain receptors in an inactive form with high affinity for steroid

69
Q

what keeps steroid receptors in the unactivated state

A

Heat shock proteins / chaperones

70
Q

what is nuclear hormone response element

A

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

71
Q

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

A

as dimers

72
Q

what does nuclear hormone response element do (2 words)

A

initiate transcription

73
Q

what is transrepression

A

repression of gene transcription activated by other transcriptional factors

74
Q

what activates repression of gene transcription (transrepression)

A

transcription factors

75
Q

which transcription factor do glucocorticoids suppresss

A

the activity of the pro-inflammatory TF

76
Q

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

A
  • 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
77
Q

how does the nuclear hormone response element cause transcription

A

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

78
Q

how does the nuclear hormone response element cause inhibition

A

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

79
Q

what two things work together to do transrepression

A

the TF and the glucocorticoid receptor (protein protein interactions)

80
Q

which 2 protein protein interactions cause transrepression

A

the TF and the glucocorticoid receptor

81
Q

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

A

protein-protein interactions between TF and GR

82
Q

what cant the blocked TF bind to

A

transcription factor elements

83
Q

do you require dimerization of receptors for transrepression

A

it may not be required

84
Q

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

A

there is a reduction

because the TF cant bind to the transcription factor elements

85
Q

what are 3 molecular mechanisms of corticosteroids on gene expression

A
  • homodimerization/transactivation
  • transrepression
  • heterodimerization
86
Q

what is homodimerization/transactivation

A

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

87
Q

where do the homodimerization/transactivation dimers bind to

A

a common nuclear hormone response element

88
Q

what is heterodimerization

A

formation of heterodimers between different steroid receptors

89
Q

what do the heterodimers do

A

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

90
Q

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

A
  • steroid receptors on plasma
  • cytosolic steroid receptors
  • non-specific interactions of steroids with cellular membranes
91
Q

what happens with binding of steroids to cytosolic receptors

A

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

92
Q

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

A

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

PMCOL 343 (31 decks)

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