Mstn Ii - Lecture 31

Front 1

Graves disease

Back 1

- protruding or swelling eyes
- increase in thyroid hormone (TH)
- antibodies to the thyroid are produced with this disease causing an increase in fat deposition around the eye, pushin it forward.
- muscle degeneration
- maybe not be able to close eyelid (eyes can dry out)

Front 2

Cretens

Back 2

- short stature
- decreased mental acuity
- decrease in TH which is needed for brain development
- TH linked to growth hormone (GH), so Cretens do not have proper levels of GH.

- treated soon after birth, normal development can occur.

Front 3

hypothyroidism

Back 3

downwards mouth

can be treated

Front 4

thyroid hormones are only made in:

Back 4

thyroid tissue by the sequential addition of iodine to tyrosine to form 3-monoiodotyrosine (MIT) and 3.5-diiodotyrosine (DIT)

Front 5

two iodinated tyrosines are coupled to form:

Back 5

3,5,3'-triiodothyronine (T3) and 3,5,3'5'-tetraiodothyronine (T4)

Front 6

In the periphery T4 can

Back 6

converted to T3 and reverse T3 (rT3)

- rT3 is a marker for starvation

Front 7

thyoidglobulin protein (TgB)

Back 7

tyrosine is bound to this protein

Front 8

TH is made in:

stored in:

Back 8

made in the follicular cells

stored in the colloid

Front 9

TSH has receptors on:

Back 9

follicular cells so it stimulates the production and release of TH.

Front 10

TSH receptor structure:

Back 10

- 7 membrane domains
- N terminus extracellular
- C-terminus intracellular

Front 11

TSH and controlling the thyroid:

Back 11

TSH controls the actual growth of the gland itself, increasing the size of the thyroid.

Front 12

transport of iodine into a thyroid follicle cell:

Back 12

- a pump on the basolateral membrane
- this symport transports both Na+ and I- into cells.
- small percentage of iodine can enter and levae by diffusion

Front 13

I pump requires:

inhibited by:

Back 13

irequires the E dependent Na+/K+ pump

inhibited by ouabain

Front 14

iodine pump inhibited by 2 classes of drugs:

Back 14

1) drugs that compete with iodide and are concentrated in the thyroid

2) drugs that compete with iodide but are not concentrated in the thyroid

Front 15

drugs that compete with I and are concentrated in the thyroid:

Back 15

- perchlorate (ClO4-)
- Perrhenate (ReO4-)
- Pertechnetate (TcO4-)
- same partial specific volume as I-.
- ratdioactive deriviatives of these inhibitors can be used for radiographic imaging of the thyroid.
- perchlorate -> treat hyperthyroidism

Front 16

drugs that compete with iodide but are not concentrated in the thyroid

Back 16

thiocyanate SCHN-

Front 17

propylthiouracil (PTU)

Back 17

- anti-thyroid drug
- do not inhibit the pump
- inhibits all other thyroid events except the I pump

Front 18

ratio of iodine inside a thyroid follicle cell to that in serum (T:S ratio)

Back 18

25

reflection of the activity of the pump

Front 19

activity of the pump is controlled by:

Back 19

the pituitary hormone TSH.

- animals conronically stimulated with TSH have a T:S ratio of about 500
- hypophysectomized animals have a T:S ratio of about 5

Front 20

TSH receptor increases the activity of the iodide pump by:

Back 20

increasing cAMP levels in cells (G-protein-coupled, adenyl cyclase)
- other effects on thyroid cells maybe due to phospholipase A2 activation

Front 21

follicular lumen and the exterior of the cell:

Back 21

follicular lumen has the same electrochemical characteristics as the exterior of the cell, iodide rapidly travels down the electrochemical gradient to and across the apical membrane and into the lumen.

Front 22

thyroperoxidase (TPO)

Back 22

I travels towards the apical membrane side of the cell
- it is oxidized by TPO
- this enzyme adds iodide to tyrosines bound to TgB making the MITs and DITs
- then it fuses them to generate Ts/T4
- TgB is phagocytosed back into the follicular cell after the coupling occurs.

Front 23

organification

Back 23

iodination of tyrosine

Front 24

model of iodide metabolism in the thyroid follicle:

Back 24

- a follicular cell
- iodide enters the thyroid by a pump and by passive diffusion
- thyroid hormone synthesis occurs in the follicular space through a serires of rxns, many o fwhich are peroxidase-mediated.
- thyroid hormones are released from thyroglubulin by hydrolysis

Front 25

thyroglobulin

Back 25

larg glycoprotein that is considered to be a pro-hormone.
- has number of sites that can be iodinated.

Front 26

Propylthiouracil (PTU)

Back 26

antithyroid drug
- inhibit any step of the iodination or organification of tyrosine
- prevent the formation of MIT, DIT, T3 or T4.
- inhibit TPO
- treats hyperthyroidism

Front 27

thiourea class of antithyroid drugs

Back 27

thiourea
thiouracil
propylthiouracil (PTU)
methimazole

Front 28

Iodide Oxidation

Back 28

- can only take place in the thyroid
- occurs on the luminal surface
- other tissues can take up and concentrate iodide but cannot oxidize it

Front 29

thyroperoxidase (TPO)

Back 29

heme containing glycosylated enzyme that has an absolute requirement for hydrogen peroxide
- TSH increases the synthesis of thyroperoxidase

H2O2 produced by an NADPH-dependent enzyme resembling cytochrome C reductase

Front 30

thyroperoxidase and iodination of tyrosine

Back 30

catalyzes the iodination of tyrosine residues on luminal thyroglobulin gives MIT which is then iodinated at the 5 position to give DIT

Front 31

free tyrosine and the iodination of tyrosine

Back 31

free tyrosine can be iodinated to MIT but cannot be incorporated into the polypeptide chain of a protein since a rTNA does not recognize it

Front 32

MIT + DIT =

Back 32

T3

Front 33

DIT + DIT =

Back 33

T4

Front 34

coupling of iodotyrosils:

Back 34

- bound to thyroglobulin
- coupling rxn does not cleave the peptide bond - it leaves behind dehydroalanine
- direct addition of MIT or DIT to an iodotyrosine has not been ruled out
- catalyzed by thyroperoxidase.
- inhibited by PTU

Front 35

structure of thyroglobulin

Back 35

- homodimer of MW 660,000 with 8-10% carb, 0.2% - 1% Iodide, 5496 amino acids (2748/polypeptide)
- 134 tyrosine residues, 5 MIT, 4.5 DIT, 2.5 T4, 0.7 T3
- 3435 ATPs are required per molecule of T3 or T4 (2 ATP/peptide bond)
- many weeks supple of hormone stored in the extracellular colloid

Front 36

Release of T3 and T4

Back 36

- stimulated by TSH by activation of adenylate cyclase
- occurs by complete hydrolysis of thyroglobulin
- thyroglobulin is engulfed by phagocytosis, these vesicles fuse with lysosomes to give secondary lysosomes (phagolysosomes)
- hydrolysis of thyroglobulin in the secondary lysosomes -> iodinated AA derivatives T3, T4, DIT, and MIT
- some specific deiodination of T4 and T3, however most deiodination of T4 occurs in the periphery. T3 and T4 are released from the cell
- DIT and MIT are deiodinated by a deiodinase, requires NADPH, and products recycled

Front 37

reabsorption of iodide

Back 37

30% of dietary iodide is absorbed (150 ug required for the average daily synthesis of T4 and T3 containing 50ug iodide)

Front 38

affinity for TH receptor of T3 and T4

Back 38

T3 has 10X affinity for TH receptors than T4 does.

Front 39

rT3

Back 39

- also made in the periphery, has little activity
- high in chronic disease, starvation and fetus

Front 40

excess levels of iodide:

Back 40

control thyroid hormone synthesis

- increased idide inhibit T3 and T4 production
- iodide treatment is often used clinically to prevent thyroid storm

Front 41

Wolfe-Chaikoff Effect

Back 41

short term effect

- transient block in organification due to high intracellular levels of iodide
- relieved after 48 hours due to increased export of iodide

Front 42

medium term effect of excess iodide

Back 42

- increased organification -> increased MIT and DIT but decreased T3/T4
- decreased release of T3/T4 due to decreased T3/T4 content of thyroglobulin
- cells recover after 7-10 days

Front 43

long term effects of excess levels of iodide

Back 43

- unusual cases, the iodide block becomes permanent and a goiter and hypothyroidism develop.
- probably due to some underlying defet in the thyroid

Front 44

mech. of recovery from iodide inhibition:

Back 44

involve iodinated arachidonic acid

Front 45

T3 and T4

bound %, free%, half life:

Back 45

T3:
bound: 99.7%, free: 0.3%, half life: 1.5 days

T4:
bound: 99.07%, free: 0.03%, half life: 6.5 days

Front 46

over 99% of T3 and T4 are bound:

Back 46

to carrier proteins thyroxine-binding globulin (TBG) (70%)

thyroxine-binding prealbumin (TBPA) (10-15%)

albumin (15-20%)

Front 47

TBC's affinity for T3 and T4 compared with TBPA

Back 47

100x more

Front 48

for clinical purposes it is important to measure:

Back 48

free as well as total hormone levels since many agents alter TBG levels and thus total hormone without altering free hormone levels

Front 49

TBG:

synthesized in:
increased by
decreased by:
binding:

Back 49

liver synthesizes TBG

estrogen increases

androgens and glucocorticoids decrease

phenytoin and salicylates compete for binding to TBG

Front 50

T3 inhibit:

Back 50

- TSH from the pituitary
- TRH synthesis and release from the hypothalamus

Front 51

T3 stimulate:

Back 51

- low T3 stimulate TRH release

Front 52

TRH stimulates:

Back 52

TSH release

Front 53

somatostatin inhibits:

Back 53

TSH release
GH (somatotropin) release

Front 54

IGF, somatomedin

Back 54

- insulin like growth factor
- GH induce the production of them by the liver

Front 55

high levels of IGF:

Back 55

stimulate somatostatin release

Front 56

TRE thyroid response elements

Back 56

TR is bound to specific DNA sequences termed TRE whether hormone is present or not

Front 57

TR in the absence and presence of hormone

Back 57

absenceL TR represses transcription

presenceL receptor activates transcription by recruiting transcriptioal coactivators that interact with the initiation complex

Front 58

TR can bind to DNA as:

Back 58

- homodimer

- heterodimer with RXR

RXR-TR heterodimer is usually most active

Front 59

2 genes encode thyroid hormones receptors:

Back 59

TRalpha

TRbeta

Front 60

TRbeta

Back 60

2 splice variants, TRbeta1, TRbeta2; both are active receptors with differential expression

Front 61

TRalpha

Back 61

2 splice variants of TRalpha, TRapha1 and TRapha2. These splice variants do not bind hormones and their fcn is unknown

Front 62

hormone binding domain

DNA binding domain

Back 62

27000 daltons

10000 daltons (2 Zn coordinated cysteine fingers)

Front 63

thryoid hormone receptor are member of:

Back 63

retinoid/thyroid/stteroid hormone superfamily of receptors

Front 64

TR binds to:

Back 64

TRE mainly as a heterodimer with RXR

Front 65

TRE:

Back 65

- consist of inverted (palindromic) or direct repeats of the ocnsensus sequences AGGTCA
- when present as direct repeats, the repeats are usually separated by 4 base pairs
- found in the GH gene
- found in cardiac sarcoplasmic reticulum Ca2+-ATPase gene SERCA2 .

Front 66

SERCA2

Back 66

controls the uptake of Ca2+ into the ER, a rate -limiting event in muscle contraction.

Front 67

T3 increases:

Back 67

- heart rate by increasing the transcription of specific isoforms of myosin
- SERCA2 -> heart rate

Front 68

nTRE

Back 68

- TR inhibition of transcription
- DNA sequences termed nTREs mediate transcriptional repression
- TR usually binds to nTREs as a monomer
- nTREs are found in genes such as those for the TSH alpha and beta subunits

Front 69

TH biological effects:

Back 69

+ oxygen consumption due to increasing the # of Na+/K+ ATPase molecules (major E drain)
+ protein synthesis giving a positive nitrogen balance

amphibian metamorphosis is dependent on TH

Front 70

Endemic goiter

Back 70

insufficient dietary intake of iodine -> insufficient production of TH -> constitutiive production of TSH

Front 71

Hashimoto's thyroiditis:

Back 71

- autoimmune disease
- production of antibodies against thyroglobulin
- slow destruction of the thyroid leading to hypothyroidism

Front 72

drug interactions:

iodine:

lithium

Back 72

iodine: transient block in organification due to the Wolff-Chiakoff effect. with Hashimoto's may lead to guiter and hypothyroidism

Lithiuml inhibits TH release. 25% of patients have a goiter and are hypothyroid.