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Thyroid hormones
Thyroid hormones
Regulation of metabolism
- increasing oxygen consumption
- modulating levels of other hormones
(insulin, glucagon, somatotropin, adrenalin)
- important in cell differenciation
- crucial role in development of CNS, gonads
and bones
Effects of thyroid disruption
Hypothyroidism Hyperthyroidism
Effects of thyroid disruption
- In prenatal development - severe
damage of CNS (cretenism,
delayed eye opening, cognition)
- Megalotestis
- Histological changes in thyroid
gland (goitre)
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Thyroid hormones
O OH
I
I
II
OH
O
NH2
O OH
I
I
II
OH
O
NH2
Thyroxine (T4)
O OH
I
I
I
OH
O
NH2
3,5,3'-Triiodothyronine (T3)
O OH
I
I
I
OH
O
NH2
O OH
I
I
I
OH
O
NH2
3,5,3'-Triiodothyronine (T3)
- T4 ­ prohormone
- 5´-deiodination leads to active form, T3
Thyroid hormones
- T4 and small amount of T3
produced in thyroid gland
- Most T3 produced by deiodination
in target tissues (deiodinases)
- T4 synthesis - iodination of tyrosin residues on
tyreoglobulin
- coupling of two iodotyrosines conducted by thyroid
peroxidase
Pituitary-thyroid axis
-Regulation of thyroid
synthesis
-Negative feedback
-TSH stimulates both I-
uptake and iodination of
tyrosine resides on Tg
Enzymes involved in thyroid
metabolism
- Thyroid peroxidases
- iodination of tyrosyl residues
- coupling of iodinated tyrosyl residues
- Thyroid deiodinases
- D1, D2 - activation of T4 into T3 via deiodination on
,,outer" ring (formation of T3)
- D3 - deactivation into rT3 via deiodination on ,,inner"
ring
O OH
I
I
II
OH
O
NH2
O OH
I
I
II
OH
O
NH2
,,outer"
,,inner"
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Mechanism of action
-Alike other nuclear receptors
-5 isoforms of TR
-After activation formation of homo- and
heterodimers
-Binding to thyroid responsive elements
-Gene expression
Thyroid binding proteins
- Regulating free T4 and T3 levels in blood
- 3 types :
-Thyroid-binding prealbunin (transthyretin) (20-25%)
-Albumin (5-10%)
-Thyroid binding globulin (75%)
Competitive binding to
thyroid binding proteins
- OH-PCBs, brominated and chlorinated flame
retardants, DDT, dieldrin
- OH-PCBs ­ equal affinity to TBP as T4 and T3
- More of free T4 in blood => increased depletion
Competitive binding to TR
- Probably less important than binding to TBP
- Chemicals that affect thyroid signalling in vivo
mostly don´t bind to TR (DDT, PCBs) or bind
with much lesser affinity than T3 (OH-PCBs ­
10000x)
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Accelerated depletion of TH
- UDP-glucuronosyltransferase ­ detoxication
enzyme (II.biotransformation phase)
- Induced by PCBs, dioxins
- Key enzyme in thyroid catabolism
- Increased by disruption of TBP binding
In vivo assessment
- TH serum levels ­ simple, nondestructive x
variation witin time of day, age, sensitive to
other than biochemical stresses
- Thyroid gland weight and folicular cells number
- Delayed eye opening, abnormalities in brain
development and cognition
- Increased testis weight and sperm counts
- Perchlorate discharge test (TH synthesis)
In vitro assessment
- Enzyme inhibition assays (thyroid peroxidase,
deiodinases)
- Competitive binding assays with TBP
- TH- dependent proliferation assay (pituitary tumor GH3,
thyroid tumors like FRTL-5 cell line) or TSH-dependent
proliferation assay (thyroid tumors)
- Receptor-reporter gene assays with luciferase (monkey
kidney CV-1, chinese hamster ovary CHO or insect Sf9
cell lines)