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PNMT
HO
OH CH 3
HO CH 2 CH 2 NH
Epinephrine
Eicosanoids
COO-
Made from arachidonic acid, a fatty acid with 20 carbons (eikosi O
= 20 in Greek) and 4 double bonds (20:4).
O C CH 3
Arachidonic acid can be converted into prostaglandin H2 by
prostaglandin synthase
Aspirin
Prostaglandin synthase has two components, a (Acetylsalicylate)
cyclooxygenase and a hydroperoxidase
+
Prostaglandin H2 (PGH2) is the precursor to prostacyclin, E Ser OH
thromboxanes and other prostaglandins.
The cyclooxygenase is inhibited by aspirin (acetylsalicylate) Salicylate
due to acetylation of a specific serine in the enzyme. Aspirin
therefore has anti-inflammatory activity. O
E Ser O C CH 3
EICOSANOIDS
OH
COO-
CH 3 OH
Leukotriene B 4
Lipoxygenases
COO-
CH 3
Arachidonate
COO-
O
CH 3
O
COO-
COO-
O CH 3 O
Other prostaglandins CH 3
O
OH
OH
OH Prostacyclin (PGI 2) Thromboxane
Danielsen 10
Mode of Action
Classical Endocrine
The classic definition: hormones are chemicals secreted by specific tissues into the blood stream
that then act on target organs. Examples include:
Paracrine
Hormones act on an adjacent cell type to the one that produced the hormone. All chemical classes of
hormone can potentially act in a paracrine manner. Examples include:
Amino acid derivatives histamine, released by mast cells, acts locally on blood vessels.
Neurotransmitters and neuromodulators
Eicosanoids prostaglandins released in inflammation
Autocrine
Hormones act on the cells that produce the hormone. This is a much rarer event than paracrine or
endocrine action. It requires that the hormone producing cells have the receptor for that hormone. It is
not thought to occur with steroid or thyroid hormones. Examples include:
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Endocrine System Hormones secreted by specific tissues into the blood
stream and then act on target organs. This is the classic
definition of a hormone.
Testosterone produced by the testis acts on skin.
Paracrine System Hormones secreted by one cell type and act on an adjacent
cell type in the same tissue/organ.
Histamine, released by mast cells, acts locally on blood
vessels.
Testosterone synthesized in the Leydig cells, acts on
seminiferous tubules
Autocrine System Hormones secreted by one cell type and act on the same
cell type.
Prostaglandins, possibly some growth factors.
e.g.
Intracellular Processing Before Secretion. Tissue specific processing of the 285 amino
acid polypeptide pro-opiomelanocortin
(POMC) to ACTH, -lipotropin, -endorphin,
MSH, MSH.
Proinsulin, Preproparathyroid hormone,
Thyroglobulin to T3 and T4.
e.g.
Activated Peripherally in Target Tissues. Thyroxine (T4) to triiodothyronine (T3).
Testosterone to dihydroxytestosterone.
Testosterone to 17-estradiol.
Structural similarity, functional e.g The glycoproteins TSH, LH, FSH, and hCG
diversity are heterodimers with and subunits. The
subunits are all the same.
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Biosynthesis and Modification
Much of the specificity of hormone action is due to the way in which hormones are synthesized and
modified.
Synthesis
Steroid hormones
Derived from cholesterol and are synthesized in either the ER or mitochondria.
The types of steroids produced by specific cells is determined by their complement of enzymes.
Since they are lipid soluble, they are not stored within cells but are released immediately synthesis
The main mechanism controlling circulating levels of steroid hormones is the rate of synthesis.
Thyroid hormones
Synthesized as an inactive precursor within the colloid of the thyroid (as part of thyroglobulin)
Many weeks of thyroid hormone can be stored in the thyroid.
The main mechanism controlling circulating levels of thyroid hormones is therefore release.
Proteins/glycoproteins/peptides/amino acid derivatives
Synthesized on the RER and Golgi
Stored in secretory vesicles
Can be stored as inactive complexes
The main mechanism controlling circulating levels of these hormones is therefore release.
Eicosanoids
Synthesized in membranes
Have a very short half-life.
They are not stored.
Act locally.
Modification
Steroid Hormones
Secreted in an active form.
Can be converted into more active forms at the target tissue.
Can be converted into a hormone with a different specificity at the target tissue. For instance,
testosterone can be converted into estradiol.
Thyroid hormones
Both T4 and T4 are released from the thyroid.
T4 can be converted into the more active T3 at the target tissue.
Proteins/glycoproteins/peptides/amino acid derivatives
All protein-derived hormones are made as a precursor
The modification of the precursor to give the active hormone can be tissue specific.
One precursor can give rise to more than one hormone
Eicosanoids
All are produced from arachidonic acid.
They are not stored
Product formed depends on the compliment of enzymes present in the synthesizing cell.
Have the potential to be modified in the target cell.
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Hormone Transport
Carrier proteins act as a reservoir for hormone; they protect against degradation, and thus increase
the half-life of the hormone.
Carrier proteins act as a buffer to prevent large surges in hormone levels
Only isoprenoid derived hormones and insulin like growth factors (IGFs) bind to carrier proteins.
There are at least 6 IGF-binding proteins. These are unusual in that they bind hormone with high
affinity and that they play a role in the control of IGF activity.
HORMONE TRANSPORT
Aldosterone Albumin 50
Cortisol CBG 90
Estrogen TeBG uncertain
Testosterone TeBG/albumin 97
Vitamin D D-Binding protein Varies by type of Vit. D
Retinoic acid Albumin uncertain
Triiodothyronine (T3) TBG 99.7
Thyroxine (T4) TBG 99.97
IGF1 IGF-binding proteins Varies by BP (6 forms of BP).
CBG, Corticosteroid Binding Globulin, TeBG, testosterone binding globulin,
TBG Thyroid hormone binding globulin.
Carrier-
bound
hormone
Hormone
degradation Biological
Danielsen effects 14
Hormone Receptors
All receptors transduce a signal, therefore at least 2 functional domains.
Hormone binding domain. Specific high affinity, reversible binding, can be determined by binding
assays (Scatchard plots).
Agonists bind and bring about a response.
Antagonists bind and inhibit agonist responses.
Antagonists are often weak agonists.
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