Transcript 4. cholest and steroid

CHOLESTEROL
AND
STEROIDS
• Sterols (steroids) are class of lipids that
are derivatives of a tetracyclic
hydrocarbon
Steroids
• Steroids are lipids containing a steroid nucleus (core
structure)
• The steroid nucleus is a fused ring system consisting of three
cyclohexane rings and one cyclopentane ring
• The rings are designated A, B, C and D
• Attachment of different groups to the core steroid structure
leads to a wide variety of steroid compounds, including
cholesterol, bile salts and steroid hormones
C
A
B
D
CHOLESTEROL
“Cholesterol is the most highly decorated small molecule in biology.
Thirteen Nobel Prizes have been awarded to scientists who devoted
major parts of their careers to cholesterol. Ever since it was isolated
from gallstones in 1784, cholesterol has exerted an almost hypnotic
fascination for scientists from the most diverse areas of science and
medicine…. Cholesterol is a Janus-faced molecule. The very property
that makes it useful in cell membranes, namely its absolute
insolubility in water, also makes it lethal.”
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Cholesterol
• Cholesterol is the most abundant steroid in animals
- plants have very small amounts (but have related compounds)
- it’s a major component of cell membranes, and affects the fluidity
of the membrane due to its bulky structure
- is a precursor for biosynthesis of many other steroids
• Cholesterol is called a sterol because it contains an alcohol group
• We can obtain cholesterol from our diet (animal products), but our
liver can also synthesize all the cholesterol that we need
- the liver synthesizes more cholesterol when dietary intake is low
- excessive blood cholesterol is associated with atherosclerosis and
formation of gallstones
HO
History
1855 – Addison’s disease
1856 – Adrenal glands essential for life
1930 – Cortex > medulla
1932 – Cushing’s syndrome
1949 – Hench et al (Steroids in rheumatoid arthritis)
1952 – Aldosterone
CHOLESTEROL IS THE BIOSYNTHETIC
SOURCE OF ALL STEROIDS
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Steroid Hormones
• Hormones act as
chemical messengers
• They are important in
control of many
biological functions
• They are secreted
from endocrine
glands (and placenta)
• They react with
receptors on cell
surfaces to trigger a
cascade response
• Usually control
metabolism at the
gene level
• Steroid hormones are
biosynthesized from
cholesterol
Adrenal Corticosteroids
• Adrenal corticosteroids are hormones produced in the adrenal
glands (located just above the kidneys)
• Cortisone (a glucocorticoid) raises the blood glucose level by
causing tissues other than the brain to switch to metabolizing fats
and proteins; it also suppresses the immune response and can be
used as an anti-inflammatory anti-allergy medication
• Aldosterone (a mineralcorticoid) regulates ion balance by
promoting re-absorbtion of Na+, Cl- and HCO3- by the kidneys
• Prednisone is a synthetic corticoid used to treat various
inflammatory conditions, such as asthma and rheumatoid arthritis
CHOLESTEROL IS THE BIOSYNTHETIC SOURCE OF ALL
STEROID HORMONES
• Five major classes of hormones
– Progestins (regulate events during pregnancy and are
precursors to all other steroid hormones)
– Androgens (male sexual characteristic development
and maintenance)
– Estrogens (female sexual characteristics development
and maintenance)
– Glucocorticoids (promote gluconeogenesis, and in
certain doses suppress inflammation rxns)
– Mineralocorticoids (regulate ion balance in kidney)
Actions… 1
• Direct (Intended) Actions
Anti-inflammatory
Anti-allergy
Anti-immunity
• Permissive Actions
•Lipolytic effects
•Effect on BP
•Effect on bronchial muscles
Actions …2
• Glucocorticoids (e.g., prednisolone) used to
suppress inflammation, allergy and immune
responses.
• Anti-inflammatory therapy is used in many illnesses
(e.g., Rheumatoid Arthritis, Ulcerative Colitis,
Bronchial Asthma, eye and skin inflammations).
-Useful in, say, tissue transplantation and
lymphopoiesis (leukemias and lymphomas).
• Striking improvements can be obtained, but severe
adverse, but highly predictable, effects ensue.
Glucocorticoids (e.g., prednisolone) used to suppress
inflammation, allergy and immune responses.
Anti-inflammatory therapy is used in many illnesses
(e.g., Rheumatoid Arthritis, Ulcerative Colitis,
Bronchial Asthma, eye and skin inflammations).
Actions .. 3
• Hydrocortisone used for: orally for
replacement therapy, i.v. for shock and
asthma, topically for eczema (ointment) and
enemas (ulcerative colitis).
• Triamcinolone: used for severe asthma and for
local joint inflammation (intra-articular inj.).
Triamcinolone: used for severe asthma and
for local joint inflammation (intra-articular
inj.).
Actions .. 4
• Betamethasone and dexamethasone: very
potent, w/o salt-retaining properties; thus,
very useful for high-dose therapies (e.g.,
cerebral edemas).
• Beclometasone, diproprionate, budesonide:
pass membranes poorly; more active when
applied topically (severe eczema for local antiinflammatory effects) than orally; used in
asthma, (aerosol).
•
Beclometasone, diproprionate, budesonide: used in asthma,
(aerosol).
BILE ACIDS ARE CHOLESTEROL
DERIVATIVES
• Emulsify dietary lipids
• Secreted from liver, stored in gall bladder,
passed through bile duct into intestine
• Bile acids represent a major metabolic fate of
cholesterol, accounting for more than half of
the 800 mg/day of cholesterol metabolized
(steroid hormones represent about 50 mg of
cholesterol per day)
• Bile acids are recycled through small intestine
Bile Salts
• Bile salts are synthesized from cholesterol in the liver
- they are stored in the gall bladder and released into the
upper small intestine to help break down fats and oils
(like soaps)
- too much accumulated cholesterol in the gall bladder
can lead to gallstones; if a gallstone passes into the bile
duct, severe pain results and the gallbladder often has to
be removed
cholic acid, a bile acid
O
CH3
OH
CH3
CH3
HO
C
N
CH2
-
H
glycine, an amino acid
OH
sodium glycocholate, a bile salt
+
COO Na
Bile acids
Tauro ~
Gliko ~
H
N
CH2 CH2 SO3H
H
N
CH2 COOH
COOH
HO
Cholesterol
Tauro ~
Glyco ~
HO
OH
H
COOH
Chenodeoxycholic acid
HO
COOH
HO
H
Litocholic acid
HO
H
OH
Cholic acid
HO
COOH
Primary bile
acid
Deoxycholic acid
HO
H
Secondary bile acids
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OTHER ISOPRENOID COMPOUNDS:
• Vitamin A, D, K, E
• Terpenes – generic term for all compounds
biosynthesized from isoprene precursors;
hence all the molecules we have discussed
today are terpenes.
• isoprene, has the molecular formula C5H8
FATE OF CHOLESTEROL
• Cholesterol is used by cells to decrease fluidity
of cell membrane
• Used in steroid hormone biosynthesis
• Used in Vit A D E K biosynthesis
• Cholesterol can also be exported from liver as
bile acids, cholesteryl esters, or biliary
cholesterol
– Cholesteryl esters are transported to other other
tissues to use cholesterol
Androgens
• - male sex hormones
– synthesized in the testes
– responsible for the development of male secondary
sex characteristics
H3 C
H3 C
OH
H
H
H
O
H3 C O
H3 C
H
H
H
HO
Testosterone
Androsterone
H
Negative Health Effects
•
•
•
•
Acne
Irritability and aggression (ROID RAGE)
Elevated cholesterol levels
Adolescent use may cause a premature stop in
lengthening bones (Stunted growth)
• Mood swings (extremes)
Negative Effects, cont.
• Injecting users subject themselves to Hepatitis or
HIV.
• Withdrawal symptoms when one stops using
steroids: mood swings, fatigue, restlessness, loss of
appetite, insomnia, reduced sex drive, and
depression.
• Depression can lead to suicide.
• If untreated, the withdrawal symptoms could last up
to a year after stopping the use.
Bell Ringer
• Answer the following question.
• Why would someone want to take steroids?
Are athletes the only users? Why or why not.
Who Uses Steroids?
• Athletes in sports that rely on size and strength: football,
baseball, and wrestling.
• Endurance athletes: track and swimming.
• Weight training or body building athletes.