1. Student Learning Outcomes:
Chapt. 34/5
Ch. 34/5
Student Learning Outcomes:
Describe how steroid hormones are from cholesterol:
Adrenal corticol hormones include:
Cortisol, aldosterone, adrenal sex steroids
Gonadal hormones include:
Sex steroids testosterone, estrogen
Briefly describe structure/ function of Eicosanoids:
Prostaglandins, thromboxanes, leukotrienes

2. Cholesterol is precursor of steroid hormones
From diet, synthesized in tissues, intracellular pools, LDL
Glucocorticoids – cortisol from adremal gland,
synthesis stimulated by ACTH (adrenocorticotropic hormone)
Mineralocorticoids – aldosterone from adrenal cortex, secreted in response to antiotension II, III, ↑K+ levels, low Na+
Androgens – testosterone from Leydig cells of testes; secreted in response to LH (luteinizing hormone)
Estrogens – from ovarian follicle, corpus luteum; secretion stimulated by FSH (follicle stimulating hormone)
Progestins – progesterone from corpus luteum, secretion stimulated by LH

3. Steroid hormones bind intracellular receptors:
Travel through blood bound to albumin or other proteins
Hydrophobic hormones diffuse across cell membrane
Bind cytoplasmic or
nuclear receptors
to alter transcription
Fig steroid hormones bind intracellular receptors, activate transcription

4. Overview Steroid hormones
Steroid hormone synthesis:
Adrenal cortex, gonads
From cholesterol (diet or synthesis)
4 cytochrome P450 enzymes
Mono-oxygenases transfer e-
from NADPH to O2; oxidize ring
Some enzymes work in
more than one path
3-b-HSD not a P450 enzyme
Fig

5. 10 gene families, 100 isozymes (CYP)
P450 enzymes
Cytochrome P450 enzymes
10 gene families, 100 isozymes (CYP)
Induced by substrates (alcohol, drugs, toxicants)
Mono-oxygenases
Donate single e- to O2
Figs.19.12, 13

6. I. Cholesterol to progesterone:
Steroid hormones I
I. Cholesterol to progesterone:
Mitochondrial inner membrane
Rate-limiting step P450SCC (CYPIIA)
Cleavage of side chain
Forms pregnenolone
Then Smooth ER for other steps
3-b-HSD is not a P450 enzyme
Fig top

7. A. Cortisol synthesized in Adrenal cortex:
Steroid hormones
A. Cortisol synthesized in Adrenal cortex:
ACTH stimulates synthesis and secretion,
G-protein coupled receptor, cAMP, PKA
Middle layer of adrenal cortex – Zona fasciculata
Dietary cholesterol or synthesized; stored as ester
Mitochondrion and ER involved
Fig

8. B. Aldosterone is synthesized in Adrenal cortex:
Steroid hormones
B. Aldosterone is synthesized in Adrenal cortex:
Zona glomerulosa layer of adrenal cortex
Cholesterol to pregesterone, then differ → DOC
Some enzymes same as for cortisol
Octapeptide angiotensin II stimulate synthesis
Also hyperkalemia, low Na+
Stimulates Na+ uptake by kidney, ↑ extracellular fluid
Fig part

9. C. Adrenal androgens are weak androgens:
Sex hormones
C. Adrenal androgens are weak androgens:
Converted to testosterone or estrogens in other tissues
Made in zona reticulosum
DHEA, androstenedione
Most of androgens made by adrenal gland
Figs ,25

10. D. Testosterone, Dihydroxytesterone from testes
LH from anterior pituitary stimulates
synthesis (controls CYPIIA)
Testosterone made in Leydig cells,
path like adrenal
5-a-reductase forms DHT
DHT stimulate production sperm proteins
in Sertoli cells, secondary sex characters

11. E. Estrogens, progestins from ovaries
CytP450 enzymes in all cells; FSH signals
Granulosa cells mostly secrete estrogen
Thecal, stromal cells mostly secrete androgens
Corpus luteum mostly progestins
Estrones more in muscle, adipose

12. XI. Vitamin D: Vitamin D Family of calciferols
Involved with Ca2+ homeostasis
From diet or synthesized in body
Skin needs UV to synthesize cholecalciferol
Liver and kidney finish
Binds nuclear hormone receptor VDR
Activates transcription of genes
Fig
Vitamin D
calcitrol

13. Table 34.5 Lipid-lowering agents
Agent mechanism ↓total cholesterol
Statins inhibit HMG-CoA reductase %
Bile acid resins ↑fecal excretion bile salts %
Niacin activates LPL; reduces %
hepatic production of VLDL;
reduces catabolism of HDL
Fibrates antagonizes PPAR-a, %
causes ↑ in LPL activity,
↓in apo CIII, ↑ in apoA1
Ezetimibe reduces intestinal absorption of %
free cholesterol from gut lumen

14. Treatment of Diabetes II with Metformin:
Sex hormones
Treatment of Diabetes II with Metformin:
Impairs gluconeogenesis (liver is resistant to insulin effects)
Metformin activates LKB1 kinase, activates AMPK → PO4, sequester TORC2 (cofactor of CREB) in cytoplasm so NOT increase gluconeogenic gene expression
AMPK also inhibits liver lipogenesis,
AMPK increases muscle uptake of glucose
Fig

15. Cholesterol is precursor of steroid hormones
Key concepts of chapt. 34
Cholesterol is precursor of steroid hormones
Cholesterol obtained from diet or synthesized
HMG-CoA reductase is rate-limiting
Defects in LDL receptor increase blood cholesterol
Adrenal gland, gonads synthesize steroid hormones
Lipid-lowering agents include statins, bile acid resins, niacin, fibrates, and ezetimibe

16. Eicosanoids: Prostaglandins (PG) Thrombaxanes (TX) Leukotrienes (LT)
Chapter 35
Eicosanoids:
Prostaglandins (PG)
Thrombaxanes (TX)
Leukotrienes (LT)
Every cell, signal activates phospholipase
Potent ‘local hormones’ act nearby
Produced from fatty acids, from
membrane phospholipids
Arachidonic acid is
major precursor, 3 paths
Short half-lives
Fig overview of eicosanoid metabolism

17. Inflammatory response after infection, injury:
Roles of Eicosanoids
Inflammatory response after infection, injury:
Vasodilation increases blood flow in damage area
Control bleeding through clots, activate complement
White blood cells move to injury, make cytokines
Can give symptoms pain, swelling, fever
Inappropriate response is allergy, hypersensitivity
Smooth muscle contraction
Increase water, sodium excretion by kidney
Some constrictors of blood vessels,
Some dilators
Regulate blood pressure
Aspirin inhibits COX enzyme

18. Arachidonic acid precursor
Arachidonic acid is precursor
Polynsaturated C20 fatty acid, from diet or made from essential Linoleate fatty acid
Phospholipases cleave from phospholipid in plasma membrane (C2 position)
Stimuli include histamines, cytokines
Fig. 35.2
Fig

19. II. Pathways of eicosanoids
II. Pathways for eicosanoid synthesis:
A. Cyclo-oxygenase (COX) → PG, TX
B. Lipoxygenase → Leukotrienes
C. Cytochrome P450 → epoxides
Different enzymes in different tissues gives specialization
Fig. 35.3

20. Cyclo-oxygenase pathway
Prostaglandins are large family:
Letter = ring substituents
Numeral subscript = double bonds
PGF also have subscript
Ex. PGA1, PGF2a
Fig PG generic structure: C20 fatty acid;
5-membered ring
Fig numeral is double bonds: 2 is most common
Fig PG structures

21. Cyclo-oxygenase pathway
Thromboxanes
TXA2 from platelets is most common thromboxane:
stimulates platelet aggregation
causes vasoconstriction
Fig TX generic structure: C20 fatty acid, 6-member ring with O
TXA2 has extra O C9-11

22. Formation of prostaglandins and thromboxane
Prostaglandins, thromboxane from Arachidonic:
Mostly the 2 series in normal diet
COX enzyme adds 2 O2 → PGG2
Peroxidase forms PGH2
Tissue-specific next steps
COX-1 constitutive, all tissues
only form in platelets
COX-2 inducible
(inflammation)
COX-2 inhibitors
Provide pain relief
Fig. 8

23. COX inhibitors provide pain relief
COX inhibitors reduce prostaglandin production:
Reduce inflammatory response, provide pain relief
Nonsteroidal anti-inflammatory drugs (NSAIDs):
Aspirin irreversibly inactivates enzyme
acetaminophen, ibuprofen reversible inhibitors
Block both COX-1 and COX-2
Search for selective COX-2:
Less side-effects (GI and
anti-platelet)
Ex. Celebrex, Vioxx
Fig. 9

24. Tables 35.1, 35.2 Functions of prostaglandins, thromboxanes
Functions of prostaglandins, thromboxanes: PGI2, PGE2, PGD2 ↑ vasodilation, cAMP ↓ platelet aggregation, leukocyte aggregation, T-cell proliferation, IL-1 and IL-2, lymphocyte migration PGF2a ↑ vasoconstriction, bronchconstriction, smooth muscle contraction TXA2 ↑ vasoconstriction, platelet aggregation, lymphocyte proliferation, bronchoconstriction Compounds are rapidly inactivated by oxidation

25. Lipoxygenase pathway: leukotrienes
B. Lipoxygenase path brief: leukotrienes (LT)
Adds O2 to form –OOH hydroperoxy (at C 5, 12, 15): 5-HPETE
LT made in leukocytes (triene = 3 C=C)
LTB4 increases:
Vascular permeability
T-cell proliferation
Leukocyte aggretation
INF-g (interferon),
IL-1, IL-2
LTC4, LTD4 increase:
Brochoconstriction
INF-g (interferon)
Fig. 11*

26. Prostaglandin and thromboxane receptors:
Table 35.4
Prostaglandin and thromboxane receptors:
Specific receptors for different hormones
all are G-protein coupled
signal through increase Ca2+ in cytosol
(PGF2a, TXA2, leukotrienes)
signal through adenylate cyclase-cAMP-PKA
(PGE, PGD, PGI series)

27. Key concepts: Key concepts
Eicosanoids (postaglandins, thromboxanes, leukotrienes) are potent regulators of cellular function)
Eicosanoids are derived from polyunsaturated fatty acid (20C)
Eicosanoids are important for inflammatory response, smooth muscle contraction, blood pressure.
PG and T require cyclo-oxygenase (COX)
LT requires lipooxygenase
Eicosanoids bind membrane receptors,
alter PKA or Ca2+ levels

28. Review question: Review question
5. Certain prostaglandins, when binding to their receptor, induce an increase in intracellular calcium levels. The signal that leads to the elevation of intracellular calcium is initiated by which of the following enzyme?
Protein kinase A
Phospholipase C.
Phospholipase A2
Protein kinase C
Cyclo-oxygenase