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House Pharmacology > Eicosanoid, nitric oxide and inflammatory reactions > Flashcards

Eicosanoid, nitric oxide and inflammatory reactions Flashcards

1
Q

Prostaglandins & related compounds:

“local hormones” synthesized from the _________________.

They have specific effects on target cells close to their site of formation.
They are (slowly or rapidly?) degraded, so they are _________________

A

polyunsaturated fatty acid arachidonate

Rapidly

not transported to distal sites within the body.

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2
Q

Prostaglandins & related compounds

Examples: list 5

A

prostaglandins, prostacyclins, thromboxanes, leukotrienes, epoxyeicosatrienoic acids (EETs).

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3
Q

Prostaglandins & related compounds:

Has Roles in _________, _________, regulation of __________ , blood ________, ____________ modulation, control of reproductive processes & tissue growth, ___________ cycle regulation.

A

inflammation

fever

blood pressure

clotting

immune system

sleep/wake cycle regulation.

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4
Q

Prostaglandins & related compounds are collectively known as ____________.

They are produced from ___________, a ___-C poly- unsaturated fatty acid

A

eicosanoids

arachidonic acid

20

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5
Q

20-C poly- unsaturated fatty acid

=

__,____,____,____,- ___________ acid).

A

5,8,11,14

eicosatetraenoic

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6
Q

PGE2 (_________________)

is an example of a prostaglandin.

A

prostaglandin E2

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7
Q

Prostaglandins

•all have a ________ ring.

A letter code is based on __________ (e.g., ______ or _____ groups).

A subscript refers to the ___________________

A

cyclopentane

ring modifications; hydroxyl or keto

number of double bonds in the two side-chains.

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8
Q

Thromboxanes are similar to Prostaglandins but have instead a _________________ ring.

A

6-member

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9
Q

Prostaglandins & related compounds are transported out of the cells that synthesize them.

Most affect other cells by interacting with plasma membrane _____________________.
Depending on the cell type, the activated _________ may stimulate or inhibit formation of ______, or may activate a _________ signal pathway leading to intracellular __________

A

G-protein coupled receptors

G-protein; cAMP; phosphatidylinositol

Ca++ release.

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10
Q

Prostaglandins & related compounds

Another prostaglandin receptor, designated ______, is related to a family of ______ receptors with transcription factor activity.

A

PPARg

nuclear

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11
Q

Prostaglandin receptors are specified by the same letter code. E.g.:

Receptors for E-class prostaglandins are ______.

Thromboxane receptors are designated _____.

A

EP

TP

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12
Q

Multiple receptors for a prostaglandin are specified by subscripts (E.g., _____,______,_____ , etc.).

A

EP1, EP2, EP3

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13
Q

Different receptors for a particular prostaglandin may activate different signal cascades.

T/F

A

T

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14
Q

The fatty acid arachidonate is often ______ to ____ on C2 of ________- lipids, especially _______________

A

esterified

OH

glycerophospho

phosphatidyl inositol.

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15
Q

Arachidonate is released from _______ by _______ catalyzed by _______________

A

phospholipids; hydrolysis

Phospholipase A2.

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16
Q

Phospholipase A2.

This enzyme hydrolyzes the ______ linkage between a ________ and the ____________ of the ______ backbone, releasing the ___________ & a _________ as products.

A

ester; fatty acid

OH at C2

glycerol

fatty acid; lysophospholipid

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17
Q

Corticosteroids are anti-inflammatory because they prevent inducible ________ expression, reducing _________ release.

A

Phospholipase A2

arachidonate

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18
Q

There are multiple Phospholipase A2 enzymes, subject to activation via different signal cascades.

The inflammatory signal , ___________ is involved in activating some Phospholipase A2 variants.

A

platelet activating factor

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19
Q

Attempts have been made to develop drugs that ________________________, for treating inflammatory diseases.

Success has been limited by the __________________, and the fact that arachidonate may give rise to _________ or _____________ eicosanoids in different tissues.

A

inhibit particular isoforms of Phospholipase A2

diversity of Phospholipase A2 enzymes

inflammatory or anti-inflammatory

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20
Q

Phosphatidyl inositol signal cascades may lead to release of __________.

A

arachidonate

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21
Q

After Phosphatidyl inositol is phosphorylated to ________, cleavage via ___________ yields __________ and _________

A

PIP2; Phospholipase C

diacylglycerol (and IP3).

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22
Q

Arachidonate release from diacylglycerol is then catalyzed by ___________

A

Diacylglycerol Lipase.

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23
Q

______ major pathways of eicosanoid metabolism.

A

Two

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24
Q

Cyclic pathway:

•_____________ catalyzes the committed step in the “cyclic pathway” that leads to production of ________,_______, and _____________.

Different cell types convert PGH2 to different compounds.

A

Prostaglandin H2 Synthase

prostaglandins, prostacyclins, & thromboxanes

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25
Q

PGH2 Synthase is a _____-containing _______, bound to _____ membranes.

A

heme

dioxygenase

ER

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26
Q

A dioxygenase incorporates ____ into a substrate

A

O2

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27
Q

PGH2 Synthase exhibits 2 activities:

_____________ and ___________

A

cyclooxygenase &peroxidase.

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28
Q

PGH2 Synthase is sometimes referred to as ____________, abbreviated ______.

A

Cyclooxygenase

COX

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29
Q

The interacting cyclooxygenase and peroxidase reaction pathways are complex.

T/F

A

T

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30
Q

A peroxide job is to _______ the _______

The product (________) accepts an electron from a nearby _____________

The resulting ____________ is proposed to extract a ___ atom from _______, generating a radical species that reacts with _____.

A

oxidizes; heme iron.

oxidized heme; tyrosine residue (Tyr385).

tyrosine radical ; H; arachidonate

O2

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31
Q

The signal molecule ·NO (nitric oxide) may initiate prostaglandin synthesis by reacting with ___________ to produce ____________, which —————— enabling electron transfer from the active site ________.

A

superoxide anion (O2·)

peroxynitrite

oxidizes the heme iron

tyrosine

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32
Q

Prostaglandin synthesis in response to some inflammatory stimuli is diminished by inhibitors of Nitric Oxide Synthase.

T/F

A

T

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33
Q

Membrane- binding domain:

____ (short or long?) ________ -______ that insert into one leaflet of the bilayer, facing the ____________.

A

4 short amphipathic -helices

ER lumen

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34
Q

Arachidonate, derived from membrane lipids, approaches the heme via a _______ channel extending from the ____________

In the image above, the channel is occupied by an inhibitor, an ibuprofen analog.

A

hydrophobic

membrane-binding domain.

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35
Q

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ______ and derivatives of _________, inhibit _______ activity of ________

A

aspirin

ibuprofen

cyclooxygenase

PGH2 Synthase.

36
Q

Non-steroidal anti-inflammatory drugs (NSAIDs)

They inhibit formation of prostaglandins involved in ______,_______, and ———-

They inhibit blood clotting by blocking _________ formation in blood platelets.

A

fever, pain, & inflammation.

thromboxane

37
Q

Non-steroidal anti-inflammatory drugs (NSAIDs)

Ibuprofen and related compounds block the ______________ by which _________ enters the cyclooxygenase active site.

A

hydrophobic channel

arachidonate

38
Q

Aspirin ________ a ________ group near the active site, preventing arachidonate binding.

The inhibition by aspirin is (reversible or irreversible?) .

However, in most body cells _________________ would restore cyclooxygenase activity.

A

acetylates

serine hydroxyl

irreversible

re-synthesis of PGH2 Synthase

39
Q

Many people take a daily aspirin for its _________ effect, attributed to inhibition of __________ in blood platelets.

A

anti-clotting

thromboxane formation

40
Q

Thromboxane A2 stimulates blood platelet _________, essential to the role of platelets in ___________

A

aggregation; blood clotting.

41
Q

This effect of aspirin is (short or long?) -lived because ______________________________________________.

A

Long

platelets lack a nucleus and do not make new enzyme

42
Q

Two isoforms of PGH2 Synthase are ______ and ______ (_________________________)

A

COX-1 & COX-2 (Cyclooxygenase 1 & 2)

43
Q

Two isoforms of PGH2 Synthase are COX-1 & COX-2

COX-1 is constitutively expressed at (low or high?) levels in many cell types.

COX-2 expression is stimulated by _____,________, and ________

A

Low

growth factors, cytokines, and endotoxins.

44
Q

COX-1 is essential for ________ formation in blood platelets, and for maintaining ——— of the gastrointestinal epithelium.

A

thromboxane

integrity

45
Q

COX-2 levels _____ease in inflammatory diseases such as arthritis. Inflammation is associated with ___-regulation of COX-2 & ____eased amounts of particular prostaglandins.

A

incr

up

incr

46
Q

COX-2 expression is increased in some cancer cells.

_________, which is essential to tumor growth, requires COX-2.

Overexpression of COX-2 leads to increased expression of _____

Regular use of NSAIDs has been shown to decrease the risk of developing ______ cancer.

A

Angiogenesis

VEGF

colorectal

47
Q

Most NSAIDs inhibit both COX I & COX II.

T/F

A

T

48
Q

Selective COX-2 inhibitors have been developed,
e.g., _______ and ______

A

Celebrex and Vioxx.

49
Q

COX-2 inhibitors are anti-inflammatory & block pain, but are (more or less?) likely to cause gastric toxicity associated with chronic use of NSAIDs that block COX-1.

A

Less

50
Q

A tendency to develop blood clots when taking some of these drugs has been attributed to:

•decreased production of an anti-thrombotic (clot blocking) prostaglandin (________) by endothelial cells lining small blood vessels

•lack of inhibition of COX-__-mediated formation of _________________________________ in platelets.

A

PGI2

1

pro-thrombotic thromboxanes

51
Q

Some evidence suggests the existence of a third isoform of PGH2 Synthase, designated COX-3, with roles in _____________________, and subject to inhibition by ___________________

A

mediating pain and fever

acetaminophen (Tylenol).

52
Q

Acetaminophen has (little or major?) effect on COX-1 or COX-2, and thus lacks _________ activity.

A

Little ; anti-inflammatory

53
Q

The 1st step of the Linear Pathway for synthesis of leukotrienes is catalyzed by __________.

A

Lipoxygenase

54
Q

Mammals have a family of Lipoxygenase enzymes that catalyze _______________________________________________ at different sites.

Many of the products have signal roles.

A

oxygenation of various polyunsaturated fatty acid

55
Q

5-Lipoxygenase, found in __________, catalyzes conversion of _________ to __________ , which is converted to _______________, which in turn may be converted to various other leukotrienes.

A

leukocytes

arachidonate to 5-HPETE

leukotriene-A4

56
Q

5-HPETE

=

???

A

5-hydroperoxy- eicosatetraenoic acid

57
Q

A ___________ is the prosthetic group of Lipoxygenase enzymes.

A

non-heme iron

58
Q

Lipoxygenase enzymes

Ligands to the Fe include 3 _____ atoms & the _______________.

The arachidonate substrate binds in a _________ pocket, adjacent to the ________________

O2 is thought to approach from the ___________ of the substrate than the iron, for a ________ reaction.

A

His N

C-terminal carboxylate O

hydrophobic ; catalytic iron atom.

opposite side ; stereospecific

59
Q

Lipoxygenase reaction starts with extraction of ____ from ________, with transfer of the electron to the iron, reducing it from ______ to ______

The resulting fatty acid radical reacts with ______ to form a __________ group.

A

H; arachidonate

Fe3+  Fe2+.

O2; hydroperoxy

60
Q

Leukotrienes have roles in inflammation and induce asthmatic _______________________

Some leukotrienes act via specific G-protein coupled receptors (GPCRs) in the plasma membrane.

A

constriction of the bronchioles.

61
Q

Anti-asthma medications include:

inhibitors of 5-Lipoxygenase, e.g., _______(____________)

drugs that block leukotriene-receptor interactions.
E.g., ____________(_______) , _______(________)

A

Zyflo (zileuton)

Singulair (montelukast) & Accolate (zafirlukast)

62
Q

Anti-asthma medications include:

_____________________, e.g., Zyflo (zileuton)

drugs that ______________________
E.g., Singulair (montelukast) & Accolate (zafirlukast)

A

inhibitors of 5-Lipoxygenase

block leukotriene-receptor interactions.

63
Q

5-Lipoxygenase requires the membrane protein ________ (______________).

This membrane protein binds _________, facilitating its interaction with the enzyme.

A

FLAP

5-lipoxygenase-activating protein

arachidonate

64
Q

A complex including ____________, FLAP, & ______________ forms in association with the ______________ during leukotriene synthesis in leukocytes.

A

5-Lipoxygenase

Phospholipase A2

nuclear envelope

65
Q

A beta- barrel domain at the ____-terminus of _________ enzymes has a role in membrane binding.

A

N

Lipoxygenase

66
Q

Cytochrome P450 epoxygenase pathways:

_______________(EETs) and _____________ acids are formed from arachidonate by enzymes of the ___________ family.

A

Epoxyeicosatrienoic acids

hydroxyeicosatrienoic

cytochrome P450

67
Q

EETs are modified by additional enzyme-catalyzed reactions to produce many distinct compounds.
T/F

A

T

68
Q

EETs

They may be incorporated into ________, and released by action of __________.

A

phospholipids; phospholipases

69
Q

EETs have roles in regulating cellular ________, _________ , ________ secretion, & various signal pathways relevant to cardiovascular and renal functions.

A

proliferation

inflammation

peptide hormone

70
Q

Eicosanoids

(Localized or Generalized ?)

(short or long?) -lived hormone-like activities

Duration =_______

Very (low or high?) cellular concentrations

Action initiated by signal transduction
Like hormones

A

Localized

Short ; a few seconds

Low

71
Q

Prostaglandin synthase = _____

Has _______ and ———- activity

Forms ____-membered cyclic structure

A

COX

Oxygenase and peroxidase

five

72
Q

PG____ and PG____: in sleep center in brain

PG___: promotes sleep
PG_____: induces wakefulness

A

E2; D2

D2

E2

73
Q

Painkillers

Nonsteroidal anti-inflammatory drug = NSAID

Inhibition of ______ and ______

Acetaminophen: inhibits ____

Side effects: _____ problems

A

COX-1 and COX-2

COX-3

gastric

74
Q

COX inhibitors

More selective for COX-____, not on COX-____

Rheumatoid arthritis, osteoarthritis, and acute pain
May increase risk of ———- and ____

A

2; 1

heart attack and stroke

75
Q

Leukotrienes

Cause ______ of smooth muscle

Especially in ______

A

contraction

lungs

76
Q

Leukotrienes

Asthma attack and allergic reaction
May be caused by ______________

A

overproduction of leukotriene

77
Q

What is Nitric Oxide?

First described in 1979 as a potent _______ of peripheral vascular smooth muscle.

Used by the body as a _________

Serves different functions depending on body system. i.e. ________,______,______

A

relaxant

signaling molecule.

neurotransmitter, vasodilator, bactericide.

78
Q

First gas known to act as a biological messenger is???

A

Nitric Oxide

79
Q

Nitric Oxide is an Environmental Pollutant

T/F

A

T

80
Q

Nitric oxide is (Short or Long?) lived, usually degraded or reacted within ____________

A

Short

a few seconds

81
Q

The natural form of nitric oxide is a _____

A

gas

82
Q

This reaction is catalyzed by ____________, a 1,294 aa enzyme

A

nitric oxide synthase

83
Q

Activation of NOS

Glutamate neurotransmitter binds to ______ receptors

_______ channels open causing ________ into cell

Activation of _________, which activates NOS

Mechanism for start of synthesis dependent on body system
NO synthesis takes place in endothelial cells, lung cells, and neuronal cells

A

NMDA

Ca++; Ca influx

calmodulin

84
Q

Types of NOS

NOS I
Central and peripheral neuronal cells

Ca+2 (dependent or independent?) , used for __________

NOS II
Most ______ cells, particularly ________

(dependent or independent?) of intracellular Ca+2

Inducible in presence of inflammatory cytokines

A

dependent ; neuronal communication

nucleated; macrophages

independent

85
Q

Types of NOS

NOS III
Vascular endothelial cells
Ca+2 (dependent or independent ?) Vascular regulation

A

dependent

86
Q

What is the role of Nitric Oxide in the human body?

Nitric Oxide in the human body has many uses which are best summarized under five categories.

NO in the ___________ system
NO in the ___________ system
NO in the ___________ system
NO in the ___________ system
NO in the ___________ system

A

NO in the nervous system
NO in the circulatory system
NO in the muscular system
NO in the immune system
NO in the digestive system

House Pharmacology (50 decks)

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