UNIT I.

BIOMOLECULES, RESPIRATION AND METABOLISM

Free Radicals and Oxidative Stress

Toxicity

1. ___________________ are foreign compounds taken in/found in living systems.

a. Can be acquired through ______________, ______________, ______________, ______________

b. Not all adverse effects are toxic. They are toxic only when:

i. They are ______________.

ii. ______________ is given or absorbed

2. A ______________ is a substance that causes disturbances in organisms via chemical or molecular

means when an organism absorbs a sufficient quantity (______________).

3. ______________: biological in source; something that comes from living organisms; ______________

______________: (abiotic) environmental in source; ______________

4. The risk of adverse outcome = ______________ x ______________

a. Toxicity
______________ physicochemical properties
interactions:

______________

______________

______________

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 b. _________________
Properties/parameters:

______________

______________

______________

______________

______________

c. __________________________

______________ toxicity x exposure

______________, ______________,

______________/______________/______________/______________status

______________

5. Disturbances may impair:

a. ______________ necessary for survival and perpetuation.

energy production, respiration, proliferation, adaptation, regulation

b. ______________ vital to survival

cell membrane, catalytic proteins, genetic code

6. Substances vital to life (water, oxygen, sunlight) may be detrimental when given in _________________
amounts or when the living systems natural defenses or internal homeostasis is disrupted.

7. The smooth ER of the liver cell employs two types of mechanism to deal with xenobiotics: __________
and __________ reactions.

8. Phase I reactions result in small chemical changes that make a compound more _______________, so

it can be effectively eliminated by the ___________.

a. They usually involve either adding or unmasking a _________ group, or some other hydrophilic

group such as an ______________ or ______________ group, and usually involve

______________, ______________ or ______________ mechanisms.

b. _______________________ enzymes are responsible for most Phase I reactions.

9. Phase II reactions usually involve adding a __________________, such as ______________, to further

increase the compounds solubility.

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 a. They take place if Phase I is ______________ to clear a compound from circulation, or if Phase I

generates a ______________ metabolite.

b. __________________ enzymes are responsible for most Phase II reactions.

10. General modes of reducing toxicity upon exposure:

a. _______________ exposure, absorption and distribution.

b. _______________ inactivation or elimination of drug or bodys intrinsic protective mechanisms.

c. Introduce _______________ to countereffect or enhance elimination.

_______________ toxic effects

Faster _______________ and _______________ of toxin

_______________ toxin to neutralize it (convert to a nonharmful substance)

11. There are two main mechanisms of toxicity:

a. Inhibitors of __________________________________

b. ____________________________

Inhibitors of Oxidative Phosphorylation

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1. They decrease __________ yield via site-specific inhibitors:

a. Site I (____________________________)

_____________, _____________, _____________, _____________

b. Site II (____________________________)

_______________

c. Site III (____________________________)

______________, ______________, ______________

2. ______________ oxidation and phosphorylation

a. ______________ (_______), ______________ (_______)

Blocks ______________________________

b. ______________ (_______)

binds to and dissipates _____________

c. _________________

Channels for _____________

dissipates _______________________ gradient

d. _____________, ____________________ (_____)

blocks _______________________

e. _______________ (________)
responsible for neonatal nonshivering __________________ in neonates and hibernating
animals
found in ___________________________

Oxidative Stress

1. Oxidative stress is defined as a condition in which the rate of ______________ of _______ exceeds our

ability to __________ ourselves against them, resulting in an increase in ______________ damage to

biomolecules.

a. It is a characteristic feature of _______________ diseases.

2. Reactive oxygen species (ROS) are derived from:

a. __________

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 b. ___________________ and ___________________

3. Oxygen is a ___________ molecule.

a. It contains _______ unpaired electrons.

b. It is activated by metal ions.

4. Free radicals are highly reactive molecular species with ____________ electron.

a. They initiate ___________________ by extracting an ______ from a neighboring molecule to

complete their own orbitals to produce a ___________________.

Reactive Species Properties

Produced by ______

__________ diffuse far from site of origin

Generates other ROS

Not a free radical, but can generate free radicals by reaction with transition
metals

__________ diffuse into and through cell membranes

The _________ reactive species in attacking biological molecules

Produced from ________ in the Fenton reaction in the presence of

______ or ______
Organic free radicals

Produced from ______, ______, ___________ attack

An organic peroxyl radical

Occurs during _________degradation

Produced from absorption of _______________

______
A free radical produced by ____________________________
Binds to metal ions
Combines with O2 (or other ROS) to form other RNOS

______
A strong oxidizing agent that is not a free radical

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Major Sources of Primary ROS in the Cell

1. ___________________

2. ___________________, ___________________, and ___________________

a. ___________________ and transfer single e- to it via a metal

b. ___________________
Catalyze reactions in which a single e- is transferred to ______ and an ___________________

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3. Ionizing radiation

a. Has _________ energy

b. Can split _________ into ____________ and _____ radicals

Oxygen Radical Reactions with Cellular Components

1. Formation of _______________________________

a. Hydroxy radical extracts ____ atom from double bond of _________ in membrane lipid

b. O2 adds to form _____________________ and _____________________

c. Lipid degradation occurs.

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2. Proteins and peptides

a. ____, ____, ____, ____, ____ = susceptible to hydroxyl radical attack and oxidative damage

b. Protein may __________________

c. Residues may form __________________

3. DNA
a. __________________

b. __________________________ via attack on deoxyribose backbone

Cellular Defense Against Oxygen Toxicity

1. Antioxidant scavenging enzymes:

a. __________________

b. __________________

c. _______________________________ and _______________________________

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2. Nonenzymatic antioxidants
a. Vitamins
Vit E (a-tocopherol): protects against lipid peroxidation
Vit A (b-carotene, retinoids, carotenoids) and similar compounds (lutein, zeaxanthin)
Vit C (ascorbic acid): regenerate reduced Vit E

b. Flavonoids
c. Uric acid
d. Melatonin

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Diseases

1. Myocardial Infarction
Limited blood flow (__________________) due to __________ formed within arteries

Tissue is deprived of __________ and __________

During __________ phase:

o ETC is __________________

During _______________________:

o ETC is suddenly _________________, causing high __________ to be rapidly produced

2. Iron deficiency anemia

Lack of Fe2+ for __________
Reduced amount of Fe2+ for ______ complexes in ______
3. Iron overload
Increased production of ______
Individuals at risk: patients suffering from ________________, ________________

4. Hyperoxia
Patients suffering from ____________ can also experience hyperoxia during their treatment

5. Emphysema
Lung disease
_________________ (________) is an irreversible inhibitor of _________________, a protease that
digests tissues
Excess elastase destroys alveolar walls in the lungs by digesting elastic fibers and other connective-
tissue proteins
Cigarette smoke causes _________________ of a specific ________ residue (________) in A1AT,

a residue important for ________________ of A1AT to elastase.

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Beneficial Effects of ROS

1. ROS are essential for many ________________ and ________________ pathways.

2. ROS activates ______ (________________ _________________ _________________).

ARE-dependent enzymes: _________________, _________________

3. Radiotherapy
Radiation produces a flux of ______________ radicals (from ______) and ______________ radicals
from the site of the tumor.

______________ oxidative stress causes damage to all biomolecules to the tumor cell.

o Tumor ______________ is prevented.

4. Respiratory burst
a. It is caused by the response of the ________________ system (via ________________ cells) to

________________ agents and other stimuli.

b. It rapidly consumes ______ to generate ______, ______, and ______ in order to destroy the
phagocytosed material.

________________ catalyzes formation of superoxide and NADPH

________________ generates ______, which is a powerful oxidant and destroys the contents of
the phagosome.

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