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LAST MEDCHEM OF UR LIFE > 43/44 - Bilirubin & Antioxidants > Flashcards

43/44 - Bilirubin & Antioxidants Flashcards

1
Q

Chain-Breaking Antioxidants

A

act by reacting with PEROXYL RADICALS
ROO*

DONOR Antioxidant
tocopherol (VIT E) // VIT C // Uric Acid
makes a less reactive radical

SACRIFICAL Antioxidant
Nitric Acid
does NOT form a radical –> LOONO / DNIC

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2
Q

How is UROBILIGINOGEN formed?

A

Conjugated Bilirubin
Transported to the INTESTINES
​VVVVVV
Hydrolyzed & Reduced by
BACTERIA in the GUT
​VVVVVV
UROBILIGINOGEN
colorless compound

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3
Q

What happens to the FREE IRON?
from the breakdown of HEME –> Biliverdin + CO
by HO1?

A

Heme + HO1 –> CO + Biliverdin
+ Fe2+

Used for
Ferritin = Storage
Iron-Sulfur Clusters = Electron Transfer
Heme Recycled = Catalytic Activity

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4
Q

Characteristic of a GOOD

CHAIN-BREAKING ANTIOXIDANT

A

BOTH Antioxidant + ATRadical should be generally UNREACTIVE

ATRadical should decay to harmless products

does NOT add O2 to make a peroxyl radical

Recylced/renewed

MIDDLE OF THE PECKING ORDER
of redox potentials

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5
Q

Redox Potentials

A

Higher the Redox Potential = Greater the OXIDANT
FERRIC Iron = Fe3+ is a GOOD OXIDANT
readily accepts electron –> ferrous iron Fe2+

Iron bound to Transferrin or Ferritin
DOES NOT Redox cycle

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6
Q

PREVENTATIVE Antioxidants
that act by Removing Hydroperoxides

A
  • *Glutathione Peroxidases**
  • slow on its own*, but FAST when Coupling Enzyme Reactions + GSH
  • *Acetaminophen toxicity –> glutatione depletion**

Catalase

Pyruvate

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7
Q

2 Classes of Antioxidants

A
  • *PREVENTATIVE**
  • *intercept** oxidizing species before damange is done
  • *Deactivate metals** // Remove Hydroperoxides // Quench O’s

CHAIN BREAKING
slow or stop oxidative processes after they begin
by intercepting the chain-carrying radicals
Vitamin E –> lipid peroxidation
Donor or Sacrificial

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8
Q

Lipid Peroxidation
type of Oxidative Stress

A

RADICAL CHAIN REACTION** + **AUTOOXIDATION

  • *1 Free Radical (OH.)** leads to
  • *many oxidized lipids**

PROPAGATION

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9
Q

Free Hydroxyl leads to:

A

DNA Strand Breaks

BASE Modifications

Protein OXIDATIONS

Lipid PEROXIDATIONS

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10
Q

PREVENTATIVE Antioxidants
that act by Deactivating Metals

A
  • *Biological Chelators**
  • *Transferrin_ & _FERRITIN**

Chemical Chelators
Desferal / Detapac / EDTA

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11
Q

Fenton Reaction

A

OCCURS FAST
Fe2+ + H2O2 -> HO• + OH- + Fe3+

IRON + other metals
Catalyze the formation of the
OH RADICAL:
causes nonspecific oxidation & damage to:
Nucleic Acids / Lipids / proteins

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12
Q

Where do ANTIOXIDANTS lie in the
Pecking Order of REDOX POTENTIALS?
and why?

A

MIDDLE

enough reducing power to react w/ Reactive oxidizing species
but at the same time are:
t_oo WEAK_ to initiate reductive reactions

VITAMIN E & VITAMIN C
E is a better oxidant/higher vs C
Vitamin C can recycle Vit E because it is a better reductant

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13
Q

What is OXIDATIVE STRESS?

A

General term to describe an IMBALANCE in the relative levels of
PROOXIDANTS & ANTIOXIDANTS

in which the levels of
Prooxidants >>> Antioxidants

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14
Q

How and Where is
Bilirubin transported to?

A

Biliverdin 9 + BVR(NADPH) –>
Bilirubin
(water-insoluble / unconjugated)
vvvvv
released from macrophages
​vvvvv
bound tightly to ALBUMIN
​vvvvv
brought to the LIVER

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15
Q

WHY is Bilirubin bound to albumin?

A
  • *INCREASE ITS SOLUBILITY**
  • *UN-conjugated bilirubin** is water-insoluble

Albumin has
2 binding sites for Bilirubin
HIGH & low affinity sites

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16
Q

How does NITRIC OXIDE act as an Antioxidant?

A

Sacrificial antioxidant –> TERMINATES the Chain

Iron sequestration
Fe(2)+NO*—-> DNIC = dinitrosyl iron complexes
less redox active
reacts with the chelatable iron pool = CIP/LIP

  • *LOO*** + NO* –> LOONO = nitrolipid
  • not as reactive*
17
Q

What happens to BILIRUBIN in the LIVER?

A

Hepatic Phase:
Bilirubin is REMOVED from ALBUMIN
VVVVVV
CONJUGATED TWICE
UDPGT w/ 2x UDP-Glucuronic Acid
​VVVVVV
Conjugated Bilirubin Diglucuronide

18
Q

Define
PROOXIDANT

A

any substances that
GENERATE OXIDANTS
or
INHIBIT Anti-oxidant Systems

Excess Prooxidants >> anti-oxidants = OXIDATIVE STRESS

19
Q

Define Antioxidant

A

any molecule that

  • *Delays / prevents / Removes**
  • *oxidative damage to a target molecule**

Ex.
Ferratin / bilirubin

20
Q

Define OXIDANTS

A

molecules that GAIN ELECTRONS in redox chemical rxns
& promote oxidation of target molecules

Biological oxidants RELATIVE to OXIDATIVE STRESS:
ROS & RNS

21
Q

PREVENTATIVE Antioxidants
that act by Quenching Singlet oxygen

A

BILIRUBIN

Beta-Carotene

Lycopene

22
Q

What happens after BILIRUBIN CONJUGATION?

A

Conjugated Bilirubin (diglucuronide)
INCREASED Solubility + decreased toxicity
​VVVVVV
ACTIVELY TRANSPORTED
against a concentration gradient
​VVVVVV
BILE DUCT
​VVVVVV
INTESTINES

23
Q

What does this enzyme do?
HEME OXYGENASE 1
HO1

A

Catalyzes

  • *HEME** —-> BILIVERDIN IX + ( CO & Fe2+ )
  • —-> bilirubin*
24
Q

Vitamin C and COLDS

A
  • *LARGE DOSE ONCE –> NOT EFFECTIVE**
  • but*
  • *constant doses** can _shorten the duration of cold_

there is a
Maximum oral dose of VITAMIN C –>
we can only have a higher plasma concentration from IV INJECTION

25
Q

How does BILIRUBIN cause toxicity?

A

displaced Bilirubin (by drugs, disease) / unconjugated bilirubin (UCB)

causes MITO DYSFUNCTION:
diminished activitiy of Complex 5
–> releasing Cytochrome C
–> activated caspase-9
= TRIGGER the initiation of APOPTOSIS

ROS + RNS
reactive oxygen/nitrogen species

26
Q

What DRUGS affect BILIRUBIN?
& HOW?

A

SULFANAMIDES** // **ABx** // **Salicylates

COMPETE with bilirubin for ALBUMIN BINDING

these drugs with displace bilirubin –> allowing it to enter the brain in neonates

–> increased risk of kernicterus

27
Q

What is the problem with FREE IRON?

A
  • *OXIDATIVE STRESS**
  • *Fenton Rxn + Haber-Weiss Rxn** –> Hydroxyl radicals

TOO REACTIVE to be useful in enzyme, protein itself suffers damage from redox rxns

Only Fe // Cu // Mo should be used for redox reactions​
and there are naturally only a LITTLE of them
so….
Excess –> TOO REACTIVE when not bound

28
Q

How does FERRITIN / TRANSFERRIN act like an

ANTIOXIDANT?

A

Iron bound to Ferritin / Transferrin has a very low Redox Potential
which PREVENTS the

HABER-WEISS REACTION

29
Q

What does this enzyme do?
Biliverdin Reductase
BVR

A
  • Heme + HO1 –>*
  • *BILIVERDIN_ —> _BILIRUBIN**

BVR = NADPH-dependent

30
Q

How is STERCOBILIN formed?

A

Urobilinogen in GUT (from bacteria)
​VVVVVV
Oxidized
by intestinal bacteria
​VVVVVV
STERCOBILIN
BROWN in STOOLS

31
Q
  • *What is the RATE LIMITING STEP of**
  • *Hepatic Bilirubin Metabolism?**
A

Conjugated Bilirubin formed in LIVER —> BILE DUCT

This is an ENERGY-DEPENDENT STEP
requires Active Transport across a concentration gradient by:

MRP2 or MOAT
multidrug resistance-protein 2 // multispecific organic anion transporter

32
Q

Haer-Weiss Reaction

A

•O2- + H2O2 → •OH + HO- + O2
Occurs SLOWLY
but in the presence of METALS = CATALYTIC
Fenton + H-W = Fast reaction

generates a HYDROXYL RADICAL –> OXIDATIVE STRES

33
Q

Vitamin C & E as CO-ANTIOXIDANTS

A

Vit C = Ascorbate can help recycle
TO Radicalback toTOH(Vit E)
since it is more reducing / less oxidizing

Vitamin C = Water Soluble

Vitamin E = Lipid Soluble

34
Q

How is UROBILIN formed?

A

UROBILINOGEN
in the gut, formed by bacteria
​VVVVVV
some of it is REABSORBED
into the portal blood
​VVVVVV
KIDNEY
​VVVVVV
YELLOW UROBILIN

35
Q

HOW is Bilirubin CONJUGATED?

A

in the LIVER, after removing it from ALBUMIN
UDPGT
conjugates on 2x UDP-Glucoronic Acid
​VVVVVV
Conjugated Bilirubin
(water-soluble & POLAR, +diglucuronide)

36
Q
  • *How do we solve / fix** this CHAIN REACTION from the
  • *lipid peroxidation**?
A

TERMINATION
by
VITAMIN E
(lipid-soluble)

Vitamin E = antioxidant that will produce a NON-Radical Product

  • -> alkylperoxide
  • *stopping the chain reaction**
37
Q

HOW is Conjugated Bilirubin removed from the KIDNEYS?

A
  • *MRP2_ or _MOAT**
  • *active transport,** also rate-limiting step

Hepatocytes –> Canaliculi –> BILE DUCT

LAST MEDCHEM OF UR LIFE (11 decks)

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