43/44 - Bilirubin & Antioxidants Flashcards by Karlo Sison

Chain-Breaking Antioxidants

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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How is UROBILIGINOGEN formed?

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

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

Heme + HO1 –> CO + Biliverdin
+ Fe2+

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

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Characteristic of a GOOD

CHAIN-BREAKING ANTIOXIDANT

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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Redox Potentials

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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PREVENTATIVE Antioxidants
that act by Removing Hydroperoxides

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

Catalase

Pyruvate

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2 Classes of Antioxidants

*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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Lipid Peroxidation
type of Oxidative Stress

RADICAL CHAIN REACTION** + **AUTOOXIDATION

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

PROPAGATION

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Free Hydroxyl leads to:

DNA Strand Breaks

BASE Modifications

Protein OXIDATIONS

Lipid PEROXIDATIONS

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PREVENTATIVE Antioxidants
that act by Deactivating Metals

*Biological Chelators**
*Transferrin_ & _FERRITIN**

Chemical Chelators
Desferal / Detapac / EDTA

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Fenton Reaction

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

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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What is OXIDATIVE STRESS?

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

in which the levels of
Prooxidants >>> Antioxidants

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How and Where is
Bilirubin transported to?

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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WHY is Bilirubin bound to albumin?

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

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

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How does NITRIC OXIDE act as an Antioxidant?

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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*

What happens to BILIRUBIN in the LIVER?

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

Define
PROOXIDANT

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any substances that
GENERATE OXIDANTS
or
INHIBIT Anti-oxidant Systems

Excess Prooxidants >> anti-oxidants = OXIDATIVE STRESS

Define Antioxidant

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any molecule that

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

Ex.
Ferratin / bilirubin

Define OXIDANTS

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

Biological oxidants RELATIVE to OXIDATIVE STRESS:
ROS & RNS

PREVENTATIVE Antioxidants
that act by Quenching Singlet oxygen

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BILIRUBIN

Beta-Carotene

Lycopene

What happens after BILIRUBIN CONJUGATION?

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

What does this enzyme do?
HEME OXYGENASE 1
HO1

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Catalyzes

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

Vitamin C and COLDS

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*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

**How does BILIRUBIN cause toxicity?**

_**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

**What DRUGS affect BILIRUBIN?** & **HOW?**

**_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**

What is the **problem** with **FREE IRON?**

* *_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**

**How does FERRITIN / TRANSFERRIN** act like an ## Footnote **ANTIOXIDANT?**

**Iron** bound to **Ferritin / Transferrin** has a ***_very low Redox Potential_*** which ***_PREVENTS_*** the ## Footnote **_HABER-WEISS REACTION_**

**What does this enzyme do? Biliverdin Reductase BVR**

* Heme + HO1 --\>* * *_BILIVERDIN**_ ---\> _**BILIRUBIN_** ## Footnote **BVR = NADPH-dependent**

How is **STERCOBILIN formed?**

**_Urobilinogen_** in GUT (from bacteria) VVVVVV **Oxidized** by **_intestinal bacteria_** VVVVVV **_STERCOBILIN_** **BROWN** in STOOLS

* *What is the RATE LIMITING STEP of** * *_Hepatic Bilirubin Metabolism_?**

**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

**Haer-Weiss Reaction**

**•O₂^-** + H₂O₂ → **•OH** + HO^- + O₂ Occurs ***_SLOWLY_*** *but in the presence of* **METALS** = **CATALYTIC** **Fenton + H-W** = **Fast reaction** ## Footnote generates a **_HYDROXYL RADICAL_** --\> **OXIDATIVE STRES**

**Vitamin C & E as CO-ANTIOXIDANTS**

**Vit C = Ascorbate** can help **recycle TO Radical**back to**TOH**(**Vit E)** since it is **more reducing** / **less oxidizing** ## Footnote **Vitamin C = Water Soluble** **Vitamin E = Lipid Soluble**

How is **UROBILIN** formed?

**_UROBILINOGEN_** in the gut, formed by bacteria VVVVVV *some of it is* **_REABSORBED_** into the **portal blood** VVVVVV **_KIDNEY_** VVVVVV **_YELLOW UROBILIN_**

**HOW is Bilirubin CONJUGATED?**

_in the **LIVER**_, *after removing it from _ALBUMIN_* **_UDPGT_** conjugates on **2x UDP-Glucoronic Acid** VVVVVV **_Conjugated Bilirubin_** (**water-soluble & POLAR**, +diglucuronide)

* *How do we solve / fix** this **CHAIN REACTION** from the * *lipid peroxidation**?

**_TERMINATION_** by **VITAMIN E** (**lipid-soluble)** Vitamin E = **antioxidant** that will produce a **NON-Radical Product** - -\> **alkylperoxide** * *_stopping the chain reaction_**

**HOW is Conjugated Bilirubin removed from the KIDNEYS?**

* *_MRP2**_ or _**MOAT_** * *active transport,** also **rate-limiting step** ## Footnote **Hepatocytes --\> Canaliculi --\> _BILE DUCT_**

43/44 - Bilirubin & Antioxidants Flashcards

(37 cards)