Lecture 12 Flashcards

1
Q

What is biotransformation?

A

It is a protective mechanism of the body to remove potentially harmful substances

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2
Q

Disadvantage of biotransformation

A

It chemically modifys xenobiotic substances causes it to loose its pharmacological potency and biological function

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3
Q

Phases of biotransformation reactions:

A

Phase 1 and Phase 2

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4
Q

Phase 1 is biotransformation reactions:

A

Includes oxidation, reduction, alkylation and hydrolytic cleavage

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5
Q

Phase 2 of biotransformation reactions:

A

Includes conjugation reactions with Glucoronic acid, sulfuric acid or peptides

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6
Q

What are xenobiotics?

A

They are potentially harmful substances foreign to a living organism
-At high concentrations and it may interfere with cellular functioning

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7
Q

How can xenobiotics be removed?

A
  1. Direct excretion of the parent substances
    Or
  2. Metabolic bio transformation
    -Phase 1 or Phase 2
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8
Q

Examples of fat soluble toxins:

A

-Drugs
-Food additives
-Pollutant
-Contaminant
-Metabolites
-Alcohol
-Bacterial products

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9
Q

What does biotransformation do to fat soluble toxins?

A

It turns it into water-soluble, polar substances so they are easy to eliminate

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10
Q

Where are biotransformed waste products be removed from?

A

Through the stool or urine

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11
Q

Biotransformation causes what changes in xenobiotics?

A

-Disappearance of original foreign substance
-Loss of biological activity
-Metabolites are usually less toxic
-Polar metabolites are excreted faster

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12
Q

How does phase 1 biotransformation happen?

A

-It is a bioinactivation process (sometimes bio activation)
-The xenobiotics is altered by the introduction of polar groups (hydroxyl, carboxyl and amino)
-This alteration is caused by either oxidation, reduction or hydrolysis

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13
Q

Phase 1 takes place under the influence of what system?

A

The mixed-function oxidase (MFO) system

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14
Q

Mixed-function oxidase (MFO) system:

A

-Consists of the super family CYP450 proteins
-These are drug induced cytochrome (CY) heme proteins found in the smooth ER

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15
Q

Function of CYP450 proteins?

A

-They are critical for drug metabolism
-They work by catalyzing the oxidation of substrates

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16
Q

What is Glutathione?

A

-It is an important component involved in phase 2 biotransformation
-It is a tripeptide with a gamma peptide linkage between the carbonyl group
Of the glutamate side chain and the amine group of cysteine

17
Q

Chemical name of glutathione?

A

Gamma-glutamyl-cysteinyl-glycine TRI-peptide (GSH)

18
Q

Where is glutathione found?

A

It can be found in high concentrations in liver cells

19
Q

What is the major site of biotransformation

A

Liver cells

20
Q

Function of Glutathione transferase (GST) ?

A

It is an enzyme that catalyzes reactions where sulphydryl group (-SH) of GSH acts as a nucleophile binding to electrophiles

21
Q

What are GSH conjugated?

A

-Formed by phase 2 biotransformation reactions
-The conjugates are excreted into bile
-They may be further metabolized to form mercapturic acid derivatives

22
Q

Biotransformation of the xenobiotic Benzene:

A

It undergoes both phase 1 and phase 2 biotransformation

23
Q

Phase 1 biotransformation of Benzene:

A

-In the Mixed-function oxidase it becomes epoxide and then phenol

24
Q

Phase 2 biotransformation of Benzene:

A

The phenol is converted to phenyl glucuronide by the enzyme glucuronyl transferase

25
What are reactive intermediates
They are formed during metabolism of xenobiotics -Can potentially lead to necrosis or cancer
26
Examples of reactive intermediates formed by MFO and what they cause:
-Bromobenzene leads to liver necrosis -Carbon tetrachloride leads to liver necrosis -Vinyl chloride leads to liver cancer
27
What are Aflatoxins?
- group of mycotoxins produced as secondary metabolites by the fungus Aspergillus -Can contaminate human food and animal feed
28
Function of Aflatoxin B1?
When it is metabolized by p450 monopxygenase system in the liver it produces a reactive epoxide named Aflatoxin 8,9-epoxide
29
Aflatoxin 8,9 epoxide:
-It can form DNA adducts such as Aflatoxin-Guanine which can induce mutations and liver cancer
30
Are aflatoxins safe?
No. Large doses can lead to acute poisoning called aflatoxicosis which can cause liver failure, jaundice, lethargy, nausea and death. They also destroy crops
31
What was the first known cause of human bladder cancer?
Exposure to arylamines in industrial settings
32
Where else can arylamines be found?
Cigarette smoke and hair sprays
33
Key enzymes involved in biotransformation
-MFO (Cytochrome P450-dependent) -UGT (UDP-glucuronosyl transferase -NAT (N-acetyltransferase
34
Toxic reactive intermediate:
-Hapten formation -Direct cytotoxic effect -DNA adduct
35
Hapten formation leads to?
Antibody production which can cause cellular damage
36
Direct cytotoxic effect leads to?
Cellular injury which leads to necrosis
37
DNA adduct leads to?
Mutation which cause cancer