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BI316 > Lecture 12 > Flashcards

Lecture 12 Flashcards

1
Q

What is biotransformation?

A

A protective mechanism of the body to promote the efficient removal of potentially harmful substances.

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2
Q

What is Xenobiotic?

A

Potentially harmful foreign substance that at high concentration may interfere with cellular function

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3
Q

What are the ways to eliminate xenobiotics?

A
  1. Through direct excretion of the parent substance.
  2. Through metabolic biotransformation.
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4
Q

How many phases of metabolic biotransformation are there?

A

2 phases
Phase I transformation reaction
Phase II transformation reaction

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5
Q

Phase I transformation reaction
Two processes

A
  • Bioinactivation process
  • Bioactivation process
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6
Q

What does increased water solubility of xenobiotics following phase I reactions result in?

A
  • Disappearance of original foreign substance
  • Loss of biological activity
  • Metabolites are usually less toxic
  • Polar metabolites are excreted faster
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7
Q

What is the bioinactivation process?

A

Chemically modified xenobiotic becomes more soluble in a watery environment which leads to swift and efficient elimination from the body.

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8
Q

What is the bioactivation process?

A

Some phase I reactions yield a metabolite with higher intrinsic toxicity than the parent substance, which leads to potential toxic insult by reactive metabolite.

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9
Q

What happens during phase I biotransformation?

A
  • Conversion of lipophilic substances into more polar ones
  • The foreign molecule is altered by the introduction of polar groups such as hydroxyl (OH), carboxyl (COOH), amino (NH2)
    - These changes may be due to
    - Oxidation
    - Reduction
    - Hydrolysis
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10
Q

What determines which type of reaction a xenobiotic will undergo?

A

Its chemical structure determines the reaction

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11
Q

What does phase I reaction take place under?

A

Phase I reactions take place under the influence of the Mixed Function Oxidase

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12
Q

What do phase I reactions take place under?

A

Phase I reactions take place under the influence of the Mixed Function Oxidase.

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13
Q

What is Mixed Function Oxidase (MFO)?

A
  • It consists of several proteins which can catalyze the oxidation of a significant number of substances
  • Over 50 genes encoding the superfamily CYP450 proteins
  • Drug-induced Cytochrome P-450 heme proteins present in the smooth ER
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14
Q

Which protein families are critical for drug metabolism?

A

CYP1, CYP2 and CYP3

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15
Q

What component is essential in Phase II biotransformation, and what is it?

A

Glutatione (GSH)
- it is an unusual tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and the amine group of the cysteine.

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16
Q

Where is there a high concentration of glutathione?

A

High concentration in the liver cells, which is the primary site of biotransformation.

17
Q

What is enzyme glutathione transferase (GST)?

A

GST catalyses reactions where the sulphydryl group (SH) of GSH acts as a nucleophile binding to electrophiles.

18
Q

GSH conjugates are excreted to where?
What happens when they are further metabolized?

A
  • GSH conjugates are excreted into bile
  • GSH conjugates may be further metabolized, forming mercapturic acid derivatives.
19
Q

What are some examples of reactive metabolite formation mediated by MFO?

A
  • Bromobenzene
  • Carbon tetrachloride
  • Vinyl chloride
    (look at lecture slide 14)
20
Q

What are aflatoxins?

A

Aflatoxins are a group of mycotoxins produced as secondary metabolites by the fungus Aspergillus and may contaminate human food or animal feed. They are a serious threat to humans and livestock.

21
Q

Metabolization of Aflatoxin B1 by P450 monooxygenase system produces what?

A

Metabolization of Aflatoxin B1 by P450 monooxygenase system in the liver produces a reactive epoxide called Aflatoxin 8,9 epoxide.

22
Q

What can Aflatoxin-epoxide form?

A

Aflatoxin-epoxide can form DNA adducts (Aflatoxin-Guanine) that induce mutations and liver cancer.

23
Q

What is Aflatoxicosis?

A

Large doses of Aflatoxins lead to acute poisoning (Aflatoxicosis) that can be life-threatening, usually through damage to the liver.

24
Q

Arylamines

A
  • Occupational exposure to arylamines in industrial settings was the first known cause of human bladder cancer.
  • Arylamines are found in cigarette smoke and certain hair sprays.
25
Q

What are the key enzymes involved in the bioinactivation/bioactivation process?

A
  • MFO: Cytochrome P450-Dependent Mixed Function Oxidases
  • UGT: UDP-glucuronosyl transferase (mediates the addition of glucuronic acid moiety to xenobiotic)
  • NAT: N-acetyltransferase (N-acetylation of small molecules)

BI316 (13 decks)

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