Lecture 12 Flashcards
What is biotransformation?
A protective mechanism of the body to promote the efficient removal of potentially harmful substances.
What is Xenobiotic?
Potentially harmful foreign substance that at high concentration may interfere with cellular function
What are the ways to eliminate xenobiotics?
- Through direct excretion of the parent substance.
- Through metabolic biotransformation.
How many phases of metabolic biotransformation are there?
2 phases
Phase I transformation reaction
Phase II transformation reaction
Phase I transformation reaction
Two processes
- Bioinactivation process
- Bioactivation process
What does increased water solubility of xenobiotics following phase I reactions result in?
- Disappearance of original foreign substance
- Loss of biological activity
- Metabolites are usually less toxic
- Polar metabolites are excreted faster
What is the bioinactivation process?
Chemically modified xenobiotic becomes more soluble in a watery environment which leads to swift and efficient elimination from the body.
What is the bioactivation process?
Some phase I reactions yield a metabolite with higher intrinsic toxicity than the parent substance, which leads to potential toxic insult by reactive metabolite.
What happens during phase I biotransformation?
- 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
What determines which type of reaction a xenobiotic will undergo?
Its chemical structure determines the reaction
What does phase I reaction take place under?
Phase I reactions take place under the influence of the Mixed Function Oxidase
What do phase I reactions take place under?
Phase I reactions take place under the influence of the Mixed Function Oxidase.
What is Mixed Function Oxidase (MFO)?
- 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
Which protein families are critical for drug metabolism?
CYP1, CYP2 and CYP3
What component is essential in Phase II biotransformation, and what is it?
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.
Where is there a high concentration of glutathione?
High concentration in the liver cells, which is the primary site of biotransformation.
What is enzyme glutathione transferase (GST)?
GST catalyses reactions where the sulphydryl group (SH) of GSH acts as a nucleophile binding to electrophiles.
GSH conjugates are excreted to where?
What happens when they are further metabolized?
- GSH conjugates are excreted into bile
- GSH conjugates may be further metabolized, forming mercapturic acid derivatives.
What are some examples of reactive metabolite formation mediated by MFO?
- Bromobenzene
- Carbon tetrachloride
- Vinyl chloride
(look at lecture slide 14)
What are aflatoxins?
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.
Metabolization of Aflatoxin B1 by P450 monooxygenase system produces what?
Metabolization of Aflatoxin B1 by P450 monooxygenase system in the liver produces a reactive epoxide called Aflatoxin 8,9 epoxide.
What can Aflatoxin-epoxide form?
Aflatoxin-epoxide can form DNA adducts (Aflatoxin-Guanine) that induce mutations and liver cancer.
What is Aflatoxicosis?
Large doses of Aflatoxins lead to acute poisoning (Aflatoxicosis) that can be life-threatening, usually through damage to the liver.
Arylamines
- 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.
What are the key enzymes involved in the bioinactivation/bioactivation process?
- 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)
