Lecture 12 Flashcards
What is biotransformation?
It is a protective mechanism of the body to remove potentially harmful substances
Disadvantage of biotransformation
It chemically modifys xenobiotic substances causes it to loose its pharmacological potency and biological function
Phases of biotransformation reactions:
Phase 1 and Phase 2
Phase 1 is biotransformation reactions:
Includes oxidation, reduction, alkylation and hydrolytic cleavage
Phase 2 of biotransformation reactions:
Includes conjugation reactions with Glucoronic acid, sulfuric acid or peptides
What are xenobiotics?
They are potentially harmful substances foreign to a living organism
-At high concentrations and it may interfere with cellular functioning
How can xenobiotics be removed?
- Direct excretion of the parent substances
Or - Metabolic bio transformation
-Phase 1 or Phase 2
Examples of fat soluble toxins:
-Drugs
-Food additives
-Pollutant
-Contaminant
-Metabolites
-Alcohol
-Bacterial products
What does biotransformation do to fat soluble toxins?
It turns it into water-soluble, polar substances so they are easy to eliminate
Where are biotransformed waste products be removed from?
Through the stool or urine
Biotransformation causes what changes in xenobiotics?
-Disappearance of original foreign substance
-Loss of biological activity
-Metabolites are usually less toxic
-Polar metabolites are excreted faster
How does phase 1 biotransformation happen?
-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
Phase 1 takes place under the influence of what system?
The mixed-function oxidase (MFO) system
Mixed-function oxidase (MFO) system:
-Consists of the super family CYP450 proteins
-These are drug induced cytochrome (CY) heme proteins found in the smooth ER
Function of CYP450 proteins?
-They are critical for drug metabolism
-They work by catalyzing the oxidation of substrates
What is Glutathione?
-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
Chemical name of glutathione?
Gamma-glutamyl-cysteinyl-glycine TRI-peptide (GSH)
Where is glutathione found?
It can be found in high concentrations in liver cells
What is the major site of biotransformation
Liver cells
Function of Glutathione transferase (GST) ?
It is an enzyme that catalyzes reactions where sulphydryl group (-SH) of GSH acts as a nucleophile binding to electrophiles
What are GSH conjugated?
-Formed by phase 2 biotransformation reactions
-The conjugates are excreted into bile
-They may be further metabolized to form mercapturic acid derivatives
Biotransformation of the xenobiotic Benzene:
It undergoes both phase 1 and phase 2 biotransformation
Phase 1 biotransformation of Benzene:
-In the Mixed-function oxidase it becomes epoxide and then phenol
Phase 2 biotransformation of Benzene:
The phenol is converted to phenyl glucuronide by the enzyme glucuronyl transferase
What are reactive intermediates
They are formed during metabolism of xenobiotics
-Can potentially lead to necrosis or cancer
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
What are Aflatoxins?
- group of mycotoxins produced as secondary metabolites by the fungus Aspergillus
-Can contaminate human food and animal feed
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
Aflatoxin 8,9 epoxide:
-It can form DNA adducts such as Aflatoxin-Guanine which can induce mutations and liver cancer
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
What was the first known cause of human bladder cancer?
Exposure to arylamines in industrial settings
Where else can arylamines be found?
Cigarette smoke and hair sprays
Key enzymes involved in biotransformation
-MFO (Cytochrome P450-dependent)
-UGT (UDP-glucuronosyl transferase
-NAT (N-acetyltransferase
Toxic reactive intermediate:
-Hapten formation
-Direct cytotoxic effect
-DNA adduct
Hapten formation leads to?
Antibody production which can cause cellular damage
Direct cytotoxic effect leads to?
Cellular injury which leads to necrosis
DNA adduct leads to?
Mutation which cause cancer
