Xenobiotics Flashcards
What are Xenobiotics?
They are substances that are foreign to the host. So non-natural molecules such as drugs
What processes Xenobiotics?
Enzymes that evolved to cope with natural compounds
What are the properties of Xenobiotics and the advantages of them?
Non-polar
Lipophilic - helps them to get across
How can you change the rate of metabolism?
By reacting with other substances
Is metabolism the same for everyone?
No, everyone has their own unique metabolic profile
Name some ways drugs Xenobiotics can be absorbed?
Active absorption of molecules by transport proteins
Absorption by dissolution in fats (lipophilicity)
What factors increase Absorption?
A high concentration of Xenobiotics in the circulation, than in the site of action.
Slow movement within the GIT
Taking the drug with food will favour absorption. As the movement of the food, through the small intestine, will be slow.
Can charged Xenobiotics such as salt pass through the membrane easily?
No, because membrane proteins have charged residues designed to repel xenobiotics
Where are weak acids and weak bases absorbed in?
Weak acids are absorbed in the stomach
Weak bases are absorbed in the SI
Factors which affect Distribution?
- Log P
- Blood flow through the tissue (perfusion of the tissue)
- The mass of the tissue
- Plasma/tissue concentration gradient
What does the Tubular section provide?
An active carrier process for cations and anions
Explain the process of the Entero-hepatic shunt?
Glucuronic acid conjugates can be excreted in the bile
The B-glucuronidase in the GIT will hydrolyse the carbohydrate conjugate
Active xenobiotic may then be reabsorbed
What is the purpose of phase 1 metabolism?
To create functional groups that place Xenobiotics in a correct chemical state to be acted upon at phase 2
What are the properties of CYP(450)
Large
Membrane-bound
Contain a heme residue (iron, Fe2+/3+)
What is the equation for the oxidation of a substrate?
Mono-oxygenase biotransformation reactions
NADPH + H+ + O2 + SubstrateH
—->
NADP+ +H20 + SubstrateOH
Where are CYPs found?
Endoplasmic reticulum (ER) of Hepatocytes
Small amounts in GIT
Kidney
What do CYP family and CYP subfmaily have?
CYP family has 40% sequence homology
CYP subfamily has 55% sequence homology
Explain the CYP 450 cycle?
The drug associates with the enzyme and causes it to be reduced from Fe3+ to F2+ (e- gained).
Oxygen associates with the complex and another electron comes in. Then the oxygen becomes activated to give a poroxy substituent (OOH)
It is then activated further to give a very high active species, where the iron is activated from 2+ to 3+.
The oxygen then attacks the drug, resulting in the drug and a hydroxyl group added onto it.
Name some CYP 450 Oxidations and what they do?
Aromatic/Aliphatic hydroxylation (adds OH)
Esther hydrolysis (removes ester, OOEt)
N-dealkylation (replaces a hydrogen with an alkyl group)
Oxidative deamination (removes an ammonia group and adds a ketone group)
What is used in phase 2 metabolism?
A high-energy co-factor that is involved in the conjugation
What is the result of phase 2 metabolism?
A water-soluble product which can be readily excreted
What are the main Phase 2 pathways?
The conjugation of a-D-glucuronic acid with a carbohydrate (forms glyosidic bond)
What does the conjugation of a-D-glucuronic acid require?
UDP-glucuronic acid intermediate
and
UDP-glucuronosyltransferases (UGTs, found within cytosol)
What is needed for Sulfation?
PAPS - 3’-Phosphoadenosine-5’-phosphosulfate intermediate
and
Sulfotransferases (SULTs, usually in the cytosol)
When is Glucuronidation and Sulfation used?
Glucuronidation predominates at high substrate concentration
Sulfation predominates at low substrate concentration
Because there is less PAPS in cell cytosol than UDPGA
Summarise Glutathione conjugation?
Because Glutathione is a nucleophile, the substrates are highly electrophilic compounds.
Glutathione-S-transferase (GSTs) are used; normally found in cytosol
The conjugates can be attacked by g-glutamyltranspeptidase
and a peptidase to yield the cysteine conjugate.
Conjugates are excreted in the bile or via kidney.
