Detoxification by the Liver Flashcards
What are Xenobiotics?
Xenobiotics are foreign chemical substance, they can be absorbed across lungs, skin or ingested
- Drugs are considered xenobiotics
- Excreted in bile, urine, sweat, breath
What are pharmacologically active compounds?
Lipophilic - To pass through plasma membranes to reach
metabolising enzymes
Non-ionised at pH7.4
Bound to plasma proteins to be transported in the blood (they are lipid soluble not water(blood) soluble)
What two types of enzymes are involved in liver detoxification?
Microsomal and Non-microsomal enzymes
BOTH be involved in phase I and II reactions
-Microsomal enzymes mainly Phase I
-Non-microsomal mainly Phase II
What are microsomal enzymes? Where are they located, what do they do in phase I/II reactions
Microsomal enzymes
- Located on smooth endoplasmic reticulum
- Mostly phase I
- Phase I reactions – biotransform substances
- Phase II – glucuronidation
Activity can be induced or inhibited -Drugs, food, age, bacteria, alcohol
Examples: Cytochrome P450 (CYPs), Flavin monooxygenase (FMOs), UDP-
glucuronosyltransferase (UGT)
What are non-microsomal enzymes?
Non-microsomal enzymes
- Located in cytoplasm and mitochondria
- Non-specific so Phase I and Phase II reactions
All conjugation reactions EXCEPT
GLUCURONIDATION
Non-inducible
Genetic polymorphic – affects metabolism
Examples: protein oxidases, esterases, amidases, conjugases
(transferases), alcohol dehydrogenase, aldehyde dehydrogenase
Why is the aim of drug metabolism? Which reactions occur?
Lipophilic drugs must be made more polar so that they can be excreted by the kidneys (need to be water soluble not lipid soluble)
This mostly occurs in the liver
2 mechanisms – phase I and II reactions
Usually sequentially
What are phase I reactions? Which enzyme is the main catalyst?
Phase I
- Non-synthetic catabolic reactions
- oxidation, reduction or hydrolysis
- functionalism
- Mainly catalysed by Cytochrome P450
- Oxidation (oxidation is loss of electrons, gain of oxygen)
- Hydroxylation (add –OH)
- Dealkylation (remove –CH side chains)
- Deamination (remove –NH)
- Hydrogen removal - Reduction (reduction is gain of electrons, loss of oxygen)
- Add hydrogen (saturate unsaturated bonds)
- Hydrolysis
- Split amide and ester bonds
What is functionalism?
-Oxidation, reduction or hydrolysis, this type of reaction is known as functionalism as it:
a) Introduces reactive group to drug
b) Includes adding or exposing –OH, -SH, -NH2, -COOH
c) Product usually more reactive
d) Small increase in hydrophilicity
What are Cytochrome P450 Enzymes?
Cytochrome P450 Enzymes
- Type of microsomal enzyme (Phase I reactions)
- Haem group to oxidise substances
- Makes products more water soluble (to be excreted)
-Large family with prefix CYP – known as isoforms/
isozymes (CYP)
1st number – indicates the family the enzyme belongs to (1)
Letter – to indicate subfamilies (A)
2nd number – individual genes involved (2)
Isoforms catalyse different reactions (specificity)
Some important isozymes – CYP 1A2, CYP2C9,
CYP2C19, CYP2D6,CYP2E1, CYP3A4
What can phase I reactions do?
Phase I reactions can:
-Inactivate drug
-Further activate drug
-Activate drug from pro-drug (inactive form)
-Make a drug into a reactive intermediate (could be
carcinogenic or toxic)
What are phase II reactions?
Phase II
-Synthetic anabolic reactions
-Glucuronidation, sulfation, Glutathione conjugation,
amino acid conjugation, acetylation, methylation, water
conjugation
-Known as ‘conjugation’ reactions
1. Attachment of substituent groups (endogenous
molecules)
2. Usually inactivate products
3. Catalysed by transferases
-Significantly increase hydrophilicity for renal
excretion
-Also mainly in the liver
What is Glucuronidation? What enzyme catalyses the reaction?
Glucuronidation
1. Glucuronosyltransferase (UGT) – microsomal
enzyme, phase II reaction.
2. Uridine diphospho-glucuronic acid (UDPGA) needed
to conjugate glucuronic acid.
-Adds Glucuronide to the drug making the drug more hydrophilic! (and water soluble to be excreted)
Pathway for bilirubin conjugation and drugs
including corticosteroids & paracetamol.
-phase II reaction (however usuals a microsomal enzyme when phase II reactions usually use non-microsomal enzymes)
What are the 3 pathways of drug elimination?
- Excretion - drug is polar and does not need to be changed in order to be excreted
- Phase II → elimination (phase II reaction only)
- Phase I → Phase II → Elimination
How is aspirin excreted?
Aspirin → Phase I → Phase II → Elimination
- Analgesic, NSAID
- Non steroidal anti-inflammatory drug
- Antiplatelet
- irreversibly inhibits cyclooxygenase (COX)
- Aspirin Phase 1 metabolism (drug is activated by liver)
Prodrug so it is activated upon metabolization
Hydrolysis reaction
Aspirin (+H20) → Salcylic acid + Ethanoic acid
Salcyclic acid is the active anti-inflammatory and
analgesic
- Aspirin Phase 2 metabolism
Conjugated with glycine or glucuronic acid
Forms a range of ionised metabolites
Excreted in the urine
How is alcohol metabolised?
Ethanol → Acetaldehyde → Acetate
(ADH) (ALDH)
Acetate → CO2 + H2O
ADH – Alcohol Dehydrogenase
ALDH – Aldehyde Dehydrogenase
Operate at different speeds in different people
Acetaldehyde -Carcinogenic
High levels: Facial flushing, rapid heartbeat, nausea
