Liver detoxification Flashcards
Xenobiotics
Foreign chemical substance not normally found or produced in the body which cannot be used for energy requirements
How can Xenobiotics be absorbed
Can be absorbed across lungs, skin or ingested
How are xenobiotics excreted
Excreted in bile, urine, sweat and breath
example of xenobiotics
Drugs
three characteristics of Pharmacologically active compounds
Lipophilic: to be able to pass through plasma membranes to reach metabolising enzymes
- Non-ionised at pH 7.4
- Bound to plasma proteins to be transported in blood
Lipophilic
to be able to pass through plasma membranes to reach metabolising enzymes
Microsome
a small particle consisting of a piece of endoplasmic reticulumto which ribosomes are attached, so microsomal enzymes - are just enzymes which can be found in these microsomes
Where are microsomal enzymes located
Located on smooth endoplasmic reticulum
Mostly found in liver hepatocytes but can be found in the kidneys & lungs too
Example of a microsome
Cytochrome P450 (CYPs), Flavin monooxygenase (FMOs) & UDP glucoronosyltransferase (UGT)
Example of a Phase I reaction involving microsome
biotransform substances (transformed one chemical to another)
Involved in oxidative,reductive & hydrolytic reactions
(mainly phase I reactions but can be phase II)
What affects microsomal activity
Activity can be induced or inhibited by; drugs, food, age, bacteria & alcohol
Non-microsomal Enzymes location
Located in the cytoplasm & mitochondria of hepatocytes in the liver but also in other tissue too
Example of a Phase II reaction involving microsome
glucuronidation (the addition of glucuronic acid to a substance)
Why can non-microsomal enzymes be involved in both Phase I and Phase II reactions
Theyre non specific
What conjugation reactions are non microsomal enzymes involved in
Involved in all conjugation reactionsexcept GLUCURONIDATION
Is a non microsomal enzyme inducible
no
Examples of non microsomal enzymes
protein oxidases, esterases, amidases, conjugases (transferase), alcohol dehydrogenase, aldehyde dehydrogenase
Most drugs are excreted by the kidneys but what isn’t and why
•Most drugs are excreted by the kidneys but lipophilic drugs are not effectively removed as they are passively absorbed due to the fact they can diffuse through cell membranes easily
Aim of drug metabolism
The aim of drug metabolism is to make the drugsmore polar so they cannot get across membranes and thus are easily excreted
Where does drug metabolism occur and why
This mostly occurs in the liver•Via 2 mechanisms - Phase I & Phase II reactions which are used sequentially and mostly occur in the liver where the enzymes are located
What is a phase I reaction how does it occur and whats it aim
Aim is to make the drug more hydrophilic so that it can be excreted by the kidneys- it does this by adding a hydroxyl group to the drug
•They introduce or expose hydroxyl (-OH) groups or other reactive sites that can be used for conjugation reactions (the Phase II reactions)
What is a Non-Synthetic catabolic reaction and give an example
chemical decomposition of complex substances by the body to form simpler ones, accompanied by the release of energy
oxidation, reduction & hydrolysis
why do hydrophilic enzymes not reach the metabolising enzymes
Hydrophilic molecules usually do not reach the metabolising enzymes since they are excreted easily
Hydroxylation
add -OH
Dealkylation
remove -CH side chains
Deamination
remove-NH
Oxidation
Hydrogen removal
Hydroxylation (add -OH)
-Dealkylation (remove -CH side chains)
-Deamination (remove-NH)
Reduction
Add hydrogen (saturate unsaturated bonds)
Hydrolysis
Splitamide(peptide bond (between a carboxyl (COOH) & amino (NH) group) O=C-NH) & ester(the H from a COOH (carboxylic acid) is replaced by some sort of hydrocarbon)bonds
functionalisation what does this do
Functionalization is the process of adding new functions, features, capabilities, or properties to a material by changing the surface chemistry of the material
eg
Introduces reactive group to drug
-Includes adding or exposing; -OH,-SH,-NH2,-COOH
-The product of the reaction is usually more reactive
-There is a small increase in HYDROPHILICITY
Where does functionalisation occur
Mainly occur in the liver
What catalyses functionalisation reactions
Mainly catalysed by cytochrome P450 enzymes
What is a cytochrome P450 enzyme and what is it involved in
Type of microsomal enzyme
-Involved in Phase I reactions
how does cytochrome P450 work and what does this result in
Uses heme group (Fe2+) to oxidise substances
-Products of P450 enzymes are more water soluble
Cytochrome P450 enzymes are a large family of enzymes with the prefix CYP -
what are these also known as and what do the letters stand for
these family members are known as isoforms/isozymes-
1st number = the family the enzyme belongs to
- Letter= indicates subfamily
- 2nd number= individual genes involved
- Important P450 isozymes: CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 & CYP 3A4
What is The enzyme required to transfer electrons from NADPH to CY P450
Cytochrome P450 reductase
What does Cytochrome P450 reductase contain
Contains flavoprotein which in turn consists of; Flavin adenine dinucleotide (FAD) & flavin mononucelotide (FMN)
what happens in this reaction with cytochrome P450 reductase
NADPH + H+ + O2 + RH —> NADP+ + H2O + R-OH
FAD - accepts electrons from NADPH
•FMN - electron donor to CYPs
REMEMBER
Non-microsomal enzymes (4)
Alcohol dehydrogenase
•Aldehyde dehydrogenase
•Reduction
•Hydrolysis
Phase I reactions can: (4)
Inactivate drugs
•Further activate drug
•Activate drug from pro-drug (inactive form of drug)
•Make a drug into a reactive intermediate (could be carcinogenic or toxic)
Which reaction is Synthetic anabolic and what does this mean
the synthesis of complex molecules such as proteins & fats, from simpler ones
What type of reaction is non synthetic catabolic
Phase I
Example of Synthetic anabolic reaction
- Glucuronidation (donor compound is UDPGA)
- Sulfation
- Glutathione conjugation
- Amino acid conjugation
- Acetylation (donor compound is Acetyl CoA)
- Methylation (donor compound is S-adenodyl methionine)
- Water conjugation
Whats a conjugation reaction
Attachment of substituent groups (endogenous (from the body) molecules)
-Usually inactive products
Why are conjugation reactions important
Significantly increases hydrophilicity for renal excretion
What are conjugation reactions catalysed by
Catalysed by transferases
Where do conjugation reactions happen
Occurs mainly in the liver but can occur in other tissues like the lungs & kidneys
what is a GLUCURONIDATION REACTION
Essentially adding a glucuronic acid group (glucuronide) to the drug to make it more hydrophilic
process forms covalent bonds
Enzyme used in glucuronidation reaction
Glucuronosyltransferase (Uridine 5’-diphospho-glucuronosyltransferase) (UGT) - microsomal enzyme, used in Phase II reactions, catalyses reaction
a co-enzyme/donor compound required to conjugate glucuronic acid,
Uridine diphospho-glucuronic acid (UDPGA) -
Substances arising from glucuronidation reactions are known as
glucuronides
Look at diagram for glucuronidation reaction then explain it
explain lol
Most Phase ? reactions involve non-microsomal enzymes which are mostly found in the ? or ? of ?
Most Phase II reactions involve non-microsomal enzymes which are mostly found in the cytoplasm or mitochondria of HEPATOCYTES
OVERALL PATHWAYS FOR DRUG METABOLISM:
- Elimination (usually polar drug, excreted unchanged)
- Phase II => Elimination (functionalised without Phase I)
- Phase I => Phase II => Elimination
Give drug metabolism of Aspirin:
- Analgesic (pain relief)
- NSAID
- Antiplatelet
- Pro-drug
- Irreversibly inhibitscy clooxygenase (COX)
Phase I metabolism:
- Since its a pro-drug it is activated upon metabolism
- Hydrolysis reaction:
Aspirin + H20 —> Salcylic acid + Ethanoic acid
Phase II metabolism:
- Conjugated with glycine or glucuronic acid
- Forms a range of ionised (thus won’t be passively absorbed so can be excreted by the kidneys and excreted in the urine) metabolite
Give drug metabolism of Paracetamol:
- Also known as Acetaminophen
- Analgesic (pain relief)
- Antipyretic agent (lowers body temperature)
Metabolism:
-Predominantly metabolised via a Phase II reaction - conjugated with glucuronic acid & sulphate
•Toxicity:
- If stores of glucuronic acid and sulphate are running low
- Paracetamol will undergo Phase I metabolism via oxidation to produce toxic NAPQI
- This is removed by conjugation with glutathione
- In overdoses stores of glutathione can run low resulting in toxicity
- Treated with N-Acetyl Cysteine
Alcohol metabolism:
Ethanol — (ADH)—> Acetaldehyde — (ALDH)—> Acetate —> CO2 + H2O
- ADH - Alcohol Dehydrogenase
- ALDH - Aldehyde Dehydrogenase-Operates at different speeds in different people
- Acetaldehyde is CARCINOGENIC, indications of high levels include; facial flushing, rapid heartbeat & nausea
Iron is essential for use in
haemoglobin, myoglobin & bone marrow
Sources of iron
meat, liver, shell fish, egg yolk, beans, nuts and cereals
Normally only a small fraction of ingested iron is absorbed - however, this fraction is increased or decreased in a negative feedback manner depending on the state of the bodies iron balance
The homeostatic control of iron balance resides primarily in ..
intestinal epithelium, in the DUODENUM - which actively absorbs IRON from ingested foods
How much of injested iron is absorbed into blood everyday
Only about 10% of ingested iron is absorbed into the blood each day
How is iron transported and stored
Iron ions are actively transported into the duodenal intestinal epithelial cells
- once here some iron ions are incorporated into FERRITIN (protein-iron complex) that acts as an intracellular store for iron
when the cells at the tips of the villi disintegrate What happens the iron
Most of the iron bound to ferritin in the intestinal epithelial cells is released back into the intestinal lumen when the cells at the tips of the villi disintegrate, and the iron is then excreted in the faeces
What happens when bodies stores of iron are enough
The increased concentration of free iron in the plasma and intestinal epithelial cells leads to an increased transcription of the gene encoding for ferritin and thus an increased synthesis of ferritin protein. This results in an increased binding of Fe in the intestinal epithelial cells and a reduction in the amount of iron released into the blood
When body stores of iron are low (e.g. after blood loss),
what happens
the production of intestinal ferritin decreases resulting in a decrease in the amount of iron bound to ferritin thus increasing the unbound iron released into the blood
What happens to absorbed iron thats not bound to ferritin
The absorbed iron that does not bind to ferritin is released into the blood where it is able to circulate around the body bound to the plasma protein TRANSFERRIN
What does transferrin do
Transferrin transports iron in the blood plasma to the bone marrow to be incorporated into new erythrocytes
What happens to iron once it enters the blood
Once iron has entered the blood, the body has very little means of excreting itmeaning it accumulates in tissues, most of the iron is stored in the LIVER in liver ferritin within KUPFFER CELLS (reticulo-endothelial macrophages)
Where is most of the iron stored
most of the iron is stored in the LIVER in liver ferritin within KUPFFER CELLS (reticulo-endothelial macrophages)
The body has a considerable store of iron, mainly in the liver bound in ferritin
How much of the liver is where in the body
50% of total iron is in haemoglobin
•25% is in heme containing proteins (mainly cytochromes)
•25% is in liver ferritin
The liver is a major producer of proteins what proteins does it produce
It produces plasma proteins, clotting factors & complement factors
