Liver & Friends Flashcards
What are the functions of the liver?
carbohydrate metabolism Fat metabolism Protein metabolism Hormone metabolism Toxin/Drug metabolism Storage Bilirubin metabolism and excretion
What are xenobiotics?
Foreign chemical substances that are not normally produced or found in the body that cannot be used for energy purposes and may become toxic if not excreted
how are xenobiotics absorbed?
Skin
Across lungs
Ingested
How are xenobiotics excreted?
Sweat
Urine
Bile
Breath
Why are pharmacologically active substances lipophilic and at what pH are they non ionised
To allow them to cross plasma membranes
pH 7.4
Where are microsomal enzymes located
SER of liver hepatocytes but also in kidney and lungs too
What is a phase I reaction
Biotransformation of a substance where functional groups are added (OH, SH, NH2, COOH)
What is a phase II reaction?
Conjugation reaction to make a substance more hydrophilic
What reactions are microsomal enzymes responsible for?
Majority of drug biotransformation ie. oxidation, reduction and hydrolysis but also phase II glucuronidation reactions
What causes microsomal enzymes to be induced?
Diet and drugs
What are three examples of microsomal enzymes?
Flavin Mono-oxygenases
Cytochrome P450’s
UGT Glucuronsyltransferase (Glucuronidation)
Where are non-microsomal enzymes found?
In the cytoplasms and mitochondria of hepatocytes
What reactions do non-microsomal enzymes catalyse?
Few biotransformational reductive, hydrolytic and oxidative reactions but also any conjugation reaction except glucuronidation
Are non-microsomal enzymes inducible?
NO
Give 4 examples of non-microsomal enzymes?
protein oxidases, esterases, amidases, conjugases (transferase),
alcohol dehydrogenase, aldehyde dehydrogenase
What are the 4 things that metabolism of a substance can result in?
Inactivation or facilitation of elimination of drug
Formation of active metabolites with new activity
Activation of prodrugs
Toxification of less toxic xenobiotics
What is the function of phase I reactions
To add or expose functional groups which increases the reactivity or hydrophilicity of a substance
Describe some oxidation reactions
Hydroxylation (Additon of OH) Dealkylation (Removal of CH) Epoxidation Deamination (removal of NH2) Hydrogen removal
Describe reduction reactions
Addition of hydrogen from donor molecules including NAD(p)H and FAD
Oxygen removal
Describe hydrolysis in phase I reactions
Splitting of C-N-C (Amide) and C-O-C (ester) bonds
Are CYPs responsible for phase I or phase II reactions
Phase I
Describe the structure of CYPs that makes them suitable for their role
Contain Hb molecule with Heme Fe2+ core which oxidises substances
Write an equation for the action of CYP450 reductase
NADPH + H+ + O2+ RH –> NADP + H20 + R-OH
Describe a glucuronidation reaction
Conjugation of drug with glucuronic acid to make it more hydrophilic catalysed by UGT - forms covalent bonds but requires donor compound UDPGA
Describe the metabolism of aspirin
aspirin is a prodrug that is activated by hydrolysis metabolism
Aspirin + H2O –> Salicyclate + Ethanoic acid
Conjugated with glycine or glucuronic acid for excretion
Describe the metabolism of paracetamol
Most metabolised by phase II conjugation with glucuronidation or salvation
If glucuronic acid/ Sulfate stores are low then oxidised by CYP450 to NAPQI which is toxic but normally metabolised by glutathione-S-transferase but becomes overwhelmed in overdose and is treated with N-acetyl cysteine
What are the two routes of alcohol metabolism
- Alcohol dehydrogenase
2. Microsomal ethanol oxidising system
Describe the metabolism of alcohol by alcohol dehydrogenase
Ethanol converted into acetaldehyde with NAD+ being converted to NADH + H+ in the process
Describe the metabolism of alcohol by microsomal ethanol oxidising system
CYP450 isozyme CYP2E1 oxidises ethanol to acetaldehyde which is metabolised by acetaldehyde dehydrogenase into acetate
What happens to alcohol metabolism in chronic drinkers?
CYP450 are inducible by chronic alcohol use so alcohol is metabolised and cleared quicker meaning toxic acetaldehyde is produced faster overwhelming acetaldehyde dehydrogenase so acetaldehyde accumulates in liver where it contributes to alcohol induced hepatitis or bind to glutathione and pre-disposes cells to damage by peroxide and free radicals
where in the body and how much iron is actively reabsorbed?
10% of ingested iron is ingested in the intestinal epithelium of the duodenum
Once absorbed, where is iron mainly stored?
Bound with proteins in a protein iron complex called ferritin that acts as an intracellular store
What happens when iron stores are high?
Increased plasma Fe concentrations lead to increased transcription of ferritin so more Fe binds to ferritin and plasma Fe falls
What happens when iron stores are low?
Ferritin production decreases which increasing unbound iron in the blood stream
What happens to absorbed iron that is not incorporated into ferritin?
binds to transferrin plasma protein in blood which transports Fe to the bone marrow where its incorporated into new RBCs
In which liver cells is iron mainly stored?
Kupffer cells
