Liver & Friends

Question 1

What are the functions of the liver?

Answer 1

carbohydrate metabolism 
Fat metabolism 
Protein metabolism 
Hormone metabolism 
Toxin/Drug metabolism 
Storage 
Bilirubin metabolism and excretion

Question 2

What are xenobiotics?

Answer 2

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

Question 3

how are xenobiotics absorbed?

Answer 3

Skin
Across lungs
Ingested

Question 4

How are xenobiotics excreted?

Answer 4

Sweat
Urine
Bile
Breath

Question 5

Why are pharmacologically active substances lipophilic and at what pH are they non ionised

Answer 5

To allow them to cross plasma membranes

pH 7.4

Question 6

Where are microsomal enzymes located

Answer 6

SER of liver hepatocytes but also in kidney and lungs too

Question 7

What is a phase I reaction

Answer 7

Biotransformation of a substance where functional groups are added (OH, SH, NH2, COOH)

Question 8

What is a phase II reaction?

Answer 8

Conjugation reaction to make a substance more hydrophilic

Question 9

What reactions are microsomal enzymes responsible for?

Answer 9

Majority of drug biotransformation ie. oxidation, reduction and hydrolysis but also phase II glucuronidation reactions

Question 10

What causes microsomal enzymes to be induced?

Answer 10

Diet and drugs

Question 11

What are three examples of microsomal enzymes?

Answer 11

Flavin Mono-oxygenases
Cytochrome P450’s
UGT Glucuronsyltransferase (Glucuronidation)

Question 12

Where are non-microsomal enzymes found?

Answer 12

In the cytoplasms and mitochondria of hepatocytes

Question 13

What reactions do non-microsomal enzymes catalyse?

Answer 13

Few biotransformational reductive, hydrolytic and oxidative reactions but also any conjugation reaction except glucuronidation

Question 14

Are non-microsomal enzymes inducible?

Answer 14

NO

Question 15

Give 4 examples of non-microsomal enzymes?

Answer 15

protein oxidases, esterases, amidases, conjugases (transferase),
alcohol dehydrogenase, aldehyde dehydrogenase

Question 16

What are the 4 things that metabolism of a substance can result in?

Answer 16

Inactivation or facilitation of elimination of drug
Formation of active metabolites with new activity
Activation of prodrugs
Toxification of less toxic xenobiotics

Question 17

What is the function of phase I reactions

Answer 17

To add or expose functional groups which increases the reactivity or hydrophilicity of a substance

Question 18

Describe some oxidation reactions

Answer 18

Hydroxylation (Additon of OH)
Dealkylation (Removal of CH)
Epoxidation
Deamination (removal of NH2)
Hydrogen removal

Question 19

Describe reduction reactions

Answer 19

Addition of hydrogen from donor molecules including NAD(p)H and FAD
Oxygen removal

Question 20

Describe hydrolysis in phase I reactions

Answer 20

Splitting of C-N-C (Amide) and C-O-C (ester) bonds

Question 21

Are CYPs responsible for phase I or phase II reactions

Answer 21

Phase I

Question 22

Describe the structure of CYPs that makes them suitable for their role

Answer 22

Contain Hb molecule with Heme Fe2+ core which oxidises substances

Question 23

Write an equation for the action of CYP450 reductase

Answer 23

NADPH + H+ + O2+ RH –> NADP + H20 + R-OH

Question 24

Describe a glucuronidation reaction

Answer 24

Conjugation of drug with glucuronic acid to make it more hydrophilic catalysed by UGT - forms covalent bonds but requires donor compound UDPGA

Question 25

Describe the metabolism of aspirin

Answer 25

aspirin is a prodrug that is activated by hydrolysis metabolism
Aspirin + H2O –> Salicyclate + Ethanoic acid
Conjugated with glycine or glucuronic acid for excretion

Question 26

Describe the metabolism of paracetamol

Answer 26

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

Question 27

What are the two routes of alcohol metabolism

Answer 27

1. Alcohol dehydrogenase

2. Microsomal ethanol oxidising system

Question 28

Describe the metabolism of alcohol by alcohol dehydrogenase

Answer 28

Ethanol converted into acetaldehyde with NAD+ being converted to NADH + H+ in the process

Question 29

Describe the metabolism of alcohol by microsomal ethanol oxidising system

Answer 29

CYP450 isozyme CYP2E1 oxidises ethanol to acetaldehyde which is metabolised by acetaldehyde dehydrogenase into acetate

Question 30

What happens to alcohol metabolism in chronic drinkers?

Answer 30

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

Question 31

where in the body and how much iron is actively reabsorbed?

Answer 31

10% of ingested iron is ingested in the intestinal epithelium of the duodenum

Question 32

Once absorbed, where is iron mainly stored?

Answer 32

Bound with proteins in a protein iron complex called ferritin that acts as an intracellular store

Question 33

What happens when iron stores are high?

Answer 33

Increased plasma Fe concentrations lead to increased transcription of ferritin so more Fe binds to ferritin and plasma Fe falls

Question 34

What happens when iron stores are low?

Answer 34

Ferritin production decreases which increasing unbound iron in the blood stream

Question 35

What happens to absorbed iron that is not incorporated into ferritin?

Answer 35

binds to transferrin plasma protein in blood which transports Fe to the bone marrow where its incorporated into new RBCs

Question 36

In which liver cells is iron mainly stored?

Answer 36

Kupffer cells