Lecture 13: Liver Biochemistry

Question 1

How does blood enter and leave the liver?

Answer 1

2 ways in:
via Hepatic artery (peirpheral circulation) to feed liver with O2
via Portal vein (enteric circulation) with blood from GI tract for liver to detoxify

1 way out:
3 hepatic veins to the IVC

Question 2

Be able to label the liver anatomy diagrams

Answer 2

Ok

Question 3

What is the function of ....
Endothelial cells
Bile canaliculi 
Sinusoid 
Stellate cells
Kuppfer cells 
Pit cells
Cholangiocytes

Answer 3

• loosely packed so there is exchange between hepatocyte and blood
• collect the bile; leads to bile duct
• allows blood from HPV/HA to flow in between lobules
• stores lipids and Vit. A
• macrophages w/ lysosomes that endocytose pathogens
• NK cells that fight viruses and tumor cells
• line bile ducts, control bile flow rate and pH

Question 4

What supplies blood to each individual lobule?

Answer 4

Interlobular v (from HPV) and Interlobular A. (from HA)

Question 5

What are some important structural characteristics of the liver?

Answer 5

• No basement membrane, fenestrated cell membrane and no tight junctions > leaky = allows exchange with blood
• lots of ER, lysosomes and metabolic enzymes

Question 6

What are bile acids and bile salts?

Answer 6

Amphipathic detergents that emulsify lipids to increase lipid surface exposed to lipase

Acids - protonated form
Salts - deprotonated form

Question 7

What is the pathway of bile release?

Answer 7

hepatocytes > canaliculi >gallbladder > bile duct > duodenum release in response to food

Question 8

How does bile emulsify lipids?

Answer 8

1. ) bile acid (cholic acid) ionized to bile salt
2. ) hydrophobic core part associates with TAGs and aggregate to form micelle
3. ) hydrophilic outer part associates with lipase
4. ) lipase able to enter and digest the TAGs to release FFAs

Question 9

Draw the pathway of bile acid synthesis

Answer 9

Ok

Question 10

Why are bile acids conjugated?

Answer 10

since pH is 6 and pKa of bile acid is 6, it can’t be ionized de-novo (need pH to be low for that) so it is conjugated to be a more effective emulsifier

-the lower the pH, the more effective emulsifier

Question 11

Draw the pathway of bile acid conjugation (both types of bile acids)

Answer 11

Ok

Question 12

What is the difference between primary and secondary bile acids?

Answer 12

primary - released at duodenum

secondary - primary bile salts that are deconjugated by gut flora and are either reabsorbed in ileum or excreted in feces

Question 13

What are the secondary bile acids?

Answer 13

Deoxycholic acid (from cholic acid)
Lithocholic acid (from chenodeoxycholic acid)

Question 14

How do bile acid-binding resin drugs lower cholesterol?

Answer 14

E.g. cholestryamine

not absorbable/recyclable > bind bile acids and increases their excretion > lack of bile acids causes synthesis from cholesterol by 7a hydroxylase = depleted cholesterol levels

Question 15

Gallstones
Cause
Clinical

Answer 15

• bile supersaturated with cholesterol due to excess cholesterol or not enough bile acids to digest the lipids
• if due to bile deficiency = malabsorption syndromes like steatorrhea, fat soluble vitamin deficiency. RUQ pain

Question 16

What are metabolites and xenobiotics?

Answer 16

Xenobiotics: compounds ingested with no nutritional value
Metabolites: intermediates or end products of metabolism

*both detoxified by the liver

Question 17

What do phase 1 detoxification reactions accomplish?
What major group of enzymes accomplish this?
What types of reactions accomplish this?

Answer 17

• Make metabolites/xenobiotics more soluble ) -> primary metabolite
• CYP450 enzymes
• ROHH mechanisms (reduction, oxidation, hydroxylation, hydrolysis

Question 18

What does phase 2 detoxification reactions accomplish?

What types of reactions accomplish this?

Answer 18

• Make metabolites/xenobiotics conjugated for harmless excretion -> secondary metabolite
• CSMG (conjugation, sulfation, methylation, glucuronidation)

Question 19

What happens to drugs during liver metabolism?

Answer 19

-made less harmful for excretion, usually made less pharmacologically active, but also vice versa

Question 20

What CYP450 characteristics make it an effective enzyme for detoxification?

What cofactor does it need to be effective?

Answer 20

• low affinity of substrates so it can work with various types of substances
• heme containing

-NADPH-CYP450 Reductase

Question 21

Draw the pathway of drug metabolism via CYP450 reductase

Answer 21

Ok

Question 22

How does drug interaction reactions happen?

Answer 22

Drug 1 needs to complex with CYP to get metabolized, but Drug 2 blocks CYP activity > drug 1 accumulates > toxicity

Question 23

What happens when a substance inhibits CYP?

What happens when a substance stimulates CYP?

Answer 23

• increase in drug levels in plasma (it is not being metabolized)
• decrease in drug levels in plasma (it is being metabolized)

Question 24

What are some CYP inhibitors (e.g. competing with statin drugs example)?

What are some CYP stimulants?

Answer 24

• citrus juices, grapefruit juice > inhibit CYP > statin not metabolized = increased plasma levels of statin
• rifampicin, carbamezepine, St. John’s Wort > stimulate CYP > statin metabolized and excreted = decreased plasma levels of statin

Question 25

How can personalized medicine help in drug interactions?

Answer 25

Use information on patient’s CYP polymorphisms to personalize patient’s response to drug

Question 26

How does Acetaminophen overdose occur?
What are the effects ?
What is used as antidote to overdose?

Answer 26

Tylenol needs to be conjugated by glucuronic acid or sulfate to be excreted > too much Tylenol overwhelms the conjugation system > it becomes NABQ1 free radical (via enzyme CY3PA4)

• toxic to hepatocytes as body runs out of glutathione to metabolize NABQ1
• N-acetyl cysteine

Question 27

What is the major underlying change found in liver disease?

Answer 27

-fibrotic/collagen buildup on liver cells closes the normally “leaky” set up so blood flow and exchange to liver is impeded (portal HTN due to blockage of flow and hepatocyte damage)