Metabolic Process of the Liver

Question 1

What does the liver protect?

Answer 1

→ Major vessels from direct contact with dietary nutrients

Question 2

How does the liver contribute to the removal of glucose?

Answer 2

→ regulating the flux into pathways that remove free glucose

Question 3

How does the liver store glucose?

Answer 3

→ As glycogen

Question 4

How does the liver restore blood glucose levels?

Answer 4

→ Glycogenolysis

→ Gluconeogenesis

Question 5

What is the liver a major site of synthesis for?

Answer 5

→ Serum proteins such as albumin and blood clotting factors

Question 6

What does the liver do to excess amino acids during gluconeogenesis?

Answer 6

→ Degrades them

Question 7

What do glucogenic amino acids become?

Answer 7

→ Sugars

Question 8

What does the liver do to amino acids?

Answer 8

→ Transaminate and deaminates them

Question 9

What happens to ammonia in the liver?

Answer 9

→ Gets detoxified

Question 10

Describe the glucose alanine cycle

Answer 10

→In the muscle, branched amino acids are taken and broken down.

→The carbon skeleton is used for energy production.

→ the NH4 can be used to convert to pyruvate to Alanine. Alanine is then exported into the blood and travels to the liver.

→ alanine is then converted to glutamate via transamination (reacting with α-ketoglutarate) also producing a pyruvate.

→The pyruvate can enter the gluconeogenic pathway to form glucose, and the glucose can be transported in the blood back to the muscle where it can be used for energy.

→The glutamate will then be used along with the CO2 generated to produce urea in the liver.

Question 11

Where does synthesis of fatty acids take place?

Answer 11

→ In the cytosol of hepatocytes

Question 12

Where is the cholesterol in the body made?

Answer 12

→ 50% made by the liver

→ rest is made in the intestines, adrenal cortex and reproductive tissue

Question 13

What is cholesterol made from and what enzyme is used?

Answer 13

→ HMG- CoA reductase

→ Acetyle CoA is used

Question 14

How is cholesterol transported from the liver as?

Answer 14

→ VLDL

Question 15

How is cholesterol disposed of and why?

Answer 15

→ The body cannot degrade cholesterol

→ Disposed of by the biliary system as cholesterol or converted to bile acids or salts

Question 16

What are the two routes of metabolism of ethanol?

Answer 16

→ Oxidation through alcohol dehydrogenase - 90%

→ Microsomal oxidation using cytochrome P450 - 10-20%

Question 17

How much alcohol does the body metabolize per hour?

Answer 17

→ 10g

Question 18

What is methanol metabolized to and why is this bad?

Answer 18

→ Formaldehyde

→ Toxic and associated with paralysis, loss of consciousness, blindness

Question 19

What is the Km of ALDH2 ?

Answer 19

→ low

Question 20

What are the symptoms for ethanol intolerance?

Answer 20

→ Vasodilation
→ Facial flush
→ tachycardia
→ Nausea

Question 21

What is the consequence of alcohol metabolism not being regulated by negative feedback?

Answer 21

→ Large quantities of Acetyl CoA, NADH and ATP are formed

Question 22

What are the pathways inhibited by the metabolism of ethanol?

Answer 22

→ Acetyl CoA, NADH and ATP are formed which inhibits glucose metabolism by inhibiting PFK and pyruvate dehydrogenase
→ NADH inhibits the TCA cycle
→ Acetyl CoA results in ketone body formation and stimulation of fatty acid synthesis
→ Fatty acids are esterified to TG to transport as VLDL
→ inhibits gluconeogenesis and stimulates the conversion of pyruvate to lactate leading to hypoglycaemia and lactic acidosis

Question 23

What does the second route of metabolism of ethanol involve?

Answer 23

→ Oxidation of ethanol by members of cytochrome P450 enzymes

Question 24

What does the MESO system use?

Answer 24

→ NADPH which is needed for the synthesis of antioxidant glutathione

Question 25

What happens to acetaldehyde with excess alcohol intake?

Answer 25

→ Acetaldehyde builds up | → highly reactive

Question 26

What happens in the liver if acetaldehyde builds up?

Answer 26

→ Reduction in secretion of both serum protein and VLDL

Question 27

What can acetaldehyde enhance?

Answer 27

→ Free radical production | → Leads to tissue damage such as inflammation or necrosis

Question 28

How can cirrhosis cause death?

Answer 28

→ Ammonia accumulates resulting in neurotoxicity, coma and death

Question 29

What are xenobiotics?

Answer 29

→ Compounds with no nutritional value → Plant metabolites → Drugs → Food additives

Question 30

What compounds can be excreted easily in the urine?

Answer 30

→ Water compounds

Question 31

What is the livers aim with xenobiotics?

Answer 31

→ Make them harmless | → More readily disposed of

Question 32

What are the three phases of xenobiotic metabolism?

Answer 32

→ Oxidation → Conjugation → Elimination

Question 33

What does Phase I of xenobiotic metabolism do?

Answer 33

→ Oxidation is the most common modification there is also hydroxylation and reduction → Modification increases solubility → It introduces functional groups which enable participation in further reactions

Question 34

Where are P450 enzymes found?

Answer 34

→ In the endoplasmic reticulum of the liver

Question 35

What kind of proteins are P450 enzymes?

Answer 35

→ Haem proteins that are related to mitochondrial enzymes

Question 36

What are P450 enzymes inducible by?

Answer 36

→ Their own substrates (5-10 fold) | → but also related substrates (2-4 fold)

Question 37

Describe Phase II of xenobiotic metabolism

Answer 37

→ Modified by the addition of groups such as →Glutathione → Glucuronic acid → Sulphate

Question 38

What does modification in Phase II do?

Answer 38

→ Increases solubility and targets them for excretion

Question 39

Why is drug metabolism important?

Answer 39

→ Part of the bodies natural defences → Body cannot distinguish between harmful and beneficial compounds such as therapeutic drugs →A drug taken orally will pass through the liver first → Modifications made by the liver can significantly reduce the effectiveness of a drug → Advantageous because the liver can activate the drug

Question 40

What do statins inhibit and what are they degraded by?

Answer 40

→ HMG- CoA reductase | → Degraded by CYP3A4

Question 41

What is aflatoxin produced by and what are its effects?

Answer 41

→ Produced by the fungus aspergillus flavus → Aflatoxin is activated by P450 leading to epoxide formation → Hepatocarcinogenesis occurs

Question 42

What is CYP3A4 inhibited by?

Answer 42

grapefruit juice | → statin levels can rise by 15 fold

Question 43

How is paracetamol made soluble?

Answer 43

conjugated with either glucoronate or sulphate and excreted by the kidney.

Question 44

What happens if NADQI is not conjugated?

Answer 44

→ the NAPQI will form NAPQI-protein adducts resulting in oxidative stress, mitochondrial dysfunction, and necrotic cell death.

Question 45

How does excessive ethanol lead to unconjugated NADQI?

Answer 45

→excessive ethanol consumption is the activation of the microsomal ethanol-oxidising system which uses NADPH. →NADPH is required for the synthesis of GSH. → GSH required to clear NAPQI- conjugates to Mercapturic acid which is more soluble →NADQI builds up causing liver damage.

Question 46

What happens to the modified compounds

Answer 46

→Small water soluble molecules <60,000kDa can be removed by the kidney →Actively transported in to bile and then into the intestines

Question 47

What is the fate of these the modified compounds?

Answer 47

→Digestion →Excretion →Re-absorption via the enterohepatic circulation

Question 48

What are the stages of liver damage?

Answer 48

Stage 1: Fatty liver Stage 2: alcoholic hepatitis, groups of cells die resulting in inflammation Stage 3: Cirrhosis which includes fibrosis, scaring and cell death Cirrhosis arises in 25% of alcoholics and 75% all cirrhosis is due to alcohol

Question 49

What is the treatment for paracetamol overdose?

Answer 49

→ N-acetyl cysteine is given which is a precursor to glutathione

Question 50

What are the steps to metabolize alcohol?

Answer 50

→Ethanol → Acetaldehyde by alcohol dehydrogenase →Excess NADH produced by oxidation must be removed →Pyruvic acid → Lactic acid - requires NADH → Pyruvic acid + NADH + H+ → Lactic acid + NAD+

Question 51

What does NADH inhibit?

Answer 51

→ Normal oxidation of fats and fats may accumulate

Question 52

Describe phase 1 of the liver metabolizing drugs

Answer 52

Oxidation & Reduction → occurs in smooth ER → Catalyzed by cytochrome P450 → Makes substrate into a polar compound

Question 53

Describe phase 2 of the liver metabolizing drugs

Answer 53

Conjugation → Makes the drug more water soluble → Glucuronyl is the most prevalent conjugation group → Not all drugs use both phases → Elimination via ATPase pumps into blood or bile

Question 54

What are the 3 pathways that paracetamol is metabolized by?

Answer 54

Glucuronidation - 45-55% → Sulfation - 20-30% → N-hydroxylation & dehydration - < 15% (intermediate NAPQI is toxic)