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P1: GI > Metabolic Process of the Liver > Flashcards

Metabolic Process of the Liver Flashcards

1
Q

What does the liver protect?

A

→ Major vessels from direct contact with dietary nutrients

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2
Q

How does the liver contribute to the removal of glucose?

A

→ regulating the flux into pathways that remove free glucose

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3
Q

How does the liver store glucose?

A

→ As glycogen

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4
Q

How does the liver restore blood glucose levels?

A

→ Glycogenolysis

→ Gluconeogenesis

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5
Q

What is the liver a major site of synthesis for?

A

→ Serum proteins such as albumin and blood clotting factors

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6
Q

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

A

→ Degrades them

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7
Q

What do glucogenic amino acids become?

A

→ Sugars

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8
Q

What does the liver do to amino acids?

A

→ Transaminate and deaminates them

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9
Q

What happens to ammonia in the liver?

A

→ Gets detoxified

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10
Q

Describe the glucose alanine cycle

A

→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.

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11
Q

Where does synthesis of fatty acids take place?

A

→ In the cytosol of hepatocytes

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12
Q

Where is the cholesterol in the body made?

A

→ 50% made by the liver

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

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13
Q

What is cholesterol made from and what enzyme is used?

A

→ HMG- CoA reductase

→ Acetyle CoA is used

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14
Q

How is cholesterol transported from the liver as?

A

→ VLDL

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15
Q

How is cholesterol disposed of and why?

A

→ The body cannot degrade cholesterol

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

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16
Q

What are the two routes of metabolism of ethanol?

A

→ Oxidation through alcohol dehydrogenase - 90%

→ Microsomal oxidation using cytochrome P450 - 10-20%

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17
Q

How much alcohol does the body metabolize per hour?

A

→ 10g

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18
Q

What is methanol metabolized to and why is this bad?

A

→ Formaldehyde

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

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19
Q

What is the Km of ALDH2 ?

A

→ low

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20
Q

What are the symptoms for ethanol intolerance?

A

→ Vasodilation
→ Facial flush
→ tachycardia
→ Nausea

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21
Q

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

A

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

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22
Q

What are the pathways inhibited by the metabolism of ethanol?

A

→ 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

23
Q

What does the second route of metabolism of ethanol involve?

A

→ Oxidation of ethanol by members of cytochrome P450 enzymes

24
Q

What does the MESO system use?

A

→ NADPH which is needed for the synthesis of antioxidant glutathione

25
Q

What happens to acetaldehyde with excess alcohol intake?

A

→ Acetaldehyde builds up

→ highly reactive

26
Q

What happens in the liver if acetaldehyde builds up?

A

→ Reduction in secretion of both serum protein and VLDL

27
Q

What can acetaldehyde enhance?

A

→ Free radical production

→ Leads to tissue damage such as inflammation or necrosis

28
Q

How can cirrhosis cause death?

A

→ Ammonia accumulates resulting in neurotoxicity, coma and death

29
Q

What are xenobiotics?

A

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

30
Q

What compounds can be excreted easily in the urine?

A

→ Water compounds

31
Q

What is the livers aim with xenobiotics?

A

→ Make them harmless

→ More readily disposed of

32
Q

What are the three phases of xenobiotic metabolism?

A

→ Oxidation
→ Conjugation
→ Elimination

33
Q

What does Phase I of xenobiotic metabolism do?

A

→ 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

34
Q

Where are P450 enzymes found?

A

→ In the endoplasmic reticulum of the liver

35
Q

What kind of proteins are P450 enzymes?

A

→ Haem proteins that are related to mitochondrial enzymes

36
Q

What are P450 enzymes inducible by?

A

→ Their own substrates (5-10 fold)

→ but also related substrates (2-4 fold)

37
Q

Describe Phase II of xenobiotic metabolism

A

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

38
Q

What does modification in Phase II do?

A

→ Increases solubility and targets them for excretion

39
Q

Why is drug metabolism important?

A

→ 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

40
Q

What do statins inhibit and what are they degraded by?

A

→ HMG- CoA reductase

→ Degraded by CYP3A4

41
Q

What is aflatoxin produced by and what are its effects?

A

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

42
Q

What is CYP3A4 inhibited by?

A

grapefruit juice

→ statin levels can rise by 15 fold

43
Q

How is paracetamol made soluble?

A

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

44
Q

What happens if NADQI is not conjugated?

A

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

45
Q

How does excessive ethanol lead to unconjugated NADQI?

A

→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.

46
Q

What happens to the modified compounds

A

→Small water soluble molecules <60,000kDa can be removed by the kidney

→Actively transported in to bile and then into the intestines

47
Q

What is the fate of these the modified compounds?

A

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

48
Q

What are the stages of liver damage?

A

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

49
Q

What is the treatment for paracetamol overdose?

A

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

50
Q

What are the steps to metabolize alcohol?

A

→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+

51
Q

What does NADH inhibit?

A

→ Normal oxidation of fats and fats may accumulate

52
Q

Describe phase 1 of the liver metabolizing drugs

A

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

53
Q

Describe phase 2 of the liver metabolizing drugs

A

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

54
Q

What are the 3 pathways that paracetamol is metabolized by?

A

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

P1: GI (15 decks)

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