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PED2001 - Drug Disposition > Phase II > Flashcards

Phase II Flashcards

1
Q

Name all enzymes involved in phase 2 metabolism

A

UDP-glucuronyltransferases (UGTs)
Sulfotransferases (SULTs)
Glutathione S transferases (GSTs)
Amino acid conjugation enzymes
N-acetyltransferases (NATs)
Methytransferases

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2
Q

Where are UGTs found

A

Collocated with CYPs and FMOs in liver microsomes

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3
Q

Where are SULTs found

A

In the cytosolic - wide tissue distribution

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4
Q

Where are amino acid conjugating enzymes found

A

In mitochondria

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5
Q

Where are NATs found

A

Cytosol

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6
Q

Where are GSTs found

A

Cytosol

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7
Q

What is the most common route of phase 2 metabolism

A

Glucuronidation
Followed by sulfation

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8
Q

Why is conjugation in phase 2 necessary

A

Gives greater molecular weight
More water soluble
Less able to pass through membranes
Easier to excrete

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9
Q

What is the glucuronidation cofactor

A

UDP-glucuronic acid

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10
Q

Substrates for UDP-GTs

A

Steroids
Fatty acids
Bile acids
Bilirubin

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11
Q

Where are UGTs found

A

Endoplasmic reticulum

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12
Q

Tissue distribution of UGTs

A

Highest in liver but also kidney lung small intestine

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13
Q

How does glucuronidation promote excretion

A

Larger MW and more water soluble and loss of biological activity
However some glucuronides have biological activity (morphine glucuronide)

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14
Q

Families of UGTs?

A

UGT1 and UGT2

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15
Q

Describe elimination products of glucuronidated compounds

A

Conjugates MW>400 excreted in bile
Conjugates MW<400 excreted in urine

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16
Q

What may happen to glucuronides excreted in bile

A

Enterihepatic recirculation - increase half life

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17
Q

How do drugs undergo enterohepatic recirculation

A

Excreted to intestine via bile duct
Reabsorbed through portal vein to liver

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18
Q

UDP-glucuronic acids reacts with

A

Alcohol
Carboxylic acids
Amines
Amides
Thiols

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19
Q

Describe glucuronidation of paracetamol

A

UDP is lost
OH on paracetamol condenses with UDP-glucuronic acid

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20
Q

Example of another glucuronidation reaction

A

Formation of disulphiram glucuronide from disulphiram

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21
Q

Can UGTs be induced

A

Yes but not as much as CYPs
UGT1 induced by polycyclic aromatic hydrocarbons

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22
Q

Important SULT enzymes and their locations

A

SULT1A1 - liver
SULT1A3 - intestine
SULT1C2 - stomach & foetal liver

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23
Q

How do SULTs transfer sulfate

A

Using PAPS as a source of sulfate

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24
Q

General alcohol sulfation reaction

A

PAPS + ROH —> PAP + ROSO3-

25
Q

Example substrate of SULTs

A

Oestrone & paracetamol —> paracetamol sulfate

26
Q

Name an amine conjugated by SULTs

A

Metoclopramide - dopamine receptor agonist
Desipramine - tricyclic antidepressant

27
Q

Why isn’t sulfation as common as glucuronidation

A

Sulfate availability is limited

28
Q

Can sulfation activate carcinogens

A

Yes - sulfoxy derivatives of pro-carcinogens are unstable and spontaneously form reactive nitrenium compounds

29
Q

Example of SULT regulation

A

AhR ligands (dioxins) are SULT substrates
They can have a negative effect on SULT activity in mice

30
Q

What was the first amino acid conjugation reaction to be discovered

A

Benzoic acid metabolised to hippuric acid

31
Q

What is required for amino acid conjugation

A

Carboxyl group

32
Q

What are the major conjugating amino acids

A

Glycine
Taurine
Glutamine

33
Q

General reaction for amino acid conjugation

A

COOH to is acyl-CoA derivative
Then amide formation with amino group from amino acid

34
Q

What enzyme carries out the initial reaction in aa conjugation

A

CoA ligases (MACS)

35
Q

With what are MACS active with

A

One active with benzoic acid
One active with salicylic acid

36
Q

Benzoic acid conjugation

A

Benzoic acid —> acyl adenylate
—> benzyl CoA using MACS
—> linkage to glycine forming hippuric acid

37
Q

Conjugation of salicylate

A

Salicylic acid —> salicyl CoA (MACS)
—> salicyluric acid (glycine)

38
Q

Why are so few xenobiotics conjugated to amino acids

A

N-acyltransferase is selective
Not all CoAs formed by MACS are conjugated
Metabolite of hypoglycin is conjugated at a low rate
Hypoglycin is in Jamaican Ackee fruit and causes Jamaican vomiting sickness

39
Q

What compounds are acetylated?

A

Compounds containing amino, hydroxyl and sulfhydryl groups

40
Q

What does acetyltransferase use

A

Acetyl CoA to donate acetyl group

41
Q

What are the acetylation enzymes

A

NAT1 and NAT2

42
Q

What are the important substrates for NAT enzymes

A

Sulphamethoxazole - NAT1
Isoniazid - NAT2 (slow acetylation phenotype leads to isoniazid toxicity)

43
Q

NATs location and tissue distribution

A

Cytosol
NAT1 - most tissues
NAT2 - liver, intestine

44
Q

Are NATs inducible

A

No - they are expressed at a constant level

45
Q

Which NAT is more polymorphic

A

NAT2 - 50% of population can’t acetylate certain compounds

46
Q

What’s the effect of acetylation

A

Masks an amine group with and acetyl group
Decreased solubility

47
Q

What’s the link with NATs and cancer

A

NATs can activate arylamines in well-cooked food and produces reactive intermediates that initiate carcinogenesis

48
Q

What do GSTs do

A

Conjugate glutathione to electrophilic compounds using nucleophilic cysteine thiol group

49
Q

Subfamilies of GST

A

Alpha
Mu
Pi
Theta (small molecules)

50
Q

Which GST classes are inducible

A

Alpha and mu
- by barbiturates and hydrocarbons

51
Q

Why don’t GSTs have a general role in metabolism

A

They have a specialised role because most drugs aren’t electrophiles

52
Q

Example substrates for GSTs

A

Cyclophosphamide
Paracetamol

53
Q

Explain toxicity linked to GSTs

A

NAPQI is a metabolism product of paracetamol
It is further metabolised by GSTs
NAPQI toxicity is caused by GST depletion

54
Q

3 families of methyltransferase

A

O-methyltransferase
N-methyltransferase
S-methyltransferase

55
Q

Methylation usually increases …

A

Lipophilicity

56
Q

What cofactor to methyltramsferases use

A

SAM

57
Q

Example of methylation reaction

A

L-Dopa —> O-methyl-L-dopa

58
Q

How does methylation aid arsenic toxicity

A

Methylation of arsenic makes it more able to bind to DNA

PED2001 - Drug Disposition (13 decks)

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