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Y3 Med drug disposition > CYP450 > Flashcards

CYP450 Flashcards

1
Q

Where are the CYP enzymes located?

A
  • Membrane bound in the endoplasmic reticulum
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2
Q

How many different CYPs are there and how are they classified?

A

> 50 different CYPs isolated and sequenced in human genome

Classified based on amino acid sequence (primary structure)

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3
Q

How many CYP families are there?

A

12, with >40% homology. Families 1, 2 and 3 are important for drug metabolism

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4
Q

What are the sub-families of CYPs?

A

> 60% homology
e.g., Family 2 has 6 subfamilies - 2A, 2B, 2C, 2D, 2E, 2F
Each has 1- 15 members (different gene products)
Each CYP enzyme has a different molecular weight

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5
Q

Describe the CYP nomenclature, e.g. CYP2D6

A

The first Arabic number represents the family (2)

The capital letter designates the subfamily (D)

The second Arabic number refers to the individual gene (6)

–>
Usually different genes are for different animal species –
e.g. CYP2D6 (human), CYP2D1 (rat), CYP2D15 (dog)

Some CYP genes conserved across animal species -e.g. CYP2E1

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6
Q

What CYP enzymes are predominantly expressed in the liver?

A

CYP2D6, CYP3A5 amongst others

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7
Q

What CYP enzymes are predominantly expressed in the intestine?

A

Largely CYP3A and CYP2C9

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8
Q

How is the CYP system regulated?

A

Regulation via multiple mechansims, both genetic and environmental. e.g. PXR receptor regulates CYP enzymes - can change or activate receptors to change the activity of proteins
EXAMPLE:St johns wort effects the PXR receptor and changes CYP3A4 and equally the PXR changes will trigger changes in intestinal pgp
–> multiple pathways for elimination

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9
Q

What happens to levels of certain CYP enzymes in cancer and HIV?

A

Reported reduced activity of CYP2D6, CYP3A4 in cancer and HIV

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10
Q

What is the downregulation of CYPs mediated by?

A

Pro-inflammatory mediators affecting gene transcription (interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α)

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11
Q

What 2 steps are involved in CYP450 metabolic reactions?

A
  1. Activation of O2 (potentially dangerous)
  2. Oxidation of drug

DRUG + O2 + NADPH + H+ –> DRUG-OH + H2O + NADP+

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12
Q

What is NADPH?

A

Cofactor needed for CYP450 mediated reactions and activity of enzymes (donator of electrons)

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13
Q

What are Haemoproteins?

A

Component of CYP system:

  • cytochrome P450
  • cytochrome b5
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14
Q

What are flavoproteins ?

A

Components of CYP system:

  • FP1 - NADPH-cytochrome P450 reductase (FAD and FMN)
  • FP2 - NADH-cytochrome b5 reductase

*reductase facilitates the transfer of electrons

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15
Q

What is the CYP oxidation cycle?

A

Efficient process that protects the activated o2 species

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16
Q

How many binding sites on the CYP?

A

Two:

  • Substrate (drug molecule): active site on protein, site of catalysis, release of hydroxylated molecule
  • O2 (or CO): haeme ligand, CO binding has an absorption spectrum with a maximum at 450nm (hence the name CYP450)
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17
Q

Does CYP3A4 have multiple binding sites?

A

yes, multiple, shows steric activity

18
Q

Describe the first step CYP cycle - activation of O2

A
  1. Drug molecule binds to CYP450 reductase, causing conformational changes of enzyme active site and goes from low to high spin (changes reduction potential of enzyme - more open to accept electrons)
19
Q

What happens after the drug molecule binds to CYP450 reductase (second step)?

A
  1. Iron is now reduced, this form of an enzyme is ready to bind the oxygen, can also bind carbon monoxide. P450-reductase facilitates the donation of electrons
20
Q

What is the third step in the CYP cycle?

A
  1. Oxygen binds and goes to a form that is ready to accept another electron (by NADPH)
21
Q

What is the fourth step in the CYP cycle?

A
  1. NADPH provides another electron or another source (another flava protein), peroxyl state - active state so can be quickly protonated
22
Q

What is the fifth step in the CYP cycle?

A
  1. Protonated causing release of water molecule leaving CYP450 compound 1
23
Q

What is the sixth step in the CYP cycle?

A
  1. Release of oxidated drug molecule (R-OH) enzyme goes back to initial form
24
Q

What is FP2?

A

Second reductase

25
Q

What does FP2 use?

A
  • NAD not NADP

- cytochrome b5 not cytochrome P450

26
Q

What does cytochrome b5 use?

A
  • FP2 not FP1
  • can transfer electrons directly to cytochrome P450

*provides flexibility in electron supply and transfer

27
Q

What do CYPs have that allow them bind to certain molecules for metabolism?

A

Sites on the active site that will bind to a particular type of molecule

28
Q

What does steric hindrance do to CYP metabolism?

A

Degree of steric hindrance limits access of the iron-oxygen complex and therefore prevents metabolic reaction.

*o2 needs to have access to active site

29
Q

What needs to be easily abstracted from the C (or N or S) atom in CYP metabolism?

A

Electron or hydrogen

30
Q

What CYP enzymes are considered for metabolic DDI screening in drug development?

A

CYP1A2, -2B6, -2C8, -2C9, -2C19, - 2D6 and CYP3A

31
Q

What CYP enzyme has narrow specificity?

A

CYP2C9

32
Q

What CYP enzyme has broad and overlapping specificity?

A

CYP3A4

33
Q

What drug substrate preference does CYP2D6 have?

A

Arylalkylamines (basic) with site of oxidation 5-7Å from protonated nitrogen

e.g. ecstasy and fluoxetine

34
Q

What drug substrate preference does CYP2C9 have?

A

Neutral or acidic molecules with site of oxidation 5-8Å from H-bond donor heteroatom.

Molecules tend to be amphipathic with a region of lipophilicity at the site of hydroxylation and an area of hydrophilicity around the H-bond forming region

e.g. tolbutamide and warfarin

35
Q

What drug substrate preference does CYP3A4 have?

A

Lipophilic and ‘bulky’, neutral or basic molecules with site of oxidation often basic nitrogen (N-dealkylation) or allylic positions

e.g. midazolam and testosterone

36
Q

What are genetic polymorphisms?

A

existence of poor metabolisers (lack CYP2D6 gene – cannot metabolise drugs that are substrates for CYP2D6)

37
Q

What does polymorphism contribute to in drug pharmacokinetcs?

A

Inter-individual variability (also efficacy and safety)

  • Tacrolimus – CYP3A5
  • Mycophenolic acid – UGT1A9
  • 6-mercaptopurine - TPMT
38
Q

What may 2 drugs metabolised by the same CYP do?

A

Compete for metabolism - drug-drug interaction potential

39
Q

What is a poor metabolizer (PM)?

A

Lack of CYP2D6 gene
–> Higher plasma concentrations of CYP2D6 substrates compared to EMs – higher risk of side effects (e.g. fluvoxamine), may need to adjust the dose

40
Q

What are the ethnic differences in frequency of allelic variants?

A

For example - 7% of Caucasian population are PMs

New drugs should not be exclusively metabolised by CYP2D6!

41
Q

What is an extensive metabolizer ?

A

Normal activity

42
Q

What is an ultra-rapid metabolizer? (UM)

A

Gene duplication:
Low plasma concentrations of CYP2D6 substrates compared to EMs – likely risk of therapeutic failure. (e.g. paroxetine, SSRIs) may need to increase doses in these individuals

Y3 Med drug disposition (12 decks)

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