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Biochem > Lecture 5: Cytochromes P450 > Flashcards

Lecture 5: Cytochromes P450 Flashcards

1
Q

Cytochromes P450

A

-powerful detox system
-steroid hormone synthesis
-polyunsaturated fatty acid metabolism
-certain proteins in the ER
-proteins in liver metabolize potential toxins

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2
Q

P450 Detox system

A

-first line of defense against toxins
-susbstrates are unusual chemicals (drugs, poisons)
-convert compounds to be more easily excreted

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3
Q

Super family of P450

A

-dif ones act on molecules with dif structure
-1000s identified in the organism domains

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4
Q

Plant P450

A

-need for biosynthesis of pigments and toxins for protection
-used in metabolic efforts for large-scale medicine production

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5
Q

Nomenclature

A

Superfamily > family (CYP#)> subfamily (letter)> members (#)

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6
Q

P450 families

A

-sequence identity > 40%
-CYP1, CYP2, CYP3, etc

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7
Q

P450 subfamilies

A

-sequence identity > 55%
-CYP1A, CYP1B, CYP1C, etc

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8
Q

P450 individual members

A

-numbered
-CYP1A1, CYP1A2, CYP1A3

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9
Q

Human P450

A

-18 families
-41 subfamilies
-majority CYP1-4
-other families rarely induced

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10
Q

CYP1-4

A

-4 inducible (diet drugs etc) human P450 families
-have several members
-metabolize eicosanoid

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11
Q

Cytochromes P450 enzymatic function

A

-monooxygenases
-catalyze O from radical, one O to product, one to water
-product more hydrophilic=better substrate for detoxifying
-requires heme iron

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12
Q

Endogenous P450 substrates

A

-cholesterol
-steroid hormones
-fatty acids
-higher substrate specificity than exogenous

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13
Q

P450 substrates

A

endogenous vs exogenous
-vary in how many substrates each can metabolize

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14
Q

Exogenous P450 substrates

A

-drugs
-food additives
-environmental contaminants

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15
Q

P450 biological functions

A

-synthesis: of steroid hormones, vit A and D, lipid-like eicosanoid molecules involved in signaling
-metabolism: of fatty acids and eicosannoids
-Detoxification
-Hydroxylation

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16
Q

Hydroxylation

A

-increases aqueous solubility of lipid-soluble substrates

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17
Q

Substrate variety

A

= reaction variety

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18
Q

Drug interactions of cytochrome P450

A

-responsible for >70% of clearance of drugs
-CYP3A4 acts on 30-50% of most drugs
-some reactions harmful: acetaminophen

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19
Q

CYP3A4A

A

-liver
-act on 30-50% of drugs (ex erythromycin (antibiotic))
-catalysis of acetaminophen generates highly reactive compound that causes toxicity at high doses

20
Q

P450 structure

A

-integral membrane protein with single heme group
-anchored to membrane by N-terminal helix
-well conserved
-conformational changes can occur in binding

21
Q

P450 heme group

A

-site of oxidation
-iron coordinated with porphyrin ring and protein
-6th coord site is open or occupied by O2 or other ligands
-on top of heme just above orange sphere

22
Q

P450 Catalytic cycle

A
  1. water and iron3
  2. substrate removes water
  3. iron3 to iron 2 via e-
  4. O2 added = oxy-ferrous (one O has -1 charge)
  5. e- transfer (O-1 to O-2) = peroxanion
  6. Compound I

DOG just look at the slide 7

23
Q

Reactions catalyzed by P450

A

-aliphatic and aromatic hydroxylation
-epoxidation
-dealkylation
-N-oxidation

-all add oxygen

24
Q

aliphatic hydroxylation

A

R-CH2-CH3 –> R-CH2-CH2OH

25
Q

Aromatic hydroxylation

A

add OH to ring

26
Q

Epoxidation

A

add oxygen to alkene and makes triangle

27
Q

Dealkylation

A

R-CH2-NH-CH3 –> R-CH2-NH-CH2-OH –> R-CH2-NH2 + HCHO
-get rid of carbon
-N or O or S dealkylation

28
Q

N-oxidation

A

add OH to NH2

29
Q

Lipophilic xenobiotics

A

-drugs, food additive, environment
-oxidized by P450
-exogenous compounds

30
Q

P450 oxidation of xenobiotics

A

-exogenous compounds
-promotes elimination
-phase 1 metabolism
-phase 2 biosynthesis rxs like linking to glutatione, sulfate, etc
-CYP3A4

31
Q

CYP3A4

A

-GI tract, liver
-responsible for poor bioavailability of some drugs

32
Q

P450 isoforms of CYP3A4

A

-less discriminating
-variety of lipophlic substrates
-multiple sites of oxidation
-lower regioselectivity

33
Q

Metabolism of xenobiotic outcomes

A

-inactivation (drug metabolism)
-activation (prodrug conversion)
-formation of highly toxic metabolite (like benzoapyrene from cig burning)

34
Q

Benzo[a]pyrene

A

-weak carcinogen
-metabolized multiple times to make stronger carcinogen

35
Q

Steroid hormone pathways

A

-endogenous substrates
-higher P450 specificity
-can involve several P450s
-one P450 can catalyze multiple steps
-SLIDE 15 mech

36
Q

Induction of P450

A

decreased drug plasma levels

37
Q

inhibition of P450

A

increased drug plasma levels

38
Q

Drug-drug interactions

A

-unintended effects can occur due to altering P450 activity
-problematic for drugs requiring tight control of plasma levels
-vital importance to patient, critical side effects, small therapuetic index

39
Q

CYP3A4 induction as cause of drug interactions

A

-upregulation increases rate of metabolism of drugs in liver
-Rifampicin
-St. John’s wort

40
Q

Rifampicin (induction)

A

-antituberculosis drug
-inducer of CYP3A4
-makes many drugs less effective
-increases elimination of warfarin which might increase risk of undertreating anticoagulation

41
Q

St. John’s-wort

A

-herbal med for depression
-induces CYP3A4 and causes multiple adverse drug reactions

42
Q

CYP3A4 inhibition as a cause of drug interaction

A

-certain drug inhibits activity (erythromycin/ketoconazole)
-patient takes terfenadine for allergies
-increased plasma levels that can cause serious cardiac problems

43
Q

Terfenadine (seldane)

A

-H1 antihistamine for seasonal allergies
-pro drug rapidly metabolized by CYP3A4 into fexofenadine (the active compound)
-CYP3A4 inhibition can lead to cardiac problems
-avoid risk by using drug replaced by fexofenadine (allegra)

44
Q

NAPQI

A

-generated in a small amount from metabolization of acetaminophen by CYP2E1
-normally conjugated with glutathione (GSH) to generate non toxic form

45
Q

Acetaminophen-induced liver toxicity

A

-high doses increase NAPQI and can deplete glutathione pool
-NAPQI not conjugated = toxic
-35% of liver failure cases

46
Q

CYP2E1

A

-metabolizes acetaminophen
-induced by alcohol = more NAPQI
-BUT alcohol is one of its substrates so it can inhibit the metabolism of other drugs
-effect depends on time of drinking and taking acetaminophen

47
Q

Genetic Polymorphisms of P450: CYP2A6

A

-nicotine metabolism
-SLIDE 21

Biochem (30 decks)

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