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Cytochrome P450s in Humans David Nelson Feb. 4, 2009. Human Cytochrome P450s. Drug metabolism. Lipid metabolism. Cholesterol Steroids Bile Acids Vitamin D Fatty Acids Retinoic Acid Prostacyclins Thromboxane A. 2. Origin of the P450 name = pigment at 450nm. P450. cytosol.

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slide2

Human Cytochrome P450s

Drug metabolism

Lipid metabolism

Cholesterol

Steroids

Bile Acids

Vitamin D

Fatty Acids

Retinoic Acid

Prostacyclins

Thromboxane A

2

slide7

P450

cytosol

ER membrane

Substrate and O

2

NH

2

Cytochrome P450 membrane topology

slide10

NADPH

NADPH Cytochrome P450

-

2 e

FAD

Reductase

FMN

P450

cytosol

ER membrane

Substrate and O

2

Class II P450 enzymes

slide11

NADPH

Ferredoxin Reductase

-

2 e

FAD

Ferredoxin

FeS

P450

matrix

Mitochondrial inner membrane

Substrate and O

2

Class I P450 enzymes

slide13

Humans have 18 families of cytochrome P450 genes and 44 subfamilies

CYP1 drug metabolism (2 subfamilies, 3 genes, 1 pseudogene)

CYP2 drug, steroid, vitamin D metabolism (13 subfamilies, 16 genes, 16 pseudogenes)

CYP3 drug metabolism (1 subfamily, 4 genes, 2 pseudogenes)

CYP4 arachidonic acid or fatty acid metabolism (6 subfamilies, 12 genes, 10 pseudogenes)

CYP5 Thromboxane A2 synthase (1 subfamily, 1 gene)

CYP7A bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus (1 subfamily member)

CYP7B brain specific form of 7-alpha hydroxylase (1 subfamily member)

CYP8A prostacyclin synthase (1 subfamily member)

CYP8B bile acid biosynthesis (1 subfamily member)

CYP11 steroid biosynthesis (2 subfamilies, 3 genes)

CYP17 steroid biosynthesis (1 subfamily, 1 gene) 17-alpha hydroxylase

CYP19 steroid biosynthesis (1 subfamily, 1 gene) aromatase forms estrogen

CYP20 Unknown function (1 subfamily, 1 gene)

CYP21 steroid biosynthesis (1 subfamily, 1 gene, 1 pseudogene)

CYP24 vitamin D degradation (1 subfamily, 1 gene)

CYP26A retinoic acid hydroxylase important in development (1 subfamily member)

CYP26B retinoic acid hydroxylase (1 subfamily member)

CYP26C retinoic acid hydroxylase (1 subfamily member)

CYP27A bile acid biosynthesis (1 subfamily member)

CYP27B Vitamin D3 1-alpha hydroxylase activates vitamin D3 (1 subfamily member)

CYP27C unknown function(1 subfamily member)

CYP39 7 alpha hydroxylation of 24 hydroxy cholesterol (1 subfamily member)

CYP46 cholesterol 24-hydroxylase (1 subfamily member)

CYP51 cholesterol biosynthesis (1 subfamily, 1 gene, 3 pseudogenes) lanosterol 14-alpha demethylase

blue = mitochondrial

slide14

Induction of Cytochrome P450 Genes

endocrine control ACTH (steroid biosynthesis P450s)

PPAR peroxisome proliferators (clofibrate) CYP4 family

PXR CYP3 family

CAR phenobarbital CYP2B 40-50X in rats

AHR (benzo-a-pyrene, cigarette smoke) CYP1 family

ethanol CYP2E1 enzyme stabilization by substrate

slide17

Humans have 18 families of cytochrome P450 genes and 43 subfamilies

CYP1 drug metabolism (2 subfamilies, 3 genes, 1 pseudogene)

CYP2 drug, steroid, vitamin D metabolism (13 subfamilies, 16 genes, 16 pseudogenes)

CYP3 drug metabolism (1 subfamily, 4 genes, 2 pseudogenes)

CYP4 arachidonic acid or fatty acid metabolism (5 subfamilies, 11 genes, 10 pseudogenes)

CYP5 Thromboxane A2 synthase (1 subfamily, 1 gene)

CYP7A bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus (1 subfamily member)

CYP7B brain specific form of 7-alpha hydroxylase (1 subfamily member)

CYP8A prostacyclin synthase (1 subfamily member)

CYP8B bile acid biosynthesis (1 subfamily member)

CYP11 steroid biosynthesis (2 subfamilies, 3 genes)

CYP17 steroid biosynthesis (1 subfamily, 1 gene) 17-alpha hydroxylase

CYP19 steroid biosynthesis (1 subfamily, 1 gene) aromatase forms estrogen

CYP20 Unknown function (1 subfamily, 1 gene)

CYP21 steroid biosynthesis (1 subfamily, 1 gene, 1 pseudogene)

CYP24 vitamin D degradation (1 subfamily, 1 gene)

CYP26A retinoic acid hydroxylase important in development (1 subfamily member)

CYP26B retinoic acid hydroxylase (1 subfamily member)

CYP26C retinoic acid hydroxylase (1 subfamily member)

CYP27A bile acid biosynthesis (1 subfamily member)

CYP27B Vitamin D3 1-alpha hydroxylase activates vitamin D3 (1 subfamily member)

CYP27C unknown function(1 subfamily member)

CYP39 7 alpha hydroxylation of 24 hydroxy cholesterol (1 subfamily member)

CYP46 cholesterol 24-hydroxylase (1 subfamily member)

CYP51 cholesterol biosynthesis (1 subfamily, 1 gene, 3 pseudogenes) lanosterol 14-alpha demethylase

blue = mitochondrial

slide18

The AmpliChip CYP450 array from Roche

The first pharmacogenomics diagnostic chip

slide19

1A1

1A2

1B1

2A6

2B6

2C8

2C9

3A4 + 3A5

2C19

2D6

2E1

Human CYPs contribution to drug metabolism

slide20

CYP2D6 Substrates

* Antiarrhythmics: Flecainide, Mexiletine,

Propafenone

* Antidepressants: Amitriptyline, Paroxetine,

Venlafaxine, Fluoxetine (Prozac), Trazadone

* Antipsychotics: Clorpromazine, Haloperidol,

Thoridazine

* Beta-Blockers: Labetalol, Timolol, Propanolol,

Pindolol, Metoprolol

* Analgesics: Codeine, Fentanyl, Meperidine,

Oxycodone, Propoxyphene

oxycodone is oxycontin, a favorite drug of abuse.

slide21

CYP3A4 Substrates

* Acetominophen (Tylenol)

* Codeine (narcotic)

* Cyclosporin A (an immunosuppresant),

* Diazepam (Valium)

* Erythromycin (antibiotic)

* Lidocaine (anaesthetic),

* Lovastatin (HMGCoA reductase inhibitor,

a cholesterol lowering drug),

* Taxol (cancer drug),

* Warfarin (anticoagulant).

slide22

CASE REPORT:

Man, 63, had been receiving medication for major

depression, boarded flight from Toronto, Canada to

London, UK. Upon arrival - passenger in seat 83A

found unrousable

Carry-on bag:

Mefadazone (used for > 1 mo., for depression

Ketoconazole (fungal infection, 6 - mo. supply)

Triazolam (antipsychotic, insomnia, ? taken)

Reason: DRUG INTERACTIONS

ALL THREE DRUGS - BIND TO CYP3A4

Result of concomitant medication

DRUG INTERACTIONS -

any change of therapeutic effectiveness or

toxicity caused by concomitant uptake of two

or more drugs

slide23

Terfenadine vs. ketoconazole: 15 to 72X

increase of AUC (area under the curve) of

terfenadine (CYP3A4) (Honig et al. 1993)

Venlafaxine/quinidine: up to 20X

increase of AUC venlafaxine (CYP2D6)

subgroup of extensive metabolizers:

0.5 to 10X change of venlafaxine AUC

(Lessard et al. 1999)

slide26

24

12

3

7

slide27

CYP21

11A1

11-Deoxycorticosterone

11B1

Corticosterone

CYP17

CYP17

11B2

Aldosterone

CYP21

CYP17

CYP17

11-Deoxdycortisol

11B1

CYP19

Cortisol

slide28

24

26

27

CYP27A1

1

CYP2R1

CYP27B1

CYP24

active form

inactive

slide29

Human Rat Mouse

CYP2ABFGST

6 14 13

CYP2C

4 10 15

CYP2D

1 5 9

CYP2J

1 5 8

CYP3A

4 6 8

CYP4ABXZ

5 6 10

CYP4F

6 9 9

Total

27 55 72