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Cytochrome P450s in Humans David Nelson Feb. 4, 2009

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Humans have 18 families of cytochrome P450 genes and 44 subfamilies. CYP1 drug metabolism (2 subfamilies, 3 genes, 1 pseudogene) ... – PowerPoint PPT presentation

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Title: Cytochrome P450s in Humans David Nelson Feb. 4, 2009


1
Cytochrome P450s in Humans David Nelson Feb. 4,
2009
2
Human Cytochrome P450s
Lipid metabolism
Drug metabolism
Cholesterol Steroids Bile Acids Vitamin D Fatty
Acids Retinoic Acid Prostacyclins Thromboxane A
2
3
Origin of the P450 name pigment at 450nm
4
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5
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6
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7
P450
cytosol
ER membrane
Substrate and O
2
NH
2
Cytochrome P450 membrane topology
8
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10
NADPH
NADPH Cytochrome P450
-
FAD
2 e
Reductase
FMN
P450
cytosol
ER membrane
Substrate and O
2
Class II P450 enzymes
11
NADPH
Ferredoxin Reductase
-
2 e
FAD
Ferredoxin
FeS
P450
matrix
Mitochondrial inner membrane
Substrate and O
2
Class I P450 enzymes
12
(gt55 identity)
13
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
14
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
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16
Human CYP1A2 top and side view, J. Biol. Chem.,
Vol. 282, 14348-14355, May 11, 2007
17
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
18
The AmpliChip CYP450 array from Roche The first
pharmacogenomics diagnostic chip
19
1A1
1A2
1B1
2A6
2B6
2C8
2C9
3A4 3A5
2C19
2D6
2E1
Human CYPs contribution to drug metabolism
20
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.
21
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).
22
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 gt 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
23
Terfenadine vs. ketoconazole 15 to 72X increase
of AUC (area under the curve) of terfenadine
(CYP3A4) (Honig et al. 1993) Venlafaxine/quinidi
ne up to 20X increase of AUC venlafaxine
(CYP2D6) subgroup of extensive metabolizers 0.5
to 10X change of venlafaxine AUC (Lessard et al.
1999)
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26
24
12
3
7
27
CYP21
11A1
11-Deoxycorticosterone
11B1
Corticosterone
CYP17
11B2
CYP17
Aldosterone
CYP21
CYP17
CYP17
11-Deoxdycortisol
11B1
CYP19
Cortisol
28
24
26
27
CYP27A1
1
CYP2R1
CYP27B1
CYP24
active form
inactive
29
Human Rat Mouse
CYP2ABFGST
6 14 13
CYP2C
4 10 15
1 5 9
CYP2D
CYP2J
1 5 8
CYP3A
4 6 8
CYP4ABXZ
5 6 10
CYP4F
6 9 9
Total
27 55 72
30
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