Cytochrome P450s in Humans David Nelson Feb. 4, 2009.
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Transcript of Cytochrome P450s in Humans David Nelson Feb. 4, 2009.
Cytochrome P450s in Humans David Nelson Feb. 4, 2009
Human Cytochrome P450s
Lipid metabolismDrug metabolism
CholesterolSteroidsBile AcidsVitamin DFatty AcidsRetinoic AcidProstacyclinsThromboxane A 2
Origin of the P450 name = pigment at 450nm
P450
ER membrane Substrate and O 2
Cytochrome P450 membrane topology
cytosol
NH2
P450
FAD
FMN
NADPH2 e-
NADPH Cytochrome P450Reductase
ER membrane Substrate and O 2
Class II P450 enzymes
cytosol
P450
FAD
FeS
NADPH2 e-
Ferredoxin
Ferredoxin Reductase
Mitochondrial inner membrane
Substrate and O 2
Class I P450 enzymes
matrix
(>55% identity)
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 hydroxylaseCYP19 steroid biosynthesis (1 subfamily, 1 gene) aromatase forms estrogenCYP20 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
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
Human CYP1A2 top and side view, J. Biol. Chem., Vol. 282, 14348-14355, May 11, 2007
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 hydroxylaseCYP19 steroid biosynthesis (1 subfamily, 1 gene) aromatase forms estrogenCYP20 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
The AmpliChip CYP450 array from Roche
The first pharmacogenomics diagnostic chip
3A4 + 3A5
2D6
2C9
2C19
2E1
1A1 1A2 1B1 2A62B6
2C8
Human CYPs contribution to drug metabolism
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.
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).
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
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)
3 7
1224
Cortisol
11-Deoxdycortisol
11-Deoxycorticosterone
Corticosterone
Aldosterone
11A1
CYP17
CYP19
11B1
CYP21
CYP21
11B1
11B2CYP17
CYP17 CYP17
CYP27A1
CYP27B1
active form
CYP24
inactive
24 2627
1
CYP2R1
Human Rat Mouse
CYP2ABFGST
CYP2C
CYP2J
CYP3A
CYP4ABXZ
CYP4F
Total
6 14 13
1 5 9
1 5 8
4 6 8
5 6 10
6 9 9
27 55 72
4 10 15CYP2D