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

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Presentation on theme: "Cytochrome P450s in Humans David Nelson Feb. 4, 2009."— Presentation transcript:

1 Cytochrome P450s in Humans David Nelson Feb. 4, 2009

2 Human Cytochrome P450s Lipid metabolismDrug metabolism Cholesterol Steroids Bile Acids Vitamin D Fatty Acids Retinoic Acid Prostacyclins Thromboxane A 2

3 Origin of the P450 name = pigment at 450nm

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7 P450 ER membraneSubstrate and O 2 Cytochrome P450 membrane topology cytosol NH 2

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10 P450 FAD FMN NADPH 2 e - NADPH Cytochrome P450 Reductase ER membraneSubstrate and O 2 Class II P450 enzymes cytosol

11 P450 FAD FeS NADPH 2 e - Ferredoxin Ferredoxin Reductase Mitochondrial inner membrane Substrate and O 2 Class I P450 enzymes matrix

12 (>55% 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, , 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 3A4 + 3A5 2D6 2C9 2C19 2E1 1A1 1A2 1B1 2A6 2B6 2C8 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 > 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/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)

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27 Cortisol 11-Deoxdycortisol 11-Deoxycorticosterone Corticosterone Aldosterone 11A1 CYP17 CYP19 11B1 CYP21 11B1 11B2CYP17

28 CYP27A1 CYP27B1 active form CYP24 inactive CYP2R1

29 Human Rat Mouse CYP2ABFGST CYP2C CYP2J CYP3A CYP4ABXZ CYP4F Total CYP2D

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