Cytochrome P450s in Humans David Nelson Feb. 4, 2009

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Presentation transcript:

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

Cytochrome P450 membrane topology cytosol ER membrane Substrate and O 2 NH 2 Cytochrome P450 membrane topology

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

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

(>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 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

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 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 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

The AmpliChip CYP450 array from Roche The first pharmacogenomics diagnostic chip

Human CYPs contribution to drug metabolism 3A4 + 3A5 2C19 2D6 2E1 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)

24 12 3 7

CYP21 11A1 11B1 CYP17 CYP17 11B2 CYP21 CYP17 CYP17 11B1 CYP19 11-Deoxycorticosterone 11B1 Corticosterone CYP17 CYP17 11B2 Aldosterone CYP21 CYP17 CYP17 11-Deoxdycortisol 11B1 CYP19 Cortisol

24 26 27 CYP27A1 1 CYP2R1 CYP27B1 CYP24 active form inactive

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