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11/06/08 11/11/08 Discussion - ALL SECTIONS MEET IN ROOM 107 Peterson 11/13/08 Discussion 11/18/08 11/20/08 Bryk Group presentations meet in your discussion room Group presentations meet in your discussion room Thanksgiving Group presentations meet in your discussion room Final Exam 3-5 PM Room 107 11/25/08 11/27/08 12/02/08 12/05/08 Hints for making a clear group presentation Prions and protein folding Work in groups on your group presentations HIV/AIDS Student presentations Student presentations No class Student presentations Final exam Drug Metabolism or What’s wrong with more grapefruit juice? McGill University Health Centre Journal Grapefruit and drugs a potent mix Grapefruits are chalk full of vitamin C, potassium and natural fiber. So they have to be good for you, right? Well, not necessarily. Taking a swallow of grapefruit juice to down your prescription medication could play havoc with the digestion of certain drugs, increasing the amount of medication released into the bloodstream, which could lead to harmful levels or drug toxicity. To complicate matters, if you have always enjoyed a glass of grapefruit juice, stopping this habit could cause the opposite effect, your body will absorb too little medication. Drugs that interact with grapefruit juice. Anxiety: Xanax, Buspar, Versed, Halcion Depression: Luvox, Zoloft Allergies: Allegra Abnormal heart rhythm: Cordarone, quinidine Heart disease/stroke/blood clots: Coumadin Epilepsy: Tegretol Cancer: Cyclophosphamide, etoposide, ifosfamide, tamoxifen, vinblastine, vincristine Cough: Dextromethorphan HIV: Agenerase, Crixivan, Viracept, Norvir, Fortovase Heart disease/High blood pressure: Coreg, Cardizem, Plendil, Cardene, Adalat, Procardia, Nimotop, Sular, Covera, Calan, Verelan Asthma/Emphysema: Theophylline High cholesterol: Lipitor, Lescol, Mevacor, Zocor Pain: Alfenta, Duragesic, Actiq, Sufenta Furocoumarins in grapefruit juice inhibit certain forms of cytochrome P450 Cytochrome P450 Enzyme found mostly in liver Cytochrome P450 has a wide range of roles -steroid hormone biosynthesis from cholesterol -metabolism of xenobiotics-compounds which are not normally found in the body -Drugs -Compounds in food produced by cooking (polyaromatic hydrocarbons, also in tobacco smoke) or microorganisms -typically organic molecules which are poorly soluble in water Cytochrome P450 aids in the metabolism of xenobiotics by adding OH to increase the water solubility of the compound O2 + substrate + 2 electrons HO-substrate + H2 O The OH added by P450 can then be used to attach sulfate (SO42-) or a sugar. The modified drug can be more readily removed by the kidney. Because this enzyme catalyzes the addition of one oxygen atom, it is termed a monooxygenase. Cytochrome P450 contains heme. N N Fe N N Heme The heme group is a cofactor which contains iron. Different forms of heme are found in hemoglobins and proteins known as cytochromes. The iron in a heme can bind oxygen and transfer electrons. Cytochrome P450 Cytochrome P450’s are integral membrane proteins found in the endoplasmic reticulummembrane network in cells http://micro.magnet.fsu.edu/cells/endoplasmicreticulum/endoplasmicreticulum.html Cytochrome P450 At least 57 different isozymes in humans, over 7700 forms in Nature isozyme-catalytically and structurally similar but genetically distinct enzymes-different genes and amino acid sequences Different isozymes have different substrate specificities Individuals have several alleles for P450’s and differ in which isozymes they have Since individuals have different combinations of P450’s, they differ in their response to specific drugs A subset of cytochrome P450’s can be induced, so that more is expressed upon exposure to a compound. Because of the number of different isozymes and their different substrates and inhibitors, the metabolism of a drug can be altered if an individual takes a second drug. Some substrates of cytochrome P450 isozymes 1A2 2B6 2C8 2C19 2C9 2D6 2E1 3A4,5,7 amitriptyline caffeine clomipr amine clozapine cyclobenzaprine estradiol fluvoxamine haloperidol imipramine NDeMe mexilletine naproxen olanzapine ondansetron phenacetin acetaminophen propranolol riluzole ropivacaine tacrine theophylline tizanidine verapamil bupropion cyclophosphamide efavirenz ifosfamide methadone paclitaxel torsemide amodiaquine cerivastatin repaglinide Proton Pump Inhibitors: lansoprazole omeprazole pantoprazole rabeprazole ibuprofen meloxicam S-naproxen piroxicam suprofen Beta Blockers: Anesthetics: enflurane halothane isoflurane methoxyflurane sevoflurane erythromycin telithromycin Anti-epileptics: diazepam phenytoin(O) S-mephenytoin phenobarbitone amitriptyline carisoprodol citalopram chloramphenicol clomipr amine cyclophosphamide hexobarbital imipramine indomethacin R-mephobarbital Oral Hypoglycemic Agents: tolbutamide glipizide Angiotensin II Blockers: losartan irbesartan Sulfonylureas: glyburide/ glibenclamide glimepiride tolbutamide amitriptyline clomipr amine desipramine imipramine paroxetine Benzodiazepines: cyclosporine tacrolimus (FK506) haloperidol HIV Antivirals alprenolol amphetamine aripiprazole atomoxetine bufuralol chlorpheniramine chlorpromazine codeine Antihistamines: astemizole chlorpheniramine terfenadine fluvoxamine lidocaine metoclopramide methoxyamphetam ine Calcium Channel Blockers HMG CoA Reductase Inhibitors: atorvastatin cerivastatin Some inhibitors of cytochrome P450 isozymes 1A2 2B6 2C8 fluvoxamine ciprofloxacin thiotepa ticlopidine gemfibrozil cimetidine amiodarone fluoroquinolones furafylline interferon methoxsalen mibefradil 2C19 lansoprazole omeprazole2 trimethoprim pantoprazole rabeprazole glitazones montelukast chloramphenicol cimetidine quercetin felbamate fluoxetine fluvoxamine indomethacin ketoconazole modafinil oxcarbazepine probenicid ticlopidine topiramate 3A4,5,7 2C9 2D6 2E1 fluconazole bupropion fluoxetine paroxetine quinidine HIV Antivirals: diethyldithiocarbamate indinavir nelfinavir ritonavir duloxetine terbinafine clarithromycin itraconazole ketoconazole nefazodone saquinavir telithromycin amiodarone fenofibrate fluvastatin fluvoxamine isoniazid lovastatin phenylbutazone probenicid sertraline sulfamethoxazole sulfaphenazole teniposide voriconazole zafirlukast amiodarone cimetidine sertraline celecoxib chlorpheniramine chlorpromazine citalopram clemastine clomipramine cocaine diphenhydramine doxepin doxorubicin escitalopram halofantrine hydroxyzine levomepromazine methadone metoclopramide mibefradil aprepitant erythromycin fluconazole grapefruit juice verapamil diltiazem cimetidine amiodarone chloramphenicol delaviridine diethyldithiocarbamate fluvoxamine gestodene Some inducers of cytochrome P450 isozymes 1A2 chromosome 15 2B6 chromosome 6 broccoli phenobarbital brussel sprouts rifampin char-grilled meat insulin methylcholanthrene modafinil nafcillin beta-naphthoflavone1 omeprazole tobacco 2C8 chromosome 10 2C19 chromosome 10 2C9 chromosome 10 2D6 chromosome 22 2E1 chromosome 10 3A4,5,7 chromosome 7 rifampin carbamazepine norethindrone NOT pentobarbital prednisone rifampin rifampin secobarbital dexamethasone rifampin thanol isoniazid HIV Antivirals: efavirenz nevirapine barbiturates carbamazepine efavirenz glucocorticoids modafinil nevirapine oxcarbazepine phenobarbital phenytoin pioglitazone rifabutin rifampin St. John's wort troglitazone The reaction of cytochrome P450 can also produce a toxic compound: Metabolism of acetaminophen (Tylenol) O C HN CH3 OH Acetaminophen At normal doses, sulfate or a sugar is attached to OH and the drug is easily removed by the kidney. At high doses, this pathway cannot keep up and a liver P450 converts acetaminophen to a toxic metabolite which causes liver damage. Metabolism of neurotransmitters-monoamine oxidase Several important neurotransmitters are amines. HO HO OH HO HO NH3 dopamine NH3 norepinephrine HO HO NH3 NH3 HO NH2 CH3 epinephrine N H serotonin These are released into the blood where they bind to receptors on the surface of cells. To ensure that the action of amine neurotransmitters is short, they are destroyed by the enzyme monoamine oxidase. Monoamines also come from the diet Tyramine is formed from tyrosine. If blood levels rise they disrupt catecholamine metabolism, leading to possibly fatal hypertension. Monoamine oxidase prevents this. HO NH3 tyramine Foods containing high levels of tyramine: smoked, aged, or pickled meat or fish; sauerkraut aged cheeses (e.g., swiss, cheddar, blue, boursault, camembert, emmenthaler, stilton); yeast extracts fava beans beef or chicken liver aged sausages (e.g., bologna, pepperoni, salami, summer sausage) game meats (e.g., venison, rabbit) red wines (e.g., chianti, sherry). Monoamine oxidase An integral membrane protein in liver mitochondria. Oxidizes amines to aldehydes: HO O2 HO HO HO NH3 O + NH4 Monoamine oxidase contains FAD as a cofactor R' N N O NH N O Flavin Adenosine Dinucleotide Synthesized from the vitamin riboflavin Used in electron transfer reactions Monoamine oxidase contains FAD as a cofactor Monoamine oxidase inhibitors Monoamine oxidase (MAO) inhibitors are used as antidepressants and to treat eating disorders. They keep serotonin levels up. Serotonin controls mood. MAO inhibitors can cause overdoses: No longer break down tyramine from diet. High levels of tryptophan in diet can result in serotonin levels becoming too high. Will prevent metabolism of drugs that are amines. As a result MAO inhibitors can result in serious side effects when used with other drugs. MAO inhibitors have been replaced with drugs which prevent the binding of serotonin to cells, such as Prozac. These do not affect the metabolism of other amines, so that there are far fewer side effects.