WCRJ 2015; 2 (2): e524 CLINICALLY RELEVANT OF CYTOCHROME P450 FAMILY ENZYMES FOR DRUG-DRUG INTERACTION IN ANTICANCER THERAPY A. RAINONE 1, D. DE LUCIA 2, C.D. MORELLI 1, D. VALENTE 3,4 , O. CATAPANO 4, M. CARAGLIA 5 1GORI “Gruppo Oncologico Ricercatori Italiani” Onlus, Pordenone, Italy. 2Department of Neurology, Azienda Policlinico Second University of Naples (SUN), Naples, Italy. 3Research Center CETAC, Caserta, Italy. 4Italian Association of Pharmacogenomics and Molecular Diagnostics, Caserta, Italy. 5Department of Biochemical, Biophysical and Pathology, Second University of Naples (SUN), Naples, Italy. Absract – In the oncology field, the knowledge of secondary mechanisms for drug metabolism allow physicians to improve the efficacy of cancer therapy. This review provides an overview on the commonly occurring, functionally and/or clinically relevant Cytochrome P450 (CYP) superfamily. Particular highlight were attempt on genetic variations in the CYP2D6 gene and the pharmacoki - netics and/or response of drug-based chemotherapy. In addition, current genetic polymorphisms re - sponsible of variability in drug-drug interaction between anticancer drugs and antidepressant are discussed. Further, effective re-evaluation of drug design based on CYP enzymes profile may even - tually be personalized and individualized to the patient for maximum efficacy of the therapies. KEY WORDS: Pharmacogenetics profile, Phase I enzyme. Personalized therapy, Drug metabolism. INTRODUCTION 2 able . Drugs can interact with CYP450 enzymes as inhibitor, inducer or substrate (Table 1). Drugs that Cytochrome P450 (CYP450) isoenzymes are a inhibit CYP450 enzymes generally lead to de - group of heme-containing enzymes involved in the creased metabolism of other drugs metabolized by metabolism of many drugs, steroids and carcino - the same enzyme, resulting in higher drug levels gens 1. In particular, these isoenzymes are responsi - and increased toxicity. Induction of the CYP450 ble for catalyzing the oxygenation of a broad system results in the increased clearance of con - number and variety of endogenous and xenobiotic comitant drugs metabolized by the same enzyme. substrates. CYP450-catalyzed reactions can be di - Drugs that induce CYP450 enzymes increase the vided into four categories: hydroxylation reactions production of specific enzymes of the CYP450 sys - where a hydroxyl group replaces hydrogen atom; tem by leading to increased metabolism and de - epoxidation reactions where an oxygen is intro - creased concentrations of drugs metabolized via duced into a carbon-carbon p-bond; heteroatom ox - the same pathway. Beyond these regulatory mech - idations where an oxygen is added to a nitrogen, anisms that involve drugs which induce or inhibit sulfur, or other heteroatom; or reduction reactions CYP450 enzymes, genetic polymorphisms associ - which occur under conditions of limited oxygen as - ated with altered CYP450 expression or catalytic suming that an alternate electron acceptor is avail - activities have been identified 3. Corresponding Author : Lino del Pup, MD; e-mail: [email protected] 1 Table 1. Major human cytochrome P450 (CYP) enzymes involved in drug metabolism. CYP CYP Substrates Inhibitors Inducers Gene allele* 1A2 *1F Amitriptyline, caffeine, clomipramine Amiodarone, Brussel sprouts, char-grilled cyclobenzaprine, fluvoxamine, estradiol, cimetidine, meat, insulin, methyl haloperidol, imipramine, mexiletine, naproxen, fluoroquinolones, cholanthrene, modafinil, ondansetron (in part), phenacetin, fluvoxamine, nafcillin, anaphthoflavone, propranolol, riluzole ropivacaine, tacrine, furafylline, omeprazole, tobacco theophylline, verapamil, warfarin, zileuton, interferon, zolmitript methoxsalen, mibefradil, ticlopidine 2A6 Bilirubin, Cotinine, Coumarin, Decursinol angelate Artemisinin, 1,7dimethylaxanthine, Efavirenz, Letrozole, menthofuran, Carbamazepine, Nicotine, Pilocarpine, Tegafur 8-methoxypsoralen, Dexamethasone, Pilocarpine, Estrogens, Selegiline, Phenobarbital, Tranylcypromine Rifampicin 2B6 *6 Bupropion, cyclophosphamide ifosphamide, Thiotepa Phenobarbital, phenytoin, omeprazole rifampin 2C19 *2 Amitriptyline, citalopram, clomipramine, Cimetidine, felbamate, Carbamazepine, *3 cyclophosphamide, Clopidrogel, diazepam, fluoxetine, fluvoxamine, norethindrone, *17 E-3810, hexobarbital, imipramine N-deME, indomethacin, prednisone, rifampin indomethacin, lansoprazole, S-mephenytoin, ketoconazole, R-mephobarbital, moclobemide, nelfinavir, lansoprazole, modafinil, nilutamide, pantoprazole, phenytoin, omeprazole, paroxetine, phenobarbitone, primidone, progesterone, probenicid, ticlopidine, proguanil, propranolol, teniposide, R- warfarin topiramate 2C9 *2 *3 Amitriptyline, celecoxib, diclofenac. Amiodarone, fluconazol, Rifampin, secobarbital Fluoxetine, fluvastatin. Glipizide, ibuprofen, fluvastatin, irbesartan, losartan, naproxen, Phenytoin, fluvoxamine, isoniazid, piroxicam, rosiglitazone, sulfamethoxazole, lovastatin) paroxetine, suprofen, tamoxifen, torsemide, tolbutamide, phenylbutazone, S-warfarin probenicid, sertraline, sulfaphenazole, teniposide, trimethoprim, zafirlukast 2D6 *3 Alprenolol, amitriptyline, amphetamine, Amiodarone, celecoxib, Dexamethasone rifampin *4 bufuralol, carvedilol, chlorpromazine, chlorpheniramine, *5 clomipraminecodeine, debrisoquine, chlorpromazine, *6 desipramine, dexfenfluramine, cimetidine, clomipramine, *7 dextromethorphan, encainide, Flecainide, cocaine, doxorubicin, *10 fluoxetine, fluvoxamine, haloperidol, imipramine, fluoxetine, halofantrine, *41 lidocaine, metoclopramide, methoxyamphetamine, levomepromazinemethadone, *XN S-metoprolol, Mexiletine, minaprine, moclobemide, paroxetine, nortriptyline, ondansetron, paroxetine, quinidine, ranitidine, perhexilin, perphenazine, phenacetin, reduced haloperidol phenformin propafenone, propanolol, quanoxan, ritonavir, sertraline, risperidone, sparteine, tamoxifen, thioridazine, terbinafine timolol, tramadol, venlafaxine 2E1 Acetaminophen, aniline, benzene, Diethyl-dithiocarbamate, Ethanol, isoniazid chlorzoxazone, enflurane, ethanol, disulfiram Halothane, isoflurane, methoxyflurane, N,N-dimethylformamide, sevoflurane, theophylline We performed a review by means of a struc - P450 (CYP), anticancer drug, genotyping, and an - tured computerized search in the Medline data - tidepressant drugs. Articles exclusively in English base (1980-2015-may). Keywords were, words were selected. References in relevant arti - polymorphism, drug interactions, cytochrome cles were also retrieved. 2 CLINICALLY RELEVANT OF CYTOCHROME P450 FAMILY ENZYMES FOR DRUG-DRUG INTERACTION IN ANTICANCER THERAPY Table 1. Major human cytochrome P450 (CYP) enzymes involved in drug metabolism (Continued) . CYP CYP Substrates Inhibitors Inducers Gene allele* 3A4/ *2 Alfentanyl, alprazolam, amlodipine, astemizole, Amiodarone, azithromycin, Barbiturates, 3A5 *3 atorvastatin, azithromycin, buspirone, caffeine, cimetidine, ciprofloxacin, carbamazepine, *22 cerivastatin, chlorpheniramine, cisapride, clarithromycin, delaviridine, efavirenz, clarithromycin, cocaine, codeine, cyclosporine, diethyl-dithiocarbamate, glucocorticoids, dapsone, dextromethorphan, diazepam, diltiazem, erythromycin, modafiniln, nevirapine, diltiazem, erythromycin, estradiol, felodipine, fluconazole, fluvoxamine, Phenobarbital, fentanyl, finasteride, haloperidol, gestodene, grapefruit, phenytoin, pioglitazone, hydrocortisone, indinavir, lercanidipine, juice, indinavir, rifampin, St. John’s lidocaine, lovastatin, methadone, midazolam, interleukin-10, itraconazole, wort, troglitazone nelfinavir, nifedipine, nisoldipine, nitrendipine, ketoconazole, mibefradil, pimozide, progesterone, propranolol, quinidine, mifepristone, nefazodone, quinine, ritonavir, salmeterol, saquinavir, nelfinavir, norfloxacin, sildenafil, simvastatin, tacrolimus, tamoxifen, norfluoxetine, ritonavir, taxol, terfenadine, testosterone, trazodone, saquinavir triazolam, verapamil, vincristine, zaleplon, zolpidem *Annotation on CYP variants known to be causing poor metabolizing enzyme profile, referred to Phamacogenomics Knowl - edge Base www.pharmgkb.com Recent progresses in the knowledge on indi - terns of tissue expression. CYP1A1 is expressed vidual metabolic profile have provided exception - primarily in extrahepatic tissues such as the lungs, al opportunities to identify predictive markers for lymphocytes and placenta while CYP1A2 is ex - efficacy of cancer therapy. The medicine of the 3 rd pressed in the liver 5. millennium allow genetic identification of the pa - On the other hand, CYP1B1 is constitutively tients who will benefit from therapy, excluding expressed in a wide range of tissues such as brain, patients at high risk of severe toxicity 4. colon, heart, kidney, leukocytes, liver, lung, ovary, placenta, prostate, skeletal muscle, small intes - 6 CYP families tine, spleen, and thymus . CYP1A1 and CYP1A2 are substrate-inducible CYP450 enzymes respon - sible for the metabolism of numerous xenobiotic The nomenclature of a CYP450 enzyme indicates substrates, including polycyclic aromatic hydro - its similarity in structure to other CYPs (www.cy - carbons (PAH) such as the carcinogen palleles.ki.se accessed june 2015). CYPs that benzo(a)pyrene. In particular, these CYPs cat - have an higher amino acid sequence homology alyze the N-oxidation of carcinogenic aromatic than 40% are grouped into families, and those and heterocyclic amines found in cigarette smoke with greater than 55% homology are grouped into and in charred foods 7. Polymorphisms that influ - subfamilies.Thus