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WCRJ 2015; 2 (2): e524

CLINICALLY RELEVANT OF P450 FAMILY FOR DRUG- 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 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 allow physicians to improve the of cancer therapy. This review provides an overview on the commonly occurring, functionally and/or clinically relevant (CYP) superfamily. Particular highlight were attempt on genetic variations in the CYP2D6 and the pharmacoki - netics and/or response of drug-based . In addition, current genetic polymorphisms re - sponsible of variability in drug-drug interaction between anticancer drugs and 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 . Personalized therapy, .

INTRODUCTION 2 able . Drugs can interact with CYP450 enzymes as inhibitor, inducer or (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 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: 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 *

1A2 *1F , , , Brussel sprouts, char-grilled , , estradiol, , meat, insulin, methyl , , , naproxen, fluoroquinolones, cholanthrene, , (in part), , fluvoxamine, nafcillin, anaphthoflavone, , riluzole ropivacaine, tacrine, furafylline, , theophylline, verapamil, warfarin, , interferon, zolmitript methoxsalen, , 2A6 Bilirubin, Cotinine, Coumarin, Decursinol angelate Artemisinin, 1,7dimethylaxanthine, , Letrozole, menthofuran, Carbamazepine, , Pilocarpine, Tegafur 8-methoxypsoralen, , Pilocarpine, Estrogens, , Phenobarbital, 2B6 *6 , cyclophosphamide ifosphamide, Thiotepa Phenobarbital, phenytoin, omeprazole rifampin 2C19 *2 Amitriptyline, , clomipramine, Cimetidine, felbamate, Carbamazepine, *3 cyclophosphamide, Clopidrogel, diazepam, , fluvoxamine, norethindrone, *17 E-3810, hexobarbital, imipramine N-deME, indomethacin, prednisone, rifampin indomethacin, lansoprazole, S-mephenytoin, ketoconazole, R-mephobarbital, , nelfinavir, lansoprazole, modafinil, nilutamide, pantoprazole, phenytoin, omeprazole, , phenobarbitone, , progesterone, probenicid, ticlopidine, proguanil, propranolol, teniposide, R- warfarin topiramate 2C9 *2 *3 Amitriptyline, , diclofenac. Amiodarone, fluconazol, Rifampin, secobarbital Fluoxetine, fluvastatin. Glipizide, ibuprofen, fluvastatin, irbesartan, losartan, naproxen, Phenytoin, fluvoxamine, , piroxicam, rosiglitazone, sulfamethoxazole, lovastatin) paroxetine, suprofen, , torsemide, tolbutamide, phenylbutazone, S-warfarin probenicid, , sulfaphenazole, teniposide, trimethoprim, 2D6 *3 , amitriptyline, , Amiodarone, celecoxib, Dexamethasone rifampin *4 , , , chlorpheniramine, *5 clomipraminecodeine, debrisoquine, chlorpromazine, *6 , , cimetidine, clomipramine, *7 , , , , , *10 fluoxetine, fluvoxamine, haloperidol, imipramine, fluoxetine, , *41 , , methoxyamphetamine, levomepromazinemethadone, *XN S-, Mexiletine, , moclobemide, paroxetine, , ondansetron, paroxetine, , ranitidine, perhexilin, , phenacetin, reduced haloperidol phenformin , propanolol, quanoxan, , sertraline, , , tamoxifen, , terbinafine , , 2E1 Acetaminophen, aniline, benzene, Diethyl-dithiocarbamate, , isoniazid chlorzoxazone, , ethanol, , , methoxyflurane, N,N-dimethylformamide, , 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 - , 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, , caffeine, cimetidine, , carbamazepine, *22 cerivastatin, chlorpheniramine, , clarithromycin, delaviridine, efavirenz, clarithromycin, cocaine, , cyclosporine, diethyl-dithiocarbamate, , , dextromethorphan, diazepam, , erythromycin, modafiniln, nevirapine, diltiazem, erythromycin, estradiol, , fluconazole, fluvoxamine, Phenobarbital, fentanyl, finasteride, haloperidol, gestodene, grapefruit, phenytoin, pioglitazone, hydrocortisone, indinavir, lercanidipine, juice, indinavir, rifampin, St. John’s lidocaine, lovastatin, , midazolam, interleukin-10, itraconazole, wort, troglitazone nelfinavir, , nisoldipine, nitrendipine, ketoconazole, mibefradil, , progesterone, propranolol, quinidine, mifepristone, , , ritonavir, , saquinavir, nelfinavir, norfloxacin, sildenafil, simvastatin, tacrolimus, tamoxifen, norfluoxetine, ritonavir, taxol, terfenadine, , , 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 alyze the N-oxidation of carcinogenic aromatic than 40% are grouped into families, and those and heterocyclic found in cigarette smoke with greater than 55% homology are grouped into and in charred foods 7. Polymorphisms that influ - subfamilies.Thus CYP1, CYP2, and CYP3 repre - ence the transcriptional activity of CYP1A sent different families. A letter following the fam - seem to have a limited effect on drug metabolism ily name indicates the particular subfamily. In but they can be used as markers for predicting humans, the enzymes responsible for drug metab - cancer predisposition of some individuals 8,9 since olism belong to the CYP families 1-4 and most of the etiology of several cancers is related to the for - CYP450-catalyzed reactions can be attributed to mation of adducts between DNA and the oxidized six main enzymes (CYP1A2, 2C9, 2C19, 2D6, products obtained from cytochrome P450 cat - 2E1 and 3A4/5). CYP enzymes in families 5 or alyzed reactions. higher are typically responsible for processing In addition to its role in the bioactivation of steroids rather than drug metabolism. carcinogens, CYP1A2 also plays a significant role in the metabolism of numerous drugs, including CYP1 Family and antipyretics (acetaminophen, phenacetin, lidocaine), (olanzap - ine, ), cardiovascular drugs (propra - CYP1 family consists of three members, nolol, , triamterene), the cholinesterase CYP1A1, CYP1A2 and CYP1B1. In particular, inhibitor tacrine used for the treatment of CYP1A1 and CYP1A2 show high amino acid se - Alzheimer’s disease, (duloxe - quence homology but exhibit very different pat - tine), anti-inflammatory drugs (nabumetone), the

3 muscle relaxant , the zolpidem metabolism of several drugs such as benzpheta - used in the short term treatment of insomnia, the mine, cinnarizine, bupropion, verapamil and lido - drug riluzole used to treat amyotrophic lateral caine and environmental or abused toxicants sclerosis, the 5- inhibitor zileuton 10 . including nicotine. Numerous CYP2B6 sequence It has also been shown that CYP1A2 oxidize uro - polymorphisms have been identified; some of porphyrinogen to uroporphyrin in the course of these polymorphisms ( e.g. , C1459T or R487C) heme metabolism and hydroxylate estrogen. The are very frequent in human populations (up to ability to utilize estrogen as a substrate has impor - 32.6%) and correlate with significantly reduced tant implications for the role of this enzyme in the CYP2B6 expression and S-mephenytoin bioactivation of environmental pro-estrogens. Es - N- activity . trogens have been proposed as a possible sub - The CYP2C family comprises four genes strates also for CYP1B1 since it has been reported (CYP2C8 , CYP2C9 , CYP2C18 , and CYP2C19 ) that CYP1B1 polymorphisms are associated to al - encoding products with greater than 80% amino � 14 tered kinetics for 2- and 4-hydroxylation of 17 - acid homology . Of the four members of the sub - estradiol. As with the other members of the CYP1 family CYP2C9, and CYP2C19 are the main re - family, CYP1B1 is also involved in the bioactiva - sponsible enzyme for the metabolism of clinically tion of carcinogens 11 . administered drugs as well as several endogenous compounds including . CYP2 Family CYP2C9 is the most abundantly expressed in hepatic tissue, followed by CYP2C8 and CYP2C19. CYP2C9 shows very strong catalytic CYP2 family is the largest family of cytochrome activity toward several drugs including the antico - P450s including 13 subfamilies that consist of 16 agulant warfarin, the antidiabetic agent tolbu - functional genes ( CYP2A6, CYP2A7, CYP2A13, tamide, barbiturate such as hexobarbital, CYP2B6, CYP2C8, CYP2C9, CYP2C18, ibuprofen, diclofenac and other nonsteroidal anti- CYP2C19, CYP2D6 CYP2E1, CYP2F1, CYP2J2, inflammatory drugs, and anticonvulsants such as CYP2R1, CYP2S1, CYP2U1, CYP2W1 ) and 13 con - phenytoin, and trimethadone 13 . The frequency of firmed ( CYP2A7PT (telomeric), functional CYP2C9 polymorphisms is very low at CYP2A7PC (centromeric), CYP2A18P, CYP2B7P1, 0.25% in Caucasians and even less in Asians. CYP2B7P2, CYP2B7P3, CYP2D7AP, CYP2D8P, However, the clinical consequences of these rare, CYP2F1P, CYP2G1P, CYP2G2P, CYP2T2P, poor metabolizer polymorphism can lead to life- CYP2T3P ). Most of these CYPs play a significant threatening bleeding episodes following adminis - role in drug metabolism while other members are tration of warfarin and severe toxicity with expressed in a sex-specific manner and support phenytoin administration 15 . steroid hydroxylation. Three genes, CYP2A6 , On the other hand, CYP2C19 metabolizes pri - CYP2A7 , and CYP2A13 , comprise the human marily the anticonvulsant agent mephenytoin. CYP2A subfamily. In adults, CYP2A6 is primarily Moreover, it is responsible for metabolism of pro - expressed in the liver while it is present in extrahep - ton pump inhibitors such as omeprazole, benzodi - atic tissues at very low levels 12 . CYP2A6 oxidizes azepines such as diazepam, a variety of numerous compounds including disulfiram, fadro - antidepressants, and the antimalarial drug zole, halothane, osigamone, methoxyflurane, pilo - proguanil. carpine, , and valproic acid. Recently Among CYP2C polymorphisms, the ( S)- bilirubin has been identified as endogenous sub - mephenytoin 4’-hydroylase polymorphism of strate of CYP2A6 13 in addition to procarcinogens CYP2C19 , is the most frequently expressed (ap - (aminochrysene and aflatoxin B1), and tobacco proximately 3-5% of Caucasians and African- smoke constituents. CYP2A6 is responsible for the Americans and up to 20% of Asians). This majority of coumarin 7-hydroxylase and nicotine C- polymorphism confers a poor metabolizer pheno - oxidase activity in hepatic tissue. It has been identi - type 16 and is associated to an elevated frequency fied a CYP2A6 polymorphism present in of adverse effects following mephenytoin admin - approximately 0.3% of African-Americans and istration due to a reduced clearance of mepheny - 1.4% of Caucasians that seems to confer a poor me - toin. Moreover, it is also related to an increase in tabolizer 12 , characterized by low or non- the efficacy of proton pump inhibitors ( e.g. , existent 7-hydroxylation of coumarin 13 . Moreover, omeprazole) in the toxicity of some polymorphisms in the CYP2A6 gene may be related agents as diazepam 17 . to smoking behavior and lung cancer susceptibility. The CYP2D subfamily consists of a single The CYP2B family in humans consists of a functional member, CYP2D6 , and four pseudo - single gene CYP2B6 . CYP2B6 is involved in the genes 17 . CYP2D6 is highly expressed in the liver

4 CLINICALLY RELEVANT OF CYTOCHROME P450 FAMILY ENZYMES FOR DRUG-DRUG INTERACTION IN ANTICANCER THERAPY but also in duodenum and brain . The CYP2D6 nitrosamine NNK 27 . Moreover, CYP2E1 is also enzyme is responsible for the oxidation of more involved in the metabolism of some clinically sig - than 70 different pharmaceuticals, including b- nificant drugs such as paracetamol, enflurane and blocking agents ( e.g. , , timo - general anesthetics such as sevoflurane and lol, propanolol, , metoprolol), halothane 28 . In rare cases, CYP2E1 may convert antidepressants (e.g. , amitriptyline, paroxetine, halothane to a reactive metabolite that forms venlafaxine, fluoxetine, prozac, trazadone), an - adducts with hepatic leading to fatal he - tiarrhythmics (e.g. , flecainide, mexiletine, propa - patotoxicity 28 . fenone), antipsychotics ( e.g. , clorpromazine, Many CYP2E1 substrates, including acetone, haloperidol, thoridazine), and narcotic analgesics pyridine, pyrazole, and isoniazid, act as CYP2E1 (e.g. , codeine, fentanyl, meperidine, , inducers. Genetic polymorphisms at the CYP2E1 propoxyphene). A well known polymorphism in are more frequent in some Asian popula - CYP2D6 gene displays a bimodal distribution be - tions (28%) 28 than in Caucasian populations (7%) tween poor and extensive metabolizers. The and have also been associated with differential CYP2D6 poor metabolizer phenotype is identified susceptibility to different chemical-induced can - in about 6% of Caucasians 18 and is less common cers. in Asian and African populations 19 . This PM phe - notype significantly influence the in vivo metabo - CYP3 Family lism of several common drugs including tricyclic antidepressants, haloperidol, metoprolol, propra - nolol, codeine and dextromethorphan 20 . In most The CYP3 family in humans consists of a single clinical situations, administration of a standard subfamily (CYP3A) comprising four functional dose of a given CYP2D6 substrate results in ele - genes ( CYP3A4, CYP3A5, CYP3A7, CYP3A43 ) vated blood levels in poor metabolizers and high and two pseudogenes ( 3A5P1, 3A5P2 ). CYP3A4 toxicity. Individuals that possess multiple (up to is mainly expressed in the liver and at low levels 13) copies of the CYP2D6 gene have identified as in the small intestines. CYP3A5 is found sporadi - ultra-rapid metabolizers . Ultra-rapid metabolizers cally in the liver and is frequently expressed in ex - exhibit markedly elevated CYP2D6 levels, in - trahepatic tissues including the lungs, the colon, creased metabolism and decreased drug efficacy the kidney, the esophagus, and anterior pituitary. for CYP2D6 substrates, such as tricyclic antide - CYP3A5 and CYP3A4 metabolize the same sub - pressants. The ultra-rapid phenotype is dectected strates although usually at different turnover rates. in about 4% of Caucasians and up to 29% and CYP3A4 is the most important drug-metabo - 21% of Ethiopian and Saudi Arabian populations, lizing cytochrome P450 enzyme in humans and respectively 21 . the most abundantly expressed in the liver. It has It has been reported an association between been reported that CYP3A4 metabolizes more CYP2D6 polymorphisms and altered susceptibili - than 120 different drugs and about 60% of the cur - ty to different diseases, such as Parkinson’s dis - rently administered drugs 29 . In particular, ease and lung cancer. In this respect poor CYP3A4 shows catalytic activity toward metabolizer phenotype seems to confer protection macrolide antibiotics such as erythromycin; ben - from lung cancer probably because CYP2D6 can zodiazepine sedatives including diazepam and mi - modulate smoking behavior through involvement dazolam; immune system modulators like in the dopaminergic signal transduction pathway 22 cyclosporine; anti-arrhythmics like quinidine; (Table 2). Moreover, it appears to contribute to the HIV-directed antiviral agents such as ritonavir and bioactivation of procarcinogenic tobacco-derived saquinavir; the cisapride; antihis - nitrosamine NNK 23 . tamines such as astemizole and terfenidine; an ar - CYP2E1 is the only member of the CYP2E ray of calcium channel blockers including subfamily in humans. This cytochrome P450 iso - nifedipine and verapamil; HMG CoA reductase form is expressed in the liver and in a small num - inhibitors like lovastatin; like caffeine ber of extrahepatic tissues including lungs and and non-benzodiazepine like zolpidem. brain 24 . CYP2E1 metabolizes a broad range of CYP3A4 enzyme is the major responsible for me - substrates, the majority of which are relatively tabolism of several anticancer drugs such as taxol, small hydrophobic compounds that act as procar - etc. Moreover, it is implicated in the etiology of cinogens 25 . In particular, CYP2E1 is responsible different types of cancers including prostate can - for the metabolism of several tobacco-specific N- cer and leukemia through of procar - nitrosamines 26 associated with nasopharyngeal cinogens, such aflatoxin B1, PAHs, NNK 30 , and cancers but it does not contribute to the bioactiva - 6-aminochrysene. In addition to its important role tion of the highly carcinogenic tobacco-derived in xenobiotic metabolism, CYP3A4 metabolizes

5 endogenous steroids such as testosterone, proges - profile could get closer to reality 36 . Furthermore, terone, and androstenedione 31 . Since CYP3A4 the American Food and Drug Administration and metabolizes several clinically used drugs, it is im - European Medicines agencies (FDA and EMA) plicated in a wide number of drug interactions 32 . have recognized the clinical value of genetic vari - The metabolic activity of CYP3A4 enzymes is ants in metabolic pathways and have developed highly variable in human populations. Such vari - guidelines for industry concerning pharmacoge - ability can influence the efficacy and safety of netic data submission with new drugs. They now drugs that are metabolized by these enzymes. Al - recommend updating drug labels when compelling though the mechanisms responsible for this are data are present according to patient’s genetic pro - poorly understood, transcriptional induction plays file in the field of oncology, neurology and cardio - an important role. About 20 variant C Y P 3 A 4 al - vascular medicine. Furthermore, a detailed leles, that show either higher or lower rates of cat - knowledge of pharmacology is a prerequisite for alytic activity compared with wildtype CYP3A4, application in clinical practice, and physicians have been identified 33 . might find it difficult to interpret the clinical value of pharmacogenetic test results 37 . Hypnotizing the 38 CYP4 Family emerging of new healthy professions . Over the next few years, t he emergence of drug-drug interactions in the new therapies as re - The CYP4 family in humans consists of five sub - sults of genomic alteration (i.e. anti-HIV con - families including 12 functional genes ( CYP4A11, comitant with Antivancer), will drives diagnostics CYP4A20, CYP4A22, CYP4B1, CYP4F2, company to develop new test able to produce re - CYP4F3, CYP4F8, CYP4F11, CYP4F12, sults indicative for tailoring patient’s treatment 39 . CYP4F22, CYP4V2, CYP4X1 ) and nine pseudo - Promise, the pharmaceutical and biotechnology genes ( CYP4A21P, CYP4F9P, CYP4F10P, companies should join each other, in order to de - CYP4F23P, CYP4F24P, CYP4F25P, CYP4F26P, velop a commercial test suitable for routine diag - CYP4F27P, CYP4F28P ). nostics to genotyping and phenotyping the Members of the CYP4A family are expressed individual metabolic profile. primarily in the kidney and to a lesser degree in the liver. CYP4A enzymes is mainly responsible for the hydroxylation of fatty acids and AUTHOR DISCLOSURE . In details, CYP4A isoforms me - The authors report no conflicts of interest in this tabolize medium and long chain length fatty acids work at their w-carbon. CYP4A subfamily does not seem to play a direct role in xenobiotic metabo - 34 REFERENCES lism .

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