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Molecular genetics and epigenetics of the cytochrome P450 gene family and its relevance for cancer risk and treatment

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Abstract

The cytochromes P450 (CYPs) are very efficient catalysts of foreign compound metabolism and are responsible for the major part of metabolism of clinically important drugs. The enzymes are important in cancer since they (a) activate dietary and environmental components to ultimate carcinogens, (b) activate or inactivate drugs used for cancer treatment, and (c) are potential targets for anticancer therapy. The genes encoding the CYP enzymes active in drug metabolism are highly polymorphic, whereas those encoding metabolism of precarcinogens are relatively conserved. A vast amount of literature is present where investigators have tried to link genetic polymorphism in CYPs to cancer susceptibility, although not much conclusive data have hitherto been obtained, with exception of CYP2A6 polymorphism and tobacco induced cancer, to a great extent because of lack of important functional polymorphisms in the genes studied. With respect to anticancer treatment, the genetic CYP polymorphism is of greater importance, where treatment with tamoxifen, but also with cyclophosphamide and maybe thalidomide is influenced by CYP genetic variants. In the present review we present updates on CYP genetics, cancer risk and treatment and also epigenetic aspects of interindividual variability in CYP expression and the use of these enzymes as targets for cancer therapy. We conclude that the CYP polymorphism does not predict cancer susceptibility to any large extent but that this polymorphism might be an important factor for optimal cancer therapy using selected anticancer agents.

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Abbreviations

ADRs:

Adverse drug reactions

AIs:

Aromatase inhibitors

CNV:

Copy number variation

CPA:

Cyclophosphamide

DNMT:

DNA methyltransferase

DRE:

Dioxin response element

EMs:

Extensive metabolizers

GDEPT:

Gene directed enzyme prodrug therapy

HDAC:

Histone deacetylase

IMs:

Intermediate metabolizers

indel:

Insertion/deletion

PMs:

Poor metabolizers

SJW:

St John’s wort

SNPs:

Single nucleotide polymorphisms

UMs:

Ultrarapid metabolizer

References

  • Ando Y, Fuse E, Figg WD (2002) Thalidomide metabolism by the CYP2C subfamily. Clin Cancer Res 8:1964–1973

    CAS  PubMed  Google Scholar 

  • Ariyoshi N, Miyamoto M, Umetsu Y, Kunitoh H, Dosaka-Akita H, Sawamura Y, Yokota J, Nemoto N, Sato K, Kamataki T (2002) Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers. Cancer Epidemiol Biomarkers Prev 11:890–894

    CAS  PubMed  Google Scholar 

  • Bijl MJ, van Schaik RH, Lammers LA, Hofman A, Vulto AG, van Gelder T, Stricker BH, Visser LE (2009) The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users. Breast Cancer Res Treat [Epub ahead of print]

  • Boocock DJ, Brown K, Gibbs AH, Sanchez E, Turteltaub KW, White IN (2002) Identification of human CYP forms involved in the activation of tamoxifen and irreversible binding to DNA. Carcinogenesis 23:1897–1901

    Article  CAS  PubMed  Google Scholar 

  • Braybrooke JP, Slade A, Deplanque G, Harrop R, Madhusudan S, Forster MD, Gibson R, Makris A, Talbot DC, Steiner J, White L, Kan O, Naylor S, Carroll MW, Kingsman SM, Harris AL (2005) Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma. Clin Cancer Res 11:1512–1520

    Article  CAS  PubMed  Google Scholar 

  • Buters JT, Sakai S, Richter T, Pineau T, Alexander DL, Savas U, Doehmer J, Ward JM, Jefcoate CR, Gonzalez FJ (1999) Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas. Proc Natl Acad Sci USA 96:1977–1982

    Article  CAS  PubMed  Google Scholar 

  • Buters JT, Mahadevan B, Quintanilla-Martinez L, Gonzalez FJ, Greim H, Baird WM, Luch A (2002) Cytochrome P450 1B1 determines susceptibility to dibenzo[a, l]pyrene-induced tumor formation. Chem Res Toxicol 15:1127–1135

    Article  CAS  PubMed  Google Scholar 

  • Canova C, Hashibe M, Simonato L, Nelis M, Metspalu A, Lagiou P, Trichopoulos D, Ahrens W, Pigeot I, Merletti F, Richiardi L, Talamini R, Barzan L, Macfarlane GJ, Macfarlane TV, Holcátová I, Bencko V, Benhamou S, Bouchardy C, Kjaerheim K, Lowry R, Agudo A, Castellsagué X, Conway DI, McKinney PA, Znaor A, McCartan BE, Healy CM, Marron M, Brennan P (2009) Genetic associations of 115 polymorphisms with cancers of the upper aerodigestive tract across 10 European countries: the ARCAGE project. Cancer Res 69:2956–2965

    Article  CAS  PubMed  Google Scholar 

  • Choudhary D, Jansson I, Stoilov I, Sarfarazi M, Schenkman JB (2005) Expression patterns of mouse and human CYP orthologs (families 1–4) during development and in different adult tissues. Arch Biochem Biophys 436:50–61

    Article  CAS  PubMed  Google Scholar 

  • Colomer R, Monzo M, Tusquets I, Rifa J, Baena JM, Barnadas A, Calvo L, Carabantes F, Crespo C, Munoz M, Llombart A, Plazaola A, Artells R, Gilabert M, Lloveras B, Alba E (2008) A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma. Clin Cancer Res 14:811–816

    Article  CAS  PubMed  Google Scholar 

  • Crewe HK, Notley LM, Wunsch RM, Lennard MS, Gillam EM (2002) Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes: formation of the 4-hydroxy, 4′-hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos 30:869–874

    Article  CAS  PubMed  Google Scholar 

  • Dalton TP, Dieter MZ, Matlib RS, Childs NL, Shertzer HG, Genter MB, Nebert DW (2000) Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery. Biochem Biophys Res Commun 267:184–189

    Article  CAS  PubMed  Google Scholar 

  • Dong LM, Potter JD, White E, Ulrich CM, Cardon LR, Peters U (2008) Genetic susceptibility to cancer: the role of polymorphisms in candidate genes. JAMA 299:2423–2436

    Article  CAS  PubMed  Google Scholar 

  • Dutta U, Pant K (2008) Aromatase inhibitors: past, present and future in breast cancer therapy. Med Oncol 25:113–124

    Article  CAS  PubMed  Google Scholar 

  • Edler D, Stenstedt K, Ohrling K, Hallstrom M, Karlgren M, Ingelman-Sundberg M, Ragnhammar P (2009) The expression of the novel CYP2W1 enzyme is an independent prognostic factor in colorectal cancer—a pilot study. Eur J Cancer 45:705–712

    Article  CAS  PubMed  Google Scholar 

  • Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW, Egorin MJ (2004) Effect of St John’s wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther 76:323–329

    Article  CAS  PubMed  Google Scholar 

  • Fujieda M, Yamazaki H, Saito T, Kiyotani K, Gyamfi MA, Sakurai M, Dosaka-Akita H, Sawamura Y, Yokota J, Kunitoh H, Kamataki T (2004) Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis 25:2451–2458

    Article  CAS  PubMed  Google Scholar 

  • Gemignani F, Landi S, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Gaborieau V, Gioia-Patricola L, Bellini I, Barale R, Canzian F, Hall J, Boffetta P, Hung RJ, Brennan P (2007) Development of lung cancer before the age of 50: the role of xenobiotic metabolizing genes. Carcinogenesis 28:1287–1293

    Article  CAS  PubMed  Google Scholar 

  • Ghanayem BI, Hoffler U (2007) Investigation of xenobiotics metabolism, genotoxicity, and carcinogenicity using Cyp2e1(−/−) mice. Curr Drug Metab 8:728–749

    Article  CAS  PubMed  Google Scholar 

  • Ghotbi R, Gomez A, Milani L, Tybring G, Syvänen AC, Bertilsson L, Ingelman-Sundberg M, Aklillu E (2009) Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers. Pharmacogenomics J 9:208–217

    Article  CAS  PubMed  Google Scholar 

  • Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN (2005) Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23(36):9312–9318

    Article  CAS  PubMed  Google Scholar 

  • Goetz MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM, Desta Z, Nguyen A, Flockhart DA, Perez EA, Ingle JN (2007) The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat 101:113–121

    Article  CAS  PubMed  Google Scholar 

  • Gomez AV (2008) Epigenetic regulation and posttranslational modification of human cytochrome P450s: focus on CYP2W1, CYP1A2 and CYP2C18. Dissertation, Karolinska Institutet

  • Gomez A, Karlgren M, Edler D, Bernal ML, Mkrtchian S, Ingelman-Sundberg M (2007) Expression of CYP2W1 in colon tumors: regulation by gene methylation. Pharmacogenomics 8:1315–1325

    Article  CAS  PubMed  Google Scholar 

  • Gomez-Duran A, Ballestar E, Carvajal-Gonzalez JM, Marlowe JL, Puga A, Esteller M, Fernandez-Salguero PM (2008) Recruitment of CREB1 and histone deacetylase 2 (HDAC2) to the mouse Ltbp-1 promoter regulates its constitutive expression in a dioxin receptor-dependent manner. J Mol Biol 380:1–16

    Article  CAS  PubMed  Google Scholar 

  • Gribben JG, Ryan DP, Boyajian R, Urban RG, Hedley ML, Beach K, Nealon P, Matulonis U, Campos S, Gilligan TD, Richardson PG, Marshall B, Neuberg D, Nadler LM (2005) Unexpected association between induction of immunity to the universal tumor antigen CYP1B1 and response to next therapy. Clin Cancer Res 11:4430–4436

    Article  CAS  PubMed  Google Scholar 

  • Griskevicius L, Yasar U, Sandberg M, Hidestrand M, Eliasson E, Tybring G, Hassan M, Dahl ML (2003) Bioactivation of cyclophosphamide: the role of polymorphic CYP2C enzymes. Eur J Clin Pharmacol 59:103–109

    CAS  PubMed  Google Scholar 

  • Gunes A, Dahl ML (2008) Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms. Pharmacogenomics 9:625–637

    Article  CAS  PubMed  Google Scholar 

  • Gunzburg WH, Salmons B (2005) Use of cell therapy as a means of targeting chemotherapy to inoperable pancreatic cancer. Acta Biochim Pol 52:601–607

    PubMed  Google Scholar 

  • Habano W, Gamo T, Sugai T, Otsuka K, Wakabayashi G, Ozawa S (2009) CYP1B1, but not CYP1A1, is downregulated by promoter methylation in colorectal cancers. Int J Oncol 34:1085–1091

    Article  CAS  PubMed  Google Scholar 

  • Hammons GJ, Yan-Sanders Y, Jin B, Blann E, Kadlubar FF, Lyn-Cook BD (2001) Specific site methylation in the 5′-flanking region of CYP1A2 interindividual differences in human livers. Life Sci 69:839–845

    Article  CAS  PubMed  Google Scholar 

  • Hanzawa Y, Sasaki T, Mizugaki M, Ishikawa M, Hiratsuka M (2008) Genetic polymorphisms and haplotype structures of the human CYP2W1 gene in a Japanese population. Drug Metab Dispos 36:349–352

    Article  CAS  PubMed  Google Scholar 

  • Heidel SM, MacWilliams PS, Baird WM, Dashwood WM, Buters JT, Gonzalez FJ, Larsen MC, Czuprynski CJ, Jefcoate CR (2000) Cytochrome P4501B1 mediates induction of bone marrow cytotoxicity and preleukemia cells in mice treated with 7, 12-dimethylbenz[a]anthracene. Cancer Res 60:3454–3460

    CAS  PubMed  Google Scholar 

  • Higgins MJ, Rae JM, Flockhart DA, Hayes DF, Stearns V (2009) Pharmacogenetics of tamoxifen: ho should undergo CYP2D6 genetic testing? J Natl Compr Canc Netw 7:203–213

    CAS  PubMed  Google Scholar 

  • Ho MK, Mwenifumbo JC, Al Koudsi N, Okuyemi KS, Ahluwalia JS, Benowitz NL, Tyndale RF (2009) Association of nicotine metabolite ratio and CYP2A6 genotype with smoking cessation treatment in African-American light smokers. Clin Pharmacol Ther 85:635–643

    Article  CAS  PubMed  Google Scholar 

  • Hoskins JM, Carey LA, McLeod HL (2009) CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat Rev Cancer 9:576–586

    Article  CAS  PubMed  Google Scholar 

  • Ingelman-Sundberg M (2004) Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci 25:193–200

    Article  CAS  PubMed  Google Scholar 

  • Ingelman-Sundberg M (2005) Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 5:6–13

    Article  CAS  PubMed  Google Scholar 

  • Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C (2007) Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 116:496–526

    Article  CAS  PubMed  Google Scholar 

  • Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080

    Article  CAS  PubMed  Google Scholar 

  • Jiang Z, Dragin N, Jorge-Nebert LF, Martin MV, Guengerich FP, Aklillu E, Ingelman-Sundberg M, Hammons GJ, Lyn-Cook BD, Kadlubar FF, Saldana SN, Sorter M, Vinks AA, Nassr N, von Richter O, Jin L, Nebert DW (2006) Search for an association between the human CYP1A2 genotype and CYP1A2 metabolic phenotype. Pharmacogenet Genomics 16:359–367

    Article  CAS  PubMed  Google Scholar 

  • Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science 293:1068–1070

    Article  CAS  PubMed  Google Scholar 

  • Jones SM, Boobis AR, Moore GE, Stanier PM (1992) Expression of CYP2E1 during human fetal development: methylation of the CYP2E1 gene in human fetal and adult liver samples. Biochem Pharmacol 43:1876–1879

    Article  CAS  PubMed  Google Scholar 

  • Josephson F, Allqvist A, Janabi M, Sayi J, Aklillu E, Jande M, Mahindi M, Burhenne J, Bottiger Y, Gustafsson LL, Haefeli WE, Bertilsson L (2007) CYP3A5 genotype has an impact on the metabolism of the HIV protease inhibitor saquinavir. Clin Pharmacol Ther 81:708–712

    Article  CAS  PubMed  Google Scholar 

  • Justenhoven C, Hamann U, Pierl CB, Baisch C, Harth V, Rabstein S, Spickenheuer A, Pesch B, Brüning T, Winter S, Ko YD, Brauch H (2009) CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat 115:391–396

    Article  CAS  PubMed  Google Scholar 

  • Karlgren M, Miura S, Ingelman-Sundberg M (2005) Novel extrahepatic cytochrome P450 s. Toxicol Appl Pharmacol 207:57–61

    Article  PubMed  CAS  Google Scholar 

  • Karlgren M, Gomez A, Stark K, Svard J, Rodriguez-Antona C, Oliw E, Bernal ML, Ramon y Cajal S, Johansson I, Ingelman-Sundberg M (2006) Tumor-specific expression of the novel cytochrome P450 enzyme, CYP2W1. Biochem Biophys Res Commun 341:451–458

    Article  CAS  PubMed  Google Scholar 

  • Kiyotani K, Mushiroda T, Sasa M, Bando Y, Sumitomo I, Hosono N, Kubo M, Nakamura Y, Zembutsu H (2008) Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy. Cancer Sci 99:995–999

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Hou J, Jiang H, Wang D, Fu W, Yuan Z, Chen Y, Zhou L (2007) Polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide based regimens in multiple myeloma. Haematologica 92(9):1246–1249

    Article  CAS  PubMed  Google Scholar 

  • Li YH, Hou J, Jiang H, Huang HM, Zhu R (2008) Effect of cytochrome CYP2C19 on the antimyeloma activity of thalidomide in vitro. Zhonghua Xue Ye Xue Za Zhi 29:654–657

    PubMed  Google Scholar 

  • Li YH, Hou J, Jiang H, Huang HM (2009) Antiangiogenic activity of thalidomide in vitro mediated by cytochrome CYP2C19. Zhongguo Shi Yan Xue Ye Xue Za Zhi 17:102–106

    CAS  PubMed  Google Scholar 

  • Liang HC, Li H, McKinnon RA, Duffy JJ, Potter SS, Puga A, Nebert DW (1996) Cyp1a2(−/−) null mutant mice develop normally but show deficient drug metabolism. Proc Natl Acad Sci USA 93:1671–1676

    Article  CAS  PubMed  Google Scholar 

  • Lim HS, Ju Lee H, Seok Lee K, Sook Lee E, Jang IJ, Ro J (2007) Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25:3837–3845

    Article  CAS  PubMed  Google Scholar 

  • Ling G, Wei Y, Ding X (2007) Transcriptional regulation of human CYP2A13 expression in the respiratory tract by CCAAT/enhancer binding protein and epigenetic modulation. Mol Pharmacol 71:807–816

    Article  CAS  PubMed  Google Scholar 

  • Luby TM, Cole G, Baker L, Kornher JS, Ramstedt U, Hedley ML (2004) Repeated immunization with plasmid DNA formulated in poly(lactide-co-glycolide) microparticles is well tolerated and stimulates durable T cell responses to the tumor-associated antigen cytochrome P450 1B1. Clin Immunol 112:45–53

    Article  CAS  PubMed  Google Scholar 

  • Ma CX, Adjei AA, Salavaggione OE, Coronel J, Pelleymounter L, Wang L, Eckloff BW, Schaid D, Wieben ED, Adjei AA, Weinshilboum RM (2005) Human aromatase: gene resequencing and functional genomics. Cancer Res 65:11071–11082

    Article  CAS  PubMed  Google Scholar 

  • Maecker B, Sherr DH, Vonderheide RH, von Bergwelt-Baildon MS, Hirano N, Anderson KS, Xia Z, Butler MO, Wucherpfennig KW, O’Hara C, Cole G, Kwak SS, Ramstedt U, Tomlinson AJ, Chicz RM, Nadler LM, Schultze JL (2003) The shared tumor-associated antigen cytochrome P450 1B1 is recognized by specific cytotoxic T cells. Blood 102:3287–3294

    Article  CAS  PubMed  Google Scholar 

  • Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A (2002) Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst 94:1247–1249

    CAS  PubMed  Google Scholar 

  • McFadyen MC, Murray GI (2005) Cytochrome P450 1B1: a novel anticancer therapeutic target. Future Oncol 1:259–263

    Article  CAS  PubMed  Google Scholar 

  • McFadyen MC, Murray GI (2008) The CYP1B Subfamily. In: Ioannides C (ed) Cytochromes P450: role in the metabolism and toxicity of drugs and other xenobiotics. RSC Pub, Cambridge, pp 136–149

    Google Scholar 

  • Meyer UA (2004) Pharmacogenetics—five decades of therapeutic lessons from genetic diversity. Nat Rev Genet 5:669–676

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto M, Umetsu Y, Dosaka-Akita H, Sawamura Y, Yokota J, Kunitoh H, Nemoto N, Sato K, Ariyoshi N, Kamataki T (1999) CYP2A6 gene deletion reduces susceptibility to lung cancer. Biochem Biophys Res Commun 261:658–660

    Article  CAS  PubMed  Google Scholar 

  • Miyoshi Y, Ando A, Takamura Y, Taguchi T, Tamaki Y, Noguchi S (2002) Prediction of response to docetaxel by CYP3A4 mRNA expression in breast cancer tissues. Int J Cancer 97:129–132

    Article  CAS  PubMed  Google Scholar 

  • Miyoshi Y, Taguchi T, Kim SJ, Tamaki Y, Noguchi S (2005) Prediction of response to docetaxel by immunohistochemical analysis of CYP3A4 expression in human breast cancers. Breast Cancer 12:11–15

    Article  PubMed  Google Scholar 

  • Nakajima M, Komagata S, Fujiki Y, Kanada Y, Ebi H, Itoh K, Mukai H, Yokoi T, Minami H (2007) Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients. Pharmacogenet Genomics 17:431–445

    Article  CAS  PubMed  Google Scholar 

  • Newman WG, Hadfield KD, Latif A, Roberts SA, Shenton A, McHague C, Lalloo F, Howell S, Evans DG (2008) Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res 14:5913–5918

    Article  CAS  PubMed  Google Scholar 

  • Nowell SA, Ahn J, Rae JM, Scheys JO, Trovato A, Sweeney C, MacLeod SL, Kadlubar FF, Ambrosone CB (2005) Association of genetic variation in tamoxifen-metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients. Breast Cancer Res Treat 91:249–258

    Article  CAS  PubMed  Google Scholar 

  • Okino ST, Pookot D, Li LC, Zhao H, Urakami S, Shiina H, Igawa M, Dahiya R (2006) Epigenetic inactivation of the dioxin-responsive cytochrome P4501A1 gene in human prostate cancer. Cancer Res 66:7420–7428

    Article  CAS  PubMed  Google Scholar 

  • Okishiro M, Taguchi T, Jin Kim S, Shimazu K, Tamaki Y, Noguchi S (2009) Genetic polymorphisms of CYP2D6 10 and CYP2C19 2, 3 are not associated with prognosis, endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen. Cancer 115:952–961

    Article  CAS  PubMed  Google Scholar 

  • Oneta CM, Lieber CS, Li J, Rüttimann S, Schmid B, Lattmann J, Rosman AS, Seitz HK (2002) Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase. J Hepatol 36:47–52

    Article  CAS  PubMed  Google Scholar 

  • Poland A, Knutson JC (1982) 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 22:517–554

    Article  CAS  PubMed  Google Scholar 

  • Punglia RS, Burstein HJ, Winer EP, Weeks JC (2008) Pharmacogenomic variation of CYP2D6 and the choice of optimal adjuvant endocrine therapy for postmenopausal breast cancer: a modeling analysis. J Natl Cancer Inst 100:642–648

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Antona C, Ingelman-Sundberg M (2006) Cytochrome P450 pharmacogenetics and cancer. Oncogene 25:1679–1691

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez-Antona C, Leskelä S, Zajac M, Cuadros M, Alvés J, Moneo MV, Martín C, Cigudosa JC, Carnero A, Robledo M, Benitez J, Martínez-Delgado B (2007) Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas. Blood 110:3345–3351

    Article  CAS  PubMed  Google Scholar 

  • Rostami-Hodjegan A, Lennard MS, Woods HF, Tucker GT (1998) Meta-analysis of studies of the CYP2D6 polymorphism in relation to lung cancer and Parkinson’s disease. Pharmacogenetics 8:227–238

    Article  CAS  PubMed  Google Scholar 

  • Roy P, Waxman DJ (2006) Activation of oxazaphosphorines by cytochrome P450: application to gene-directed enzyme prodrug therapy for cancer. Toxicol In Vitro 20:176–186

    Article  CAS  PubMed  Google Scholar 

  • Ruwali M, Pant MC, Shah PP, Mishra BN, Parmar D (2009) Polymorphism in cytochrome P450 2A6 and glutathione S-transferase P1 modifies head and neck cancer risk and treatment outcome. Mutat Res [Epub ahead of print]

  • Schnekenburger M, Peng L, Puga A (2007) HDAC1 bound to the Cyp1a1 promoter blocks histone acetylation associated with Ah receptor-mediated trans-activation. Biochim Biophys Acta 1769:569–578

    CAS  PubMed  Google Scholar 

  • Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, Simon W, Eichelbaum M, Brauch H (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25:5187–5193

    Article  CAS  PubMed  Google Scholar 

  • Shiraishi M, Oates AJ, Sekiya T (2002) An overview of the analysis of DNA methylation in mammalian genomes. Biol Chem 383:893–906

    Article  CAS  PubMed  Google Scholar 

  • Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79:103–113

    Article  CAS  PubMed  Google Scholar 

  • Sim SC, Miller WL, Zhong XB, Arlt W, Ogata T, Ding X, Wolf CR, Flück CE, Pandey AV, Henderson CJ, Porter TD, Daly AK, Nebert DW, Ingelman-Sundberg M (2009) Nomenclature for alleles of the cytochrome P450 oxidoreductase gene. Pharmacogenet Genomics 19:565–566

    Article  CAS  PubMed  Google Scholar 

  • Singh G, Saxena N, Aggarwal A, Misra R (2007) Cytochrome P450 polymorphism as a predictor of ovarian toxicity to pulse cyclophosphamide in systemic lupus erythematosus. J Rheumatol 34:731–733

    CAS  PubMed  Google Scholar 

  • Sistonen J, Fuselli S, Palo JU, Chauhan N, Padh H, Sajantila A (2009) Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales. Pharmacogenet Genomics 19:170–179

    Article  CAS  PubMed  Google Scholar 

  • Stoilov I, Rezaie T, Jansson I, Schenkman JB, Sarfarazi M (2004) Expression of cytochrome P4501b1 (Cyp1b1) during early murine development. Mol Vis 10:629–636

    CAS  PubMed  Google Scholar 

  • Su HI, Sammel MD, Velders L, Horn M, Stankiewicz C, Matro J, Gracia CR, Green J, Demichele A (2009) Association of cyclophosphamide drug-metabolizing enzyme polymorphisms and chemotherapy-related ovarian failure in breast cancer survivors. Fertil Steril [Epub ahead of print]

  • Takada K, Arefayene M, Desta Z, Yarboro CH, Boumpas DT, Balow JE, Flockhart DA, Illei GG (2004) Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis. Arthritis Rheum 50:2202–2210

    Article  CAS  PubMed  Google Scholar 

  • Tan W, Chen GF, Xing DY, Song CY, Kadlubar FF, Lin DX (2001) Frequency of CYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population. Int J Cancer 95:96–101

    Article  CAS  PubMed  Google Scholar 

  • Tan SH, Lee SC, Goh BC, Wong J (2008) Pharmacogenetics in breast cancer therapy. Clin Cancer Res 14:8027–8041

    Article  CAS  PubMed  Google Scholar 

  • Timm R, Kaiser R, Lötsch J, Heider U, Sezer O, Weisz K, Montemurro M, Roots I, Cascorbi I (2005) Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19. Pharmacogenomics J 5:365–373

    Article  CAS  PubMed  Google Scholar 

  • Tokizane T, Shiina H, Igawa M, Enokida H, Urakami S, Kawakami T, Ogishima T, Okino ST, Li LC, Tanaka Y, Nonomura N, Okuyama A, Dahiya R (2005) Cytochrome P450 1B1 is overexpressed and regulated by hypomethylation in prostate cancer. Clin Cancer Res 11:5793–5801

    Article  CAS  PubMed  Google Scholar 

  • Topcu Z, Chiba I, Fujieda M, Shibata T, Ariyoshi N, Yamazaki H, Sevgican F, Muthumala M, Kobayashi H, Kamataki T (2002) CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka. Carcinogenesis 23:595–598

    Article  CAS  PubMed  Google Scholar 

  • Tsuchiya Y, Nakajima M, Yokoi T (2005) Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer Lett 227:115–124

    Article  CAS  PubMed  Google Scholar 

  • Tsuchiya Y, Nakajima M, Takagi S, Taniya T, Yokoi T (2006) MicroRNA regulates the expression of human cytochrome P450 1B1. Cancer Res 66:9090–9098

    Article  CAS  PubMed  Google Scholar 

  • Vieira I, Pasanen M, Raunio H, Cresteil T (1998) Expression of CYP2E1 in human lung and kidney during development and in full-term placenta: a differential methylation of the gene is involved in the regulation process. Pharmacol Toxicol 83:183–187

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Tang L, Sun G, Tang Y, Xie Y, Wang S, Hu X, Gao W, Cox SB, Wang JS (2006) Etiological study of esophageal squamous cell carcinoma in an endemic region: a population-based case control study in Huaian, China. BMC Cancer 6:287

    Google Scholar 

  • Wegman P, Elingarami S, Carstensen J, Stål O, Nordenskjöld B, Wingren S (2007) Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer. Breast Cancer Res 9:R7

    Article  PubMed  CAS  Google Scholar 

  • Weinshilboum R (2008) Pharmacogenomics of endocrine therapy in breast cancer. Adv Exp Med Biol 630:220–231

    Article  PubMed  Google Scholar 

  • Wienkers LC, Heath TG (2005) Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov 4:825–833

    Article  CAS  PubMed  Google Scholar 

  • Wu ZL, Sohl CD, Shimada T, Guengerich FP (2006) Recombinant enzymes overexpressed in bacteria show broad catalytic specificity of human cytochrome P450 2W1 and limited activity of human cytochrome P450 2S1. Mol Pharmacol 69:2007–2014

    Article  CAS  PubMed  Google Scholar 

  • Xie HJ, Broberg U, Griskevicius L, Lundgren S, Carlens S, Meurling L, Paul C, Rane A, Hassan M (2003) Alteration of pharmacokinetics of cyclophosphamide and suppression of the cytochrome p450 genes by ciprofloxacin. Bone Marrow Transplant 31:197–203

    Article  CAS  PubMed  Google Scholar 

  • Xie H, Griskevicius L, Stahle L, Hassan Z, Yasar U, Rane A, Broberg U, Kimby E, Hassan M (2006) Pharmacogenetics of cyclophosphamide in patients with hematological malignancies. Eur J Pharm Sci 27:54–61

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Sun Y, Yao L, Shi L, Wu Y, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, He L, Li P, Xie Y (2008) Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol 19:1423–1429

    Article  CAS  PubMed  Google Scholar 

  • Yoshioka H, Kasai N, Ikushiro S, Shinkyo R, Kamakura M, Ohta M, Inouye K, Sakaki T (2006) Enzymatic properties of human CYP2W1 expressed in Escherichia coli. Biochem Biophys Res Commun 345:169–174

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Su T, Zhang QY, Gu J, Caggana M, Li H, Ding X (2002) Genetic polymorphisms of the human CYP2A13 gene: identification of single-nucleotide polymorphisms and functional characterization of an Arg257Cys variant. J Pharmacol Exp Ther 302:416–423

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The research in the authors’ laboratories was supported by grants from The Swedish Research Council, The Swedish Cancer Foundation and by Torsten och Ragnar Söderbergs Stiftelser.

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Authors and Affiliations

  1. Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Madrid, Spain

    Cristina Rodriguez-Antona

  2. Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, 01655, USA

    Alvin Gomez

  3. Department of Pharmacy, Uppsala University, Uppsala, Sweden

    Maria Karlgren

  4. Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden

    Sarah C. Sim & Magnus Ingelman-Sundberg

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  1. Cristina Rodriguez-Antona
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  2. Alvin Gomez
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  3. Maria Karlgren
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  5. Magnus Ingelman-Sundberg
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Correspondence to Magnus Ingelman-Sundberg.

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Rodriguez-Antona, C., Gomez, A., Karlgren, M. et al. Molecular genetics and epigenetics of the cytochrome P450 gene family and its relevance for cancer risk and treatment. Hum Genet 127, 1–17 (2010). https://doi.org/10.1007/s00439-009-0748-0

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  • DOI: https://doi.org/10.1007/s00439-009-0748-0

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