Generic placeholder image

Current Pharmacogenomics and Personalized Medicine


ISSN (Print): 1875-6921
ISSN (Online): 1875-6913

Review Article

Oncogenomics and CYP450 Implications in Personalized Cancer Therapy

Author(s): G.K. Udayaraja and I. Arnold Emerson*

Volume 17 , Issue 2 , 2020

Page: [104 - 113] Pages: 10

DOI: 10.2174/1875692117999200517122652

Price: $65


Background: The Human Genome Project has unleashed the power of genomics in clinical practice as a choice of individualized therapy, particularly in cancer treatment. Pharmacogenomics is an interdisciplinary field of genomics that deals with drug response, based on individual genetic makeup.

Objective: The main genetic events associated with carcinogenesis activate oncogenes or inactivate tumor-suppressor genes. Therefore, drugs should be specific to inactivate or regulate these mutant genes and their protein products for effective cancer treatment. In this review, we summarize how polymedication decisions in cancer treatments based on the evaluation of cytochrome P450 (CYP450) polymorphisms are applied for pharmacogenetic assessment of anticancer therapy outcomes.

Results: However, multiple genetic events linked, inactivating a single mutant gene product, may be insufficient to inhibit tumor progress. Thus, genomics and pharmacogenetics directly influence a patient’s response and aid in guiding clinicians to select the safest and most effective combination of medications for a cancer patient from the initial prescription.

Conclusion: This review outlines the roles of oncogenes, the importance of cytochrome P450 (CYP450) in cancer susceptibility, and its impact on drug metabolism, proposing combined approaches to achieve precision therapy.

Keywords: Pharmacogenomics, CYP450, oncogenomics, personalized cancer therapy, cancer, inactivate tumorsuppressor genes.

Graphical Abstract
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Globocan 2012; pp. 1-6..
Liu M-Z, McLeod HL, He F-Z, Chen X-P, Zhao H-H, Shu Y, et al. Epigenetic perspectives on cancer chemotherapy response. Pharmacogenomics 2014; 15(5): 699-715.
[ ] [PMID: 24798726]
Degtyarenko KN. Structural domains of P450-containing monooxygenase systems. Protein Eng 1995; 8(8): 737-47.
[ ] [PMID: 8637843]
Buck ML. The cytochrome P450 enzyme system and its effect on drug metabolism. Pediatr Pharmacother 1997.
Barret KE, Barman SM, Brooks HL, Yuan JXJ. Ganong’s review of medical physiology. US: McGraw Hill 2012.
Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS, Holland JF, et al. Holland-Frei Cancer Medicine. 6th ed. Canada Hamilton: BC Decker 2003.
Manikandan P, Nagini S. Cytochrome P450 structure, function and clinical significance: A review. Curr Drug Targets 2018; 19(1): 38-54.
[ ] [PMID: 28124606]
Almazroo OA, Miah MK, Venkataramanan R. Drug metabolism in the liver. Clin Liver Dis 2017; 21(1): 1-20.
[] [PMID: 27842765]
McLean KJ, Sabri M, Marshall KR, Lawson RJ, Lewis DG, Clift D, et al. Biodiversity of cytochrome P450 redox systems. Portland Press Limited 2005.
Nelson DR, Zeldin DC, Hoffman SMG, Maltais LJ, Wain HM, Nebert DW. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 2004; 14(1): 1-18.
[ ] [PMID: 15128046]
Mittal B, Tulsyan S, Kumar S, Mittal RD, Agarwal G. Cytochrome P450 in Cancer Susceptibility and Treatment. Adv Clin Chem 2015; pp. 77-139.
Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007; 76(3): 391-6.
[PMID: 17708140]
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013; 138(1): 103-41.
[ ] [PMID: 23333322]
Uno Y, Uehara S, Murayama N, Yamazaki H. CYP1D1, pseudogenized in human, is expressed and encodes a functional drug-metabolizing enzyme in cynomolgus monkey. Biochem Pharmacol 2011; 81(3): 442-50.
[] [PMID: 21070747]
Nebert DW, Dalton TP, Okey AB, Gonzalez FJ. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem 2004; 279(23): 23847-50.
[ ] [PMID: 15028720]
Omiecinski CJ, Remmel RP, Hosagrahara VP. Concise review of the cytochrome P450s and their roles in toxicology. Toxicol Sci 1999; 48(2): 151-6.
[ ] [PMID: 10353305]
Feng P, Liu Z. Complex gene expansion of the CYP2D gene subfamily. Ecol Evol 2018; 8(22): 11022-30.
[ ] [PMID: 30519424]
Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA 2004; 101(20): 7711-5.
[] [PMID: 15128933]
Ioannides C. Cytochromes P450: Role in the metabolism and toxicity of drugs and other xenobiotics. London: RCS publcation. 2008.
Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: The past, present and future. Trends Pharmacol Sci 2004; 25(4): 193-200.
[] [PMID: 15063083]
Ingelman-Sundberg M, Oscarson M, McLellan RA. Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci 1999; 20(8): 342-9.
[ ] [PMID: 10431214]
Relling MV, Cherrie J, Schell MJ, Petros WP, Meyer WH, Evans WE. Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American black versus white subjects. Clin Pharmacol Ther 1991; 50(3): 308-13.
[ ] [PMID: 1680593]
Chen XW, Yu TJ, Zhang J, Li Y, Chen HL, Yang GF, et al. CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis. Oncogene 2017; 36(35): 5045-57.
[ ] [PMID: 28481877]
Chevalier D, Lo-Guidice JM, Sergent E, Allorge D, Debuysère H, Ferrari N, et al. Identification of genetic variants in the human thromboxane synthase gene (CYP5A1). Mutat Res 2001; 432(3-4): 61-7.
[PMID: 11465543]
Chiang JY. Regulation of bile acid synthesis. Front Biosci 1998; 3(4): d176-93.
Beltran-Sarmiento E, Floriano-Sanchez E, Bandala C, Lara-Padilla E, Cardenas-Rodriguez N. Association of CYP8A1 (Prostacyclin I2 synthase) polymorphism rs5602 with breast cancer in Mexican woman. Am J Cancer Res 2016; 6(2): 341-9.
[PMID: 27186408]
Fan Z, Wang Z, Chen W, Cao Z, Li Y. Association between the CYP11 family and six cancer types. Oncol Lett 2016; 12(1): 35-40.
[ ] [PMID: 27347096]
Goldstone JV, Sundaramoorthy M, Zhao B, Waterman MR, Stegeman JJ, Lamb DC. Genetic and structural analyses of cytochrome P450 hydroxylases in sex hormone biosynthesis: Sequential origin and subsequent coevolution. Mol Phylogenet Evol 2016; 94(Pt B): 676-87..
[] [PMID: 26432395]
Deeb KK, Luo W, Karpf AR, Omilian AR, Bshara W, Tian L, et al. Differential vitamin D 24-hydroxylase/CYP24A1 gene promoter methylation in endothelium from benign and malignant human prostate. Epigenetics 2011; 6(8): 994-1000.
[ ] [PMID: 21725204]
Taimi M, Helvig C, Wisniewski J, Ramshaw H, White J, Amad M, et al. A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-trans isomers of retinoic acid. J Biol Chem 2004; 279(1): 77-85.
[] [PMID: 14532297]
Tomaszewski P, Kubiak-Tomaszewska G, Pachecka J. Cytochrome P450 polymorphism--molecular, metabolic, and pharmacogenetic aspects. II. Participation of CYP isoenzymes in the metabolism of endogenous substances and drugs. Acta Pol Pharm 2008; 65(3): 307-18.
[PMID: 18646550]
Grabovec IP, Smolskaya SV, Baranovsky AV, Zhabinskii VN, Dichenko YV, Shabunya PS, et al. Ligand-binding properties and catalytic activity of the purified human 24-hydroxycholesterol 7α-hydroxylase, CYP39A1. J Steroid Biochem Mol Biol 2019; 193: 105416
[] [PMID: 31247323]
Lewinska M, Zelenko U, Merzel F, Golic Grdadolnik S, Murray JC, Rozman D. Polymorphisms of CYP51A1 from cholesterol synthesis: Associations with birth weight and maternal lipid levels and impact on CYP51 protein structure. PLoS One 2013; 8(12): e82554
[] [PMID: 24358204]
Yang XR, Wacholder S, Xu Z, Dean M, Calrk V, Gold B, et al. CYP1A1 and GSTM1 polymorphisms in relation to lung cancer risk in Chinese women. Cancer Lett 2004; 214(2): 197-204.
[ ] [PMID: 15363546]
Song N, Tan W, Xing D, Lin D. CYP 1A1 polymorphism and risk of lung cancer in relation to tobacco smoking: A case-control study in China. Carcinogenesis 2001; 22(1): 11-6.
[ ] [PMID: 11159735]
Pandey SN, Choudhuri G, Mittal B. Association of CYP1A1 Msp1 polymorphism with tobacco-related risk of gallbladder cancer in a north Indian population. Eur J Cancer Prev 2008; 17(2): 77-81.
[ ] [PMID: 18287863]
Sharma KL, Agarwal A, Misra S, Kumar A, Kumar V, Mittal B. Association of genetic variants of xenobiotic and estrogen metabolism pathway (CYP1A1 and CYP1B1) with gallbladder cancer susceptibility. Tumour Biol 2014; 35(6): 5431-9.
[] [PMID: 24535777]
Yu MW, Chiu YH, Yang SY, Santella RM, Chern HD, Liaw YF, et al. Cytochrome P450 1A1 genetic polymorphisms and risk of hepatocellular carcinoma among chronic hepatitis B carriers. Br J Cancer 1999; 80(3-4): 598-603.
[ ] [PMID: 10408872]
Tanaka Y, Sasaki M, Kaneuchi M, Shiina H, Igawa M, Dahiya R. Polymorphisms of the CYP1B1 gene have higher risk for prostate cancer. Biochem Biophys Res Commun 2002; 296(4): 820-6.
[ ] [PMID: 12200121]
Suzuki K, Matsui H, Nakazato H, Koike H, Okugi H, Hasumi M, et al. Association of the genetic polymorphism in cytochrome P450 (CYP) 1A1 with risk of familial prostate cancer in a Japanese population: a case-control study. Cancer Lett 2003; 195(2): 177-83.
[ ] [PMID: 12767526]
Murata M, Watanabe M, Yamanaka M, Kubota Y, Ito H, Nagao M, et al. Genetic polymorphisms in cytochrome P450 (CYP) 1A1, CYP1A2, CYP2E1, glutathione S-transferase (GST) M1 and GSTT1 and susceptibility to prostate cancer in the Japanese population. Cancer Lett 2001; 165(2): 171-7.
[ ] [PMID: 11275366]
Malaiyandi V, Sellers EM, Tyndale RF. Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence. Clin Pharmacol Ther 2005; 77(3): 145-58.
[ ] [PMID: 15735609]
Xu C, Goodz S, Sellers EM, Tyndale RF. CYP2A6 genetic variation and potential consequences. Adv Drug Deliv Rev 2002; 54(10): 1245-56.
[ ] [PMID: 12406643]
Kamataki T, Fujieda M, Kiyotani K, Iwano S, Kunitoh H. Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk. Biochem Biophys Res Commun 2005; 338(1): 306-10.
[ ] [PMID: 16176798]
Fujieda M, Yamazaki H, Saito T, Kiyotani K, Gyamfi MA, Sakurai M, et al. Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis 2004; 25(12): 2451-8.
[ ] [PMID: 15308589]
Ariyoshi N, Miyamoto M, Umetsu Y, Kunitoh H, Dosaka-Akita H, Sawamura YI, et al. Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers. Cancer Epidemiol Biomarkers Prev 2002; 11(9): 890-4.
[PMID: 12223434]
Tyndale RF, Sellers EM. Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior. Ther Drug Monit 2002; 24(1): 163-71.
[ ] [PMID: 11805739]
Rotger M, Tegude H, Colombo S, Cavassini M, Furrer H, Décosterd L, et al. Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals. Clin Pharmacol Ther 2007; 81(4): 557-66.
[ ] [PMID: 17235330]
Tsuchiya K, Gatanaga H, Tachikawa N, Teruya K, Kikuchi Y, Yoshino M, et al. Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. Biochem Biophys Res Commun 2004; 319(4): 1322-6.
[ ] [PMID: 15194512]
Wang J, Sonnerborg A, Rane A, Josephson F, Lundgren S, Stahle L, et al. Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz. Pharmacogenet Genomics 2006; 16(3): 191-8.
[ ] [PMID: 16495778]
Weise A, Grundler S, Zaumsegel D, Klotzek M. Development and evaluation of a rapid and reliable method for cytochrome P450 2C8 genotyping. Clin Lab 2004; 50(3-4): 141-8.
[PMID: 15074466]
Daly AK, Aithal GP, Leathart JBS, Swainsbury RA, Dang TS, Day CP. Genetic susceptibility to diclofenac-induced hepatotoxicity: Contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 2007; 132(1): 272-81.
[ ] [PMID: 17241877]
Rathore SS, Agarwal SK, Pande S, Mittal T, Mittal B. Frequencies of VKORC1 -1639 G>A, CYP2C9*2 and CYP2C9*3 genetic variants in the Northern Indian population. Biosci Trends 2010; 4(6): 333-7.
[PMID: 21248432]
Blaisdell J, Mohrenweiser H, Jackson J, Stephen F, Sherry C, Brian C, et al. Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics 2002; 12(9): 703-11.
[ ] [PMID: 12464799]
Gulati S, Yadav A, Kumar N. Kanupriya, Kumar G, Aggarwal N, et al Frequency distribution of high risk alleles of CYP2C19, CYP2E1, CYP3A4 genes in Haryana population. Environ Toxicol Pharmacol 2014; 37(3): 1186-93.
[ ] [PMID: 24814262]
Kidd KK, Rajeevan H, Cheung K-H, Soundararajan U, Stein S, Pakstis AJ, et al. ALFRED: The allele frequency database. Available From:. http//infomedyaleedu/genetics/kkidd2012.
Steiner E, Bertilsson L, Sawe J, Bertling I, Sjoqvist F. Polymorphic debrisoquin hydroxylation in 757 Swedish subjects. Clin Pharmacol Ther 1988; 44(4): 431-5.
[ ] [PMID: 3168394]
Gellner K, Eiselt R, Hustert E, Hannes A, Ina K, Michael H, et al. Genomic organization of the human CYP3A locus: Identification of a new, inducible CYP3A gene. Pharmacogenetics 2001; 11(2): 111-21.
[ ] [PMID: 11266076]
Finta C, Zaphiropoulos PG. The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons. Gene 2000; 260(1-2): 13-23.
[ ] [PMID: 11137287]
Plummer SJ, Conti DV, Paris PL, Curran AP, Casey G, Witte JS. CYP3A4 and CYP3A5 genotypes, haplotypes, and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 2003; 12(9): 928-32.
[PMID: 14504207]
Amirimani B, Walker AH, Weber BL, Rebbeck TR. RESPONSE: Re: Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1999; 91(18): 1588-90.
[ ] [PMID: 10491443]
White INH. Tamoxifen: Is it safe? Comparison of activation and detoxication mechanisms in rodents and in humans. Curr Drug Metab 2003; 4(3): 223-39.
[ ] [PMID: 12769667]
Dehal SS, Kupfer D. CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res 1997; 57(16): 3402-6.
[PMID: 9270005]
Huang Z, Roy P, Waxman DJ. Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol 2000; 59(8): 961-72.
[ ] [PMID: 10692561]
Chang TKH, Weber GF, Crespi CL, Waxman DJ. Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res 1993; 53(23): 5629-37.
[PMID: 8242617]
Sladek NE. Metabolism of oxazaphosphorines. Pharmacol Ther 1988; 37(3): 301-55.
[ ] [PMID: 3290910]
Boyd VL, Robbins JD, Egan W, Ludeman SM. 31P nuclear magnetic resonance spectroscopic observation of the intracellular transformations of oncostatic cyclophosphamide metabolites. J Med Chem 1986; 29(7): 1206-10.
[ ] [PMID: 3543359]
Shou M, Martinet M, Korzekwa KR, Krausz KW, Gonzalez FJ, Gelboin HV. Role of human cytochrome P450 3A4 and 3A5 in the metabolism of taxotere and its derivatives: Enzyme specificity, interindividual distribution and metabolic contribution in human liver. Pharmacogenetics 1998; 8(5): 391-401.
[ ] [PMID: 9825831]
Hustert E, Haberl M, Burk O, Wolbold R, He YQ, Klein K, et al. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 2001; 11(9): 773-9.
[ ] [PMID: 11740341]
Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27(4): 383-91.
[ ] [PMID: 11279519]
Tsai S-M, Lin C-Y, Wu S-H, Hau AL, Ma H, Tsai LY, et al. Side effects after docetaxel treatment in Taiwanese breast cancer patients with CYP3A4, CYP3A5, and ABCB1 gene polymorphisms. Clin Chim Acta 2009; 404(2): 160-5.
[ ] [PMID: 19332043]
Bahadur N, Leathart JBS, Mutch E, Steimel-Crespi D, Dunn SA, Gilissen R, et al. CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6α -hydroxylase activity in human liver microsomes. Biochem Pharmacol 2002; 64(11): 1579-89.
[ ] [PMID: 12429347]
Dai D, Zeldin DC, Blaisdell JA, Chanas B, Coulter SJ, Ghanayem BI, et al. Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid. Pharmacogenetics 2001; 11(7): 597-607.
[ ] [PMID: 11668219]
Henningsson A, Marsh S, Loos WJ, Karlsson MO, Garsa A, Mross K, et al. Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin Cancer Res 2005; 11(22): 8097-104.
[ ] [PMID: 16299241]
Dennison JB, Kulanthaivel P, Barbuch RJ, Renbarger JL, Ehlhardt WJ, Hall SD. Selective metabolism of vincristine in vitro by CYP3A5. Drug Metab Dispos 2006; 34(8): 1317-27.
[ ] [PMID: 16679390]
Dennison JB, Jones DR, Renbarger JL, Hall SD. Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. J Pharmacol Exp Ther 2007; 321(2): 553-63.
[ ] [PMID: 17272675]
Yang Y, Dong X, Xie B, Ding N, Chen J, Li Y, et al. Databases and web tools for cancer genomics study. Genomics Proteomics Bioinformatics 2015; 13(1): 46-50.
[ ] [PMID: 25707591]
Hong WK, Hait W, Holland JF, Kufe DW, Pollock RE. Holland-Frei Cancer Medicine 8. PMPH-USA 2010; Vol. 8.
Nagahashi M, Shimada Y, Ichikawa H, Kameyama H, Takabe K, Okuda S, et al. Next generation sequencing-based gene panel tests for the management of solid tumors. Cancer Sci 2019; 110(1): 6-15.
[ ] [PMID: 30338623]
Wakai T, Prasoon P, Hirose Y, Shimada Y, Ichikawa H, Nagahashi M. Next-generation sequencing-based clinical sequencing: Toward precision medicine in solid tumors. Int J Clin Oncol 2019; 24(2): 115-22.
[ ] [PMID: 30515675]
Sim SC, Altman RB, Ingelman-Sundberg M. Databases in the area of pharmacogenetics. Hum Mutat 2011; 32(5): 526-31.
[ ] [PMID: 21309040]
Zhang G, Zhang Y, Ling Y, Jia J. Web resources for pharmacogenomics. Genomics Proteomics Bioinformatics 2015; 13(1): 51-4.
[ ] [PMID: 25703229 ]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy