A review of the relationship between Doxorubicin and Doxorubicinol, CBR1 polymorphism, and cardiotoxicity
DOI:
https://doi.org/10.46542/pe.2024.246.105115Keywords:
CBR1 Polymorphism, DBS, Doxorubicin, Doxorubicinol, PCR, UHPLC-MS/MSAbstract
Background: Doxorubicin is a chemotherapy drug given to breast cancer patients. However, its administration is limited by its cardiotoxicity. The CBR1 enzyme in the liver catalyses doxorubicin to doxorubicinol, which also contributes to its cardiotoxicity. The polymorphism of the CBR1 enzyme affects doxorubicin and doxorubicinol levels in the body.
Objective: To review the effect of CBR1 polymorphisms on the levels of doxorubicin and doxorubicinol after administration of doxorubicin.
Methods: Relevant studies from selected databases were examined; Three main studies with 20 support studies were reviewed.
Results: The recommended methods were the analysis of doxorubicin and doxorubicinol levels using the Dried Blood Spot biosampling technique, which uses the ultra-high-performance liquid chromatography-tandem mass spectrometry (LCMS/MS), and the evaluation of the genetic profile of CBR1 using Polymerase Chain Reaction.
Conclusion: Four CBR1 genetic polymorphisms have been shown to reduce doxorubicinol levels in the body, which is associated with decreased CBR1 activity and expression. Thus, the conversion of doxorubicin to doxorubicinol is reduced. Therefore, individuals who experience CBR1 polymorphisms have a lower risk of cardiotoxicity after the administration of doxorubicin.
References
Alexieva, B., Sainova, I.V., Pavlova, V., Markova, T., & Nikolova, E. (2014). Insights into mechanisms of doxorubicin cardiotoxicity. Journal of Physiology and Pharmacology Advances, 4(3), 342‒348. https://www.researchgate.net/publication/326160854_Insights_into_Mechanisms_of_Doxorubicin_Cardiotoxicity
Aniogo, E. C., George, B. P. A., & Abrahamse, H. (2017). Phthalocyanine induced phototherapy coupled with Doxorubicin; a promising novel treatment for breast cancer. Expert Review of Anticancer Therapy, 17(8), 693–702. http://dx.doi.org/10.1080/14737140.2017.1347505
Asia WHOS. 1 989 024 042. 2019;401:2018–9.
Banerjee, S., & Mazumdar, S. (2012). Electrospray ionization mass spectrometry: A technique to access the information beyond the molecular weight of the analyte. International Journal of Analytical Chemistry, 2012, 1–40.
Damiani, R. M., Moura, D. J., Viau, C. M., Caceres, R. A., Henriques, J. A. P., & Saffi, J. (2016) Pathways of cardiac toxicity: Comparison between chemotherapeutic drugs doxorubicin and mitoxantrone. Archives of Toxicology. 90(9), 2063–76.
Davani, S., Deschaseaux, F., Chalmers, D., Tiberghien, P., & Kantelip, J. P. (2005). Can stem cells mend a broken heart. Cardiovascular Researchi, 65(2), 305–16.
Dos Santos Arruda, F., Tomé, F. D., Miguel, M. P., de Menezes, L. B., Nagib, P. R. A., & Campos, E. C. (2019). Doxorubicin-induced cardiotoxicity and cardioprotective agents: Classic and new Players in the game. Current Pharmaceutical Design, 25(2), 109–18.
Emara, S., Masujima, T., Zarad, W., Kamal, M., Fouad, M., & El-Bagary, R. (2015). A combination of isocratic and gradient elution modes in HPLC with the aid of time-overlapping process for rapid determination of methyldopa in human urine. Journal of Liquid Chromatography Relatio Technol, 38(2), 153–62.
EMEA. (2011). Guideline on bioanalytical method validation Guideline on bioanalytical method validation Table of contents. 44(2011), 1–23.
Evans, D. R. H., Romero, J. K., & Westoby, M. (2009). Chapter 9 Concentration of proteins and removal of solutes. Methods Enzymol, 463(C), 97–120.
FDA. (2018). Bioanalytical method validation guidance for industry bioanalytical method validation. FDA Guid Ind http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/ or http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm
Gavila, J., Seguí, M., Calvo, L., López, T., Alonso, J. J., & Farto, M. (2017). Evaluation and management of chemotherapy-induced cardiotoxicity in breast cancer: a Delphi study. Clinical & Translational Oncology, 19(1), 91–104.
Gonzalez-covarrubias, V., Ghosh, D., Lakhman, S. S., Pendyala, L., & Blanco, J. G. (2007). A functional genetic polymorphism on human Carbonyl Reductase 1 (CBR1 V88I) impacts on catalytic activity and NADPH binding affinity. ABSTRACT, 35(6), 973–80
Gonzalez-Covarrubias, V., Zhang, J., Kalabus, J. L., Relling, M. V., & Blanco, J. G. (2009). Pharmacogenetics of human carbonyl reductase 1 (CBR1) in livers from black and white donors. Drug Metabolism and Disposition, 37(2), 400–7. https://www.doi.org/10.1124/dmd.108.024547
Grüner, N., Stambouli, O., & Ross, R. S. (2015). Dried blood spots–preparing and processing for use in immunoassays
Gunawan, P. Y., Kaunang, E. D., Mantik, M. F. J., & Gunawan, S. (2018). Hubungan dosis kumulatif doksorubisin terhadap fungsi sistolik ventrikel kiri pada penyintas leukemia limfoblastik akut. Sari Pediatr, 20(3), 165.
Gupta, K., & Mahajan, R. (2018). Applications and diagnostic potential of dried blood spots. International Journal of Applied and Basic Medical Research, 193–5.
Hanna, A. D., Lam, A., Tham, S., Dulhunty, A. F., & Beard, N. A. (2014). Adverse effects of doxorubicin and its metabolic product on cardiac RyR2 and SERCA2A. Molecular Pharmacology, 86(4), 438–49.
Harahap, Y., Amalia, S. N., Anarta, A., & Ramadhan. (2020). Analysis of doxorubicin and doxorubicinol in dried blood spot of breast cancer patients for monitoring the cardiotoxicity of doxorubicin. International Journal of Pharmacy and Pharmaceutical Sciences, 12(4), 21–5.
Harbeck, N., Penault-Llorca, F., Cortes, J., Gnant, M., Houssami, N., Poortmans, P., Ruddy, K., Tsang, J., & Cardoso, F. (2019). Breast cancer. Nature Reviews Disease Primers, 5(1), 66. https://doi.org/10.1038/s41572-019-0111-2
Harmita, K., Harahap, Y., & Suspandi. (2019). Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).
Henninger, C., & Fritz, G. (2017). Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers. Cell Death and Disease, 8(1), 1–11. http://dx.doi.org/10.1038/cddis.2016.418
Jo, A., Choi, T. G., Jo, Y. H., Jyothi, K. R., Nguyen, M. N., & Kim, J.H. (2017). Inhibition of carbonyl reductase 1 safely improves the efficacy of doxorubicin in breast cancer treatment. Antioxidants & Redox Signaling, 26(2), 70–83.
Kadjo, A. F., Stamos, B. N., Shelor, C. P., Berg, J. M., Blount, B. C., & Dasgupta, P. K. (2016). Evaluation of amount of blood in dry blood spots: Ring-disk electrode conductometry. Analytical Chemistry, 88(12), 6531–7.
Kadri, K. (2019). Polymerase Chain Reaction (PCR) principle and applications. Synth Biol - New Interdiscip Science. https:10.5772/intechopen.86491
Kalyanaraman, B. (2020) Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree. Redox Biology, 29, 101394. https://doi.org/10.1016/j.redox.2019.101394
Kang, J. S. (2012). Principles and applications of LC-MS/MS for the quantitative bioanalysis of analytes in various biological samples. Tandem Mass Spectrom - Applied Principle.
Karger, B. L., & Guttman, A. (2009). DNA sequencing by CE. Electrophoresis. 30(1), 196–202.
Kassner, N., Huse, K., Martin, H.J., Gödtel-Armbrust, U., Metzger, A., Meineke, I., Brockmöller, J., Klein, K., Zanger, U. M., Maser, E., & Wojnowski, L. (2008). Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver. Drug Metabolism and Disposition, 36(10), 2113‒20. https://www.doi.org/10.1124/dmd.108.022251
Kaza, M., Karaźniewicz-Łada, M., Kosicka, K., Siemiątkowska, A., & Rudzki, P. J. (2019). Bioanalytical method validation: new FDA guidance vs. EMA guideline. Journal of Pharmaceutical & Biomedical Analysis, 165, 381–5.
Lal, S., Mahajan, A., Chen, W. N., & Chowbay, B. (2010). Pharmacogenetics of target genes across doxorubicin disposition pathway: A review. 115–28.
Lal, S., Sandanaraj, E., Wong, Z. W., Ang, P. C. S., Wong, N. S., & Lee, E. J. D. (2008) CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients. Cancer Science, 99(10), 2045–54.
Lal, S., Sandanaraj, E., Wong, Z. W., Ang, P. C. S., Wong, N. S., & Lee, E. J. D. (2008). CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients. Cancer Science, 99(10), 2045–54.
Leeman, M., Choi, J., Hansson, S., Storm, M. U., & Nilsson, L. (2018). Proteins and antibodies in serum, plasma, and whole blood—size characterization using asymmetrical flow field-flow fractionation (AF4). Analytical and Bioanalytical Chemistry, 410(20), 4867–73.
Lim, M. D. (2018). Review article: Dried blood spots for global health diagnostics and surveillance: Opportunities and challenges. American Journal of Tropical Medicine and Hygiene, 99(2), 256–65
Luu, A., Chowdhury, B., Al-Omran, M., Teoh, H., Hess, D., & Verma, S. (2018). Role of endothelium in doxorubicin-induced cardiomyopathy. 3(6).
Mahajan, S., Choudhary, M. C., Kumar, G., & Gupta, E. (2018). Evaluation of dried blood spot as an alternative sample collection method for hepatitis C virus RNA quantitation and genotyping using a commercial system. Virus Disease, 29(2), 141–6. https://doi.org/10.1007/s13337-018-0441-9
Malatkova, P., Master, E., & Wsol, V. l. (2010). Human carbonyl reductases. Progress in Clinical and Biological Research, 114, 261–74.
Milman, B. L. (2015). General principles of identification by mass spectrometry. TrAC - Trends Analysis Chemical, 69(2015), 24–33. http://dx.doi.org/10.1016/j.trac.2014.12.009
Mirzaei, H., & Carrasco, M. (2016). Modern proteomics – Sample preparation, analysis and practical Aapplications. Mod Proteomics - Sample Prep. Anal Practical Application, 919, 43–62. http://link.springer.com/10.1007/978-3-319-41448-5
Mitry, M. A., & Edwards, J. G. (2016). Doxorubicin induced heart failure: Phenotype and molecular mechanisms. IJC Heart Vasculature, 10, 17–24. http://dx.doi.org/10.1016/j.ijcha.2015.11.004
Moein, M. M., El-Beqqali, A., & Abdel-Rehim, M. (2017). Bioanalytical method development and validation: Critical concepts and strategies. Journal of Chromatography B http://dx.doi.org/10.1016/j.jchromb.2016.09.028
Momenimovahed, Z., & Salehiniya, H. (2019). Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer: Targets & Therapy, 11, 151–64.
Piska, K., Koczurkiewicz, P., Bucki, A., Wójcik-pszczo, K., & Ko, M. (2017). Metabolic carbonyl reduction of anthracyclines — role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitising agents. Investigational New Drugs, 35(3), 375‒385. https://www.doi.org/10.1007/s10637-017-0443-2
Pretty, J. R., Connor, T. H, Spasojevic, I., Kurtz, K. S., McLaurin, J. L., & B’Hymer, C. (2012). Sampling and mass spectrometric analytical methods for five antineoplastic drugs in the healthcare environment. Journal of oncology & pharmaceutical Practice, 18(1), 23–36.
Puspitasari. (2020). Analysis of doxorubicin hydrochloride and doxorubicinol in the plasma of cancer patients breast using liquid chromatography ultra high performance–tandem mass spectrometry. [Thesis]. Univesity of Indonesia.
QIAGEN. (2016). QIAamp DNA mini and blood mini handbook. Qiagen, (5), 1–72. http://www.qiagen.com/knowledge-and-support/resource-center/resource-download.aspx?id=67893a91-946f-49b5-8033-394fa5d752ea&lang=en
Rahman, M. T., Uddin, M. S., Sultana, R., Moue, A., & Setu, M. (2013). Polymerase Chain Reaction (PCR): A short review. Anwer Khan Mod Med Coll J, 4(1), 30–6.
Rasola, A., & Bernardi, P. (2011). Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis. Cell Calcium, 50, 222–33.
Reis-Mendes, A., Carvalho, F., Remião, F., Sousa, E., Bastos, M. D. L., & Costa, V. M. (2019). The main metabolites of Fluorouracil + Adriamycin + Cyclophosphamide (FAC) are not major contributors to FAC toxicity in H9c2 cardiac differentiated cells. Biomolecules, 9(3), 98. https://doi.org/10.3390/biom9030098
Santos, M. C. D., Morais, C. L. M., Nascimento, Y. M., Araujo, J. M. G., & Lima, K. M. G. (2017). Spectroscopy with computational analysis in virological studies: A decade (2006–2016). TrAC - Trends in Analytical Chemistry, 97, 244–56. https://doi.org/10.1016/j.trac.2017.09.015
Semreen, M. H., Alniss, H. Y., Mousa, M. K., El-Awady, R., Khan, F., & Al-Rub, K. A. (2018). Quantitative determination of doxorubicin in the exosomes of A549/MCF-7 cancer cells and human plasma using ultra performance liquid chromatography-tandem mass spectrometry. Saudi Pharmaceutical Journal, 26(7), 1027–34. https://doi.org/10.1016/j.jsps.2018.05.011
Shargel, L., & Yu, A. B. C. (2012). Applied biopharmaceutics & pharmacokinetics.
Shi, S. M., & Di, L. (2017). The role of carbonyl reductase 1 in drug discovery and development. Expert Opinion on Drug Metabolism & Toxicology, 13(8), 859–70.
Sottani, C., Poggi, G., Melchiorre, F., Montagna, B., & Minoia, C. (2013). Simultaneous measurement of doxorubicin and reduced metabolite doxorubicinol by UHPLC – MS / MS in human plasma of HCC patients treated with TACE. 916, 71–8.
Taylor, R. R., Hoffman, K. L., Schniedewind, B., Clavijo, C., Galinkin, J. L, & Christians, U. (2013). Comparison of the quantification of acetaminophen in plasma, cerebrospinal fluid and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry. Journal of Pharmaceutical & Biomedical Analysis, 83, 1–9. http://dx.doi.org/10.1016/j.jpba.2013.04.007
Tecza, K., Pamula-Pilat, J., Lanuszewska, J., Butkiewicz, D., & Grzybowska, E. (2018). Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients. Oncotarget, 9(10), 9114–36.
Van De Merbel, N., Savoie, N., Yadav, M., Ohtsu, Y., White, J., & Riccio, M. F. (2014). Stability: Recommendation for best practices and harmonization from the global bioanalysis consortium harmonization team. AAPS Journal, 16(3), 392–9.
Wenningmann, N., Knapp, M., Ande, A., Vaidya, T. R., & Ait-Oudhia, S. (2019). Insights into doxorubicin-induced cardiotoxicity: Molecular mechanisms, preventive strategies, and early monitoring. Molecular Pharmacology, 96(2), 219–32.
World Health Organisation. (2018). Data factsheets populations Indonesia. https://gco.iarc.fr/today/data/factsheets/populations/360-indonesia-fact-sheets.pdf
Zeng, X., Cai, H., Yang, J., Qiu, H., Cheng, Y, & Liu, M. (2019). Biomedicine & pharmacotherapy pharmacokinetics and cardiotoxicity of doxorubicin and its secondary alcohol metabolite in rats. Biomedicine & Pharmacotherapy, 116, 108964. https://doi.org/10.1016/j.biopha.2019.108964
Zhao, N., Woodle, M. C., & Mixson, A. J. (2018). Advances in delivery systems for doxorubicin. Journal of Nanomedicine & Nanotechnology, 9, 519. https://doi.org/10.4172/2157-7439.1000519
