Interaction of CYP3A4, CYP3A5, CYP1A1 and CYP2B6 genes in the development of organotoxic effects of chemotherapy in patients with Hodgkin's lymphoma
V. A. Vavilin,
O. B. Goreva,
Ya. Yu. Shebunyaeva,
S. I. Makarova,
M. S. Voitko,
A. Yu. Grishanova,
T. I. Pospelova https://doi.org/10.37489/2588-0527-2024-1-31-43
EDN: QMEJLP
Abstract
Relevance. Modern chemotherapy for Hodgkin lymphoma (HL) achieves long-term remissions in 80–85 % of patients. Some patients develop drugrelated toxicity. Polymorphisms in drug-metabolizing cytochrome P450 (CYP) genes contribute to individual differences in the therapeutic and side effects of chemotherapy. In this regard, chemotherapy for HL in Russia has not been sufficiently studied.
Objective. To study the relationship between polymorphic variants of CYP3A4, CYP3A5, CYP1A1, and CYP2B6 and the development of organotoxic effects of HL therapy.
Methods. Polymorphic variants CYP3A4 (rs4987161, rs28371759, rs2740574), CYP3A5 rs776746, CYP1A1 (rs1048943, rs4646421), and CYP2B6 (rs2279343) were determined by polymerase chain reaction with real-time detection. Their association with organotoxic complications was assessed by odds ratio and using Multifactorial Dimensionality Reduction (MDR).
Results. MDR analysis showed the significance of polymorphic variants of four genes for hepatotoxicity with the main contribution of CYP1A1 rs464642. Synergism was observed for CYP1A1 rs4646421 and CYP2B6 rs227934 and CYP2B6 rs227934 and CYP3A5 rs776746, and antagonism was observed for CYP1A1 rs4646421 and CYP3A5 rs776746. The main contributor to cardiotoxicity was CYP2B6 rs227934, which showed synergy with both CYP1A1 variants. The main contribution to the development of anemia was made by CYP3A5 rs776746, for which synergism with CYP1A1 rs104894 was noted; for leukopenia — CYP1A1 rs464642; for granulocytopenia — CYP2B6 rs227934, antagonism with CYP1A1 variants was noted; for thrombocytopenia — CYP3A4 rs2740574, antagonism with CYP3A5 rs776746 was observed.
Conclusion. The results show that different combinations of polymorphic variants of CYP genes are associated with different types of organotoxicity and that different genes make a major contribution.
Keywords
Hodgkin's lymphoma,
program polychemotherapy,
polymorphism,
CYP3A4,
CYP3A5,
CYP1A1,
CYP2B6,
organotoxicity
Supporting agencies: The study was carried out within the framework of the State Budget AAAA-A15-115120910171-1 of the NSMU of the Ministry of Health of the Russian Federation (work on the clinical and clinicallaboratory description of patients) and the State Order No. 122032200236-1 of the FRC FTM (work on the genotyping of polymorphic variants of CYP) using the equipment of the Center for Common Use "Proteomic Analysis" , supported by a grant from the Ministry of Education and Science of the Russian Federation (agreement No. 075-15-2021-691).
About the Authors
V. A. Vavilin
FSBSI "Federal Research Center of Fundamental and Translational Medicine"
Russian Federation
Competing Interests:
Russian Federation
Valentin A. Vavilin, PhD, Cand. Sci. (Med), Professor, Corresponding Member of the Russian Academy of Sciences, director,
Novosibirsk.
Competing Interests:
The authors declare that there is no conflict of interest in the preparation of the manuscript.
O. B. Goreva
FSBSI "Federal Research Center of Fundamental and Translational Medicine"
Russian Federation
Competing Interests:
Russian Federation
Olga B. Goreva PhD, Cand. Sci. (Biology), Senior Researcher,
Novosibirsk.
Competing Interests:
The authors declare that there is no conflict of interest in the preparation of the manuscript.
Ya. Yu. Shebunyaeva
FSBEI НЕ "Novosibirsk State Medical University" МОН Russia
Russian Federation
Competing Interests:
Russian Federation
Yana Yu. Shebunyaeva, Graduate Student of the Department of Therapy, Hematology and Transfusiology,
Novosibirsk.
Competing Interests:
The authors declare that there is no conflict of interest in the preparation of the manuscript.
S. I. Makarova
FSBSI "Federal Research Center of Fundamental and Translational Medicine"
Russian Federation
Competing Interests:
Russian Federation
Svetlana I. Makarova, PhD, Dr. Sci. (Biology), Assistant Professor, Senior Researcher,
Novosibirsk.
Competing Interests:
The authors declare that there is no conflict of interest in the preparation of the manuscript.
M. S. Voitko
FSBEI НЕ "Novosibirsk State Medical University" МОН Russia
Russian Federation
Competing Interests:
Russian Federation
Mariya S. Voitko, PhD, Cand. Sci. (Med), Assistant of the Department of Therapy, Hematology and Transfusiology,
Novosibirsk.
Competing Interests:
The authors declare that there is no conflict of interest in the preparation of the manuscript.
A. Yu. Grishanova
FSBSI "Federal Research Center of Fundamental and Translational Medicine"
Russian Federation
Competing Interests:
Russian Federation
Alevtina Yu. Grishanova, PhD, Dr. Sci. (Biol.), Professor, Head of the Laboratory of Biochemistry of Xenobiotics,
Novosibirsk.
Competing Interests:
The authors declare that there is no conflict of interest in the preparation of the manuscript.
T. I. Pospelova
FSBEI НЕ "Novosibirsk State Medical University" МОН Russia
Russian Federation
Competing Interests:
Russian Federation
Tatiana I. Pospelova, PhD, Dr. Sci. (Med.), Professor, Vice-Rector for Research,
Novosibirsk.
Competing Interests:
The authors declare that there is no conflict of interest in the preparation of the manuscript.
References
1. Demina EA. Rukovodstvo po lecheniyu limfomy Khodzhkina. Moscow: OOO «GRUPPA REMEDIUM»; 2021. (In Russ.).
2. Ansell SM. Hodgkin lymphoma: A 2020 update on diagnosis, riskstratification, and management. Am J Hematol. 2020 Aug;95(8):978-989. doi: 10.1002/ajh.25856.
3. Rossiiskie klinicheskie rekomendatsii po diagnostike i lecheniyu limfoproliferativnykh zabolevanii. Ed by. Poddubnoi IV, Savchenko VG. Moscow. Buki Vedi; 2018. (In Russ.).
4. Danilenko AA. Otdalennye posledstviya luchevoi i khimioluchevoi terapii pervichnykh bol'nykh limfomoi Khodzhkina. [dissertation] Obninsk; 2017. (In Russ).
5. Remer M, Johnson PW. Risk- and response-adapted strategies for the management of Hodgkin lymphoma. Chin Clin Oncol. 2015 Mar;4(1):13. doi: 10.3978/j.issn.2304-3865.2015.03.04.
6. Parkinson AB, Ogilvie WD, Buckley B, et al. Casarett & Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill Education, LLC; 2017:185-365.
7. Zhuo X, Zheng N, Felix CA, Blair IA. Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004 Sep;32(9):993-1000.
8. Lovett BD, Strumberg D, Blair IA, et al. Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints. Biochemistry. Feb 6 2001;40(5):1159-70. doi: 10.1021/bi002361x.
9. Tulsyan S, Agarwal G, Lal P, Mittal B. Significant role of CYP450 genetic variants in cyclophosphamide based breast cancer treatment outcomes: a multi-analytical strategy. Clin Chim Acta. Jul 1 2014;434:21-8. doi: 10.1016/j.cca.2014.04.009.
10. Mikulyak NI, Kinzirskaya YuA. Experimental study of lipid peroxidation in combination of doxorubicin and mexidol. Journal of Volgograd state medical university. 2011;1(37):101-103. (In Russ.).
11. Václavíková R, Kondrová E, Ehrlichová M, et al. The effect of flavonoid derivatives on doxorubicin transport and metabolism. Bioorg Med Chem. 2008 Feb 15;16(4):2034-42. doi: 10.1016/j.bmc.2007.10.093.
12. Le Guellec C, Lacarelle B, Catalin J, Durand A. Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes. Cancer Chemother Pharmacol. 1993;32(6):491-5. doi: 10.1007/BF00685896.
13. Kobilov OR. Substantiation and principles of correction of hematological toxicity of polychemotherapy of malignant tumors (review of literature). Bulletin of science and education. 2019;17(71):68-72. (In Russ). doi:10.24411/2312-8089-2019-11703.
14. Sharipov FK, Balenkov IuO, Kireev GV. Dynamics of free-radical oxidation processes in transplantable sarcoma-45 as indicator of tumor and body interaction. Vopr Onkol. 2005;51(2):227-9. (In Russ.)
15. Rendic S, Guengerich FP. Survey of Human Oxidoreductases and Cytochrome P450 Enzymes Involved in the Metabolism of Xenobiotic and Natural Chemicals. Chem Res Toxicol. 2015 Jan 20;28(1):38-42. doi: 10.1021/tx500444e.
16. Vitsenya MV, Ageev FT, Gilyarov MYu, et al. Prakticheskie rekomendatsii po korrektsii kardiovaskulyarnoi toksichnosti protivoopukholevoi lekarstvennoi terapii. MALIGNANT TUMOURS Russian Society of Clinical Oncology. 2021;11(#3s2):78-98. (In Russ.)]. doi: 10.18027/2224-5057-2020-10-3s2-41.
17. Ponomarenko IV. Using the method of Multifactor Dimensionality Reduction (MDR) and its modifications for analysis of gene-gene and gene-environment interactions in geneticepidemiological studies (review). Research Results in Biomedicine. 2019;5(1):4-21. (In Russ.)]. doi: 10.18413/2313-8955-2019-5-1-0-1.
18. Gendlin GE, Emelina ЕI, Nikitin IG, Vasyuk YuА. Modern view on cardiotoxicity of chemotherapeutics in oncology including anthracyclines. Russ J Cardiol. 2017;3(143): 145-154. (In Russ.)]. doi: 10.15829/1560-4071-2017-3-145-154.
19. Eaton DL, Gilbert SG. Principles of Toxicology. In: Klaassen C, ed. Casarett & Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill Education, LLC; 2017:13-48.
20. Dennison JB, Jones DR, Renbarger JL, Hall SD. Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. J Pharmacol Exp Ther. 2007 May;321(2):553-63. doi: 10.1124/jpet.106.118471.
21. Dennison JB, Mohutsky MA, Barbuch RJ, et al. Apparent high CYP3A5 expression is required for significant metabolism of vincristine by human cryopreserved hepatocytes. J Pharmacol Exp Ther. 2008 Oct;327(1):248-57. doi: 10.1124/jpet.108.139998.
22. Reid JM, Kuffel MJ, Miller JK, et al. Metabolic activation of dacarbazine by human cytochromes P450: the role of CYP1A1, CYP1A2, and CYP2E1. Clin Cancer Res. 1999 Aug;5(8):2192-7.
23. Zhuo X, Zheng N, Felix CA, Blair IA. Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos. 2004 Sep;32(9):993-1000.
24. Roy P, Yu LJ, Crespi CL, Waxman DJ. Development of a substrateactivity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos. 1999 Jun;27(6):655-66.
25. Masek V, Anzenbacherová E, Etrych T, et al. Interaction of N-(2- hydroxypropyl)methacrylamide copolymer-doxorubicin conjugates with human liver microsomal cytochromes P450: comparison with free doxorubicin. Drug Metab Dispos. 2011 Sep;39(9):1704-10. doi: 10.1124/dmd.110.037986.
26. Quintieri L, Geroni C, Fantin M, et al. Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes. Clin Cancer Res. 2005 Feb 15;11(4):1608-17. doi: 10.1158/1078-0432.CCR-04-1845.
27. Chaudhary KR, Batchu SN, Seubert JM. Cytochrome P450 enzymes and the heart. IUBMB Life. 2009 Oct;61(10):954-60. doi: 10.1002/iub.241.
28. Soucek P, Anzenbacher P, Skoumalová I, Dvorák M. Expression of cytochrome P450 genes in CD34+ hematopoietic stem and progenitor cells. Stem Cells. 2005 Oct;23(9):1417-22. doi: 10.1634/stemcells.2005-0066.
29. Larsen MC, Almeldin A, Tong T, et al. Cytochrome P4501B1 in bone marrow is co-expressed with key markers of mesenchymal stem cells. BMS2 cell line models PAH disruption of bone marrow niche development functions. Toxicol Appl Pharmacol. 2020 Aug 15;401:115111. doi: 10.1016/j.taap.2020.115111.
30. Bahari A, Mehrzad J, Mahmoudi M, et al. Cytochrome P450 isoforms are differently up-regulated in aflatoxin B1 -exposed human lymphocytes and monocytes. Immunopharmacol Immunotoxicol. 2014 Feb;36(1):1-10. doi: 10.3109/08923973.2013.850506.
31. Zordoky BN, El-Kadi AO. Induction of several cytochrome P450 genes by doxorubicin in H9c2 cells. Vascul Pharmacol. 2008 OctDec;49(4-6):166-72. doi: 10.1016/j.vph.2008.07.004.
32. Rendic SP, Guengerich FP. Human Family 1-4 cytochrome P450 enzymes involved in the metabolic activation of xenobiotic and physiological chemicals: an update. Arch Toxicol. 2021 Feb;95(2):395-472. doi: 10.1007/s00204-020-02971-4.
33. Aghazadeh-Habashi A, Asghar W, Jamali F. Drug-Disease Interaction: Effect of Inflammation and Nonsteroidal Anti-Inflammatory Drugs on Cytochrome P450 Metabolites of Arachidonic Acid. J Pharm Sci. 2018 Feb;107(2):756-763. doi: 10.1016/j.xphs.2017.09.020.
34. Shu W, Chen L, Hu X, et al. Cytochrome P450 Genetic Variations Can Predict mRNA Expression, Cyclophosphamide 4-Hydroxylation, and Treatment Outcomes in Chinese Patients With Non-Hodgkin's Lymphoma. J Clin Pharmacol. 2017 Jul;57(7):886-898. doi: 10.1002/jcph.878.
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For citations:
Vavilin V.A., Goreva O.B., Shebunyaeva Ya.Yu., Makarova S.I., Voitko M.S., Grishanova A.Yu., Pospelova T.I. Interaction of CYP3A4, CYP3A5, CYP1A1 and CYP2B6 genes in the development of organotoxic effects of chemotherapy in patients with Hodgkin's lymphoma. Pharmacogenetics and Pharmacogenomics. 2024;(1):31-43. (In Russ.) https://doi.org/10.37489/2588-0527-2024-1-31-43. EDN: QMEJLP
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