Abstract
Purpose
The intracardiac synthesis of anthracycline alcohol metabolites (e.g., daunorubicinol) contributes to the pathogenesis of anthracycline-related cardiotoxicity. Cancer patients with Down syndrome (DS) are at increased risk for anthracycline-related cardiotoxicity. We profiled the expression of anthracycline metabolizing enzymes in hearts from donors with- and without- DS.
Methods
Cardiac expression of CBR1, CBR3, AKR1A1, AKR1C3 and AKR7A2 was examined by quantitative real time PCR, quantitative immunoblotting, and enzyme activity assays using daunorubicin. The CBR1 polymorphism rs9024 was investigated by allelic discrimination with fluorescent probes. The contribution of CBRs/AKRs proteins to daunorubicin reductase activity was examined by multiple linear regression.
Results
CBR1 was the most abundant transcript (average relative expression; DS: 81%, non-DS: 58%), and AKR7A2 was the most abundant protein (average relative expression; DS: 38%, non-DS: 35%). Positive associations between cardiac CBR1 protein levels and daunorubicin reductase activity were found for samples from donors with- and without- DS. Regression analysis suggests that sex, CBR1, AKR1A1, and AKR7A2 protein levels were significant contributors to cardiac daunorubicin reductase activity. CBR1 rs9024 genotype status impacts on cardiac CBR1 expression in non-DS hearts.
Conclusions
CBR1, AKR1A1, and AKR7A2 protein levels point to be important determinants for predicting the synthesis of cardiotoxic daunorubicinol in heart.
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Abbreviations
- aCGH:
-
Array comparative genomic hybridization
- ACTB:
-
Actin B
- AKR1A1:
-
Aldo-keto reductase family 1, member A1
- AKR1C3:
-
Aldo-keto reductase family 1, member C3
- AKR7A2:
-
Aldo-keto reductase family 7, member A2
- AKRs:
-
Aldo-keto reductases
- CBR1:
-
Carbonyl reductase 1
- CBR3:
-
Carbonyl reductase 3
- CBRs:
-
Carbonyl reductases
- DS:
-
Down syndrome
- LOD:
-
Limit of detection
- LOQ:
-
Limit of quantification
References
Penningand TM, Drury JE. Human aldo-keto reductases: function, gene regulation, and single nucleotide polymorphisms. Arch Biochem Biophys. 2007;464:241–50.
Hoffmannand F, Maser E. Carbonyl reductases and pluripotent hydroxysteroid dehydrogenases of the short-chain dehydrogenase/reductase superfamily. Drug Metab Rev. 2007;39:87–144.
Rosemondand MJ, Walsh JS. Human carbonyl reduction pathways and a strategy for their study in vitro. Drug Metab Rev. 2004;36:335–61.
Menna P, Paz OG, Chello M, Covino E, Salvatorelli E, Minotti G. Anthracycline cardiotoxicity. Expert Opin Drug Saf. 2012;11 Suppl 1:S21–36.
Wouters KA, Kremer LCM, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol. 2005;131:561–78.
Krischer JP, Epstein S, Cuthbertson DD, Goorin AM, Epstein ML, Lipshultz SE. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol. 1997;15:1544–52.
O’Brien MM, Taub JW, Chang MN, Massey GV, Stine KC, Raimondi SC, et al. Cardiomyopathy in children with Down syndrome treated for acute myeloid leukemia: a report from the Children’s Oncology Group Study POG 9421. J Clin Oncol. 2008;26:414–20.
Tauband JW, Ravindranath Y. What’s up with down syndrome and leukemia-A lot! Pediatr Blood Cancer. 2011;57:1–3.
Menna P, Salvatorelli E, Minotti G. Cardiotoxicity of Antitumor Drugs. Chem Res Toxicol. 2008;21:978–89.
Mushlin PS, Cusack BJ, Boucek Jr RJ, Andrejuk T, Li X, Olson RD. Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function. Br J Pharmacol. 1993;110:975–82.
Olson RD, Mushlin PS, Brenner DE, Fleischer S, Cusack BJ, Chang BK, et al. Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci U S A. 1988;85:3585–9.
Stewart DJ, Grewaal D, Green RM, Mikhael N, Goel R, Montpetit VA, et al. Concentrations of doxorubicin and its metabolites in human autopsy heart and other tissues. Anticancer Res. 1993;13:1945–52.
Bains OS, Grigliatti TA, Reid RE, Riggs KW. Naturally occurring variants of human aldo-keto reductases with reduced in vitro metabolism of daunorubicin and doxorubicin. J Pharmacol Exp Ther. 2010;335:533–45.
Bains OS, Takahashi RH, Pfeifer TA, Grigliatti TA, Reid RE, Riggs KW. Two Allelic Variants of Aldo-Keto Reductase 1A1 Exhibit Reduced in Vitro Metabolism of Daunorubicin. Drug Metab Dispos. 2008;36:904–10.
Lakhman SS, Ghosh D, Blanco JG. Functional significance of a natural allelic variant of human carbonyl reductase 3 (CBR3). Drug Metab Dispos. 2005;33:254–7.
Miura T, Nishinaka T, Terada T. Different functions between human monomeric carbonyl reductase 3 and carbonyl reductase 1. Mol Cell Biochem. 2008;315:113–21.
Blanco JG, Leisenring WM, Gonzalez-Covarrubias VM, Kawashima TI, Davies SM, Relling MV, et al. Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer. Cancer. 2008;112:2789–95.
Lal S, Sandanaraj E, Wong ZW, Ang PC, Wong NS, Lee EJ, et al. CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients. Cancer Sci. 2008;99:2045–54.
Lal S, Mahajan A, Chen WN, Chowbay B. Pharmacogenetics of target genes across doxorubicin disposition pathway: a review. Curr Drug Metab. 2010;11:115–28.
Blanco JG, Sun CL, Landier W, Chen L, Esparza-Duran D, Leisenring W, et al. Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes–A Report From the Children’s Oncology Group. J Clin Oncol. 2012;30:1415–21.
Kalabus JL, Sanborn CC, Jamil RG, Cheng Q, Blanco JG. Expression of the anthracycline-metabolizing enzyme carbonyl reductase 1 in hearts from donors with Down syndrome. Drug Metab Dispos. 2010;38:2096–9.
Kassner N, Huse K, Martin HJ, Godtel-Armbrust U, Metzger A, Meineke I, et al. Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver. Drug Metab Dispos. 2008;36:2113–20.
O’Connor T, Ireland LS, Harrison DJ, Hayes JD. Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members. Biochem J. 1999;343(Pt 2):487–504.
Gonzalez-Covarrubias V, Zhang J, Kalabus JL, Relling MV, Blanco JG. Pharmacogenetics of human carbonyl reductase 1 (CBR1) in livers from black and white donors. Drug Metab Dispos. 2009;37:400–7.
Kalabus JL, Cheng Q, Blanco JG. MicroRNAs differentially regulate carbonyl reductase 1 (CBR1) gene expression dependent on the allele status of the common polymorphic variant rs9024. PLoS One. 2012;7:e48622.
Sultan M, Piccini I, Balzereit D, Herwig R, Saran NG, Lehrach H, et al. Gene expression variation in Down ’s syndrome mice allows prioritization of candidate genes. Genome Biol. 2007;8:R91.
Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55:611–22.
de Jong J, Guerand WS, Schoofs PR, Bast A, van der Vijgh WJ. Simple and sensitive quantification of anthracyclines in mouse atrial tissue using high-performance liquid chromatography and fluorescence detection. J Chromatogr. 1991;570:209–16.
Fetterly GJ, Aras U, Lal D, Murphy M, Meholick PD, Wang ES. Development of a preclinical PK/PD model to assess antitumor response of a sequential aflibercept and doxorubicin-dosing strategy in acute myeloid leukemia. The AAPS journal. 2013;15:662–73.
Cheng Q, Yang W, Raimondi SC, Pui CH, Relling MV, Evans WE. Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes. Nat Genet. 2005;37:878–82.
Seewald L, Taub JW, Maloney KW, McCabe ER. Acute leukemias in children with Down syndrome. Mol Genet Metab. 2012;107:25–30.
Ait Yahya-Graison E, Aubert J, Dauphinot L, Rivals I, Prieur M, Golfier G, et al. Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. American journal of human genetics. 2007;81:475–91.
Prandini P, Deutsch S, Lyle R, Gagnebin M, Delucinge Vivier C, Delorenzi M, et al. Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. American journal of human genetics. 2007;81:252–63.
Patterson D. Molecular genetic analysis of Down syndrome. Human genetics. 2009;126:195–214.
Y. Xu, W. Li, X. Liu, H. Chen, K. Tan, Y. Chen, Z. Tu, and Y. Dai. Identification of dysregulated microRNAs in lymphocytes from children with Down syndrome. Gene (2013).
McCabeand LL, McCabe ER. Down syndrome: issues to consider in a national registry, research database and biobank. Mol Genet Metab. 2011;104:10–2.
Oster-Granite ML, Parisi MA, Abbeduto L, Berlin DS, Bodine C, Bynum D, et al. Down syndrome: national conference on patient registries, research databases, and biobanks. Mol Genet Metab. 2011;104:13–22.
Weiss M. Functional characterization of drug uptake and metabolism in the heart. Expert Opin Drug Metab Toxicol. 2011;7:1295–306.
Acknowledgments and Disclosures
Adolfo Quiñones-Lombraña and Daniel Ferguson contributed equally to this manuscript. This work was supported by the National Institute of General Medical Sciences [GM073646].
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Quiñones-Lombraña, A., Ferguson, D., Hageman Blair, R. et al. Interindividual Variability in the Cardiac Expression of Anthracycline Reductases in Donors With and Without Down Syndrome. Pharm Res 31, 1644–1655 (2014). https://doi.org/10.1007/s11095-013-1267-1
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DOI: https://doi.org/10.1007/s11095-013-1267-1