NAD(P)H Oxidase and Multidrug Resistance Protein Genetic Polymorphisms Are Associated With Doxorubicin-Induced Cardiotoxicity
| العنوان: | NAD(P)H Oxidase and Multidrug Resistance Protein Genetic Polymorphisms Are Associated With Doxorubicin-Induced Cardiotoxicity |
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| المؤلفون: | Albrecht Schmidt, Peter Nürnberg, Michael Pfreundschuh, Anke Kruger, Marita Kloess, Gerd Hasenfuss, Mohammad R. Toliat, Heidi Hahn, Markus Loeffler, Lorenz Trümper, Stefan Vonhof, Markus D. Schirmer, Mladen V. Tzvetkov, Heike Bickeböller, Jürgen Brockmöller, Silvia Seifert, Gregor Schlüter, Leszek Wojnowski, Albert Rosenberger, Bettina Kulle, Eun-Kyung Suk |
| المصدر: | Circulation. 112:3754-3762 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2005. |
| سنة النشر: | 2005 |
| مصطلحات موضوعية: | Adult, Male, Adolescent, Drug-Related Side Effects and Adverse Reactions, Free Radicals, Heart Diseases, Doxorubicin transport, Pharmacology, Ventricular Function, Left, Mice, Multidrug Resistance Protein 1, Physiology (medical), medicine, Animals, Humans, Anthracyclines, Doxorubicin, ATP Binding Cassette Transporter, Subfamily B, Member 1, Aged, Mice, Knockout, Oxidase test, Cardiotoxicity, Membrane Glycoproteins, Polymorphism, Genetic, biology, business.industry, Multidrug resistance-associated protein 2, NADPH Oxidases, Biological Transport, Middle Aged, Pharmacogenetics, NAD(P)H oxidase, Case-Control Studies, NADPH Oxidase 2, biology.protein, Female, P22phox, Cardiology and Cardiovascular Medicine, business, medicine.drug |
| الوصف: | Background— A significant number of patients treated with anthracyclines develop cardiotoxicity (anthracycline-induced cardiotoxicity [ACT]), mainly presenting as arrhythmias (acute ACT) or congestive heart failure (chronic ACT). There are no data on pharmacogenomic predictors of ACT. Methods and Results— We genotyped participants of the German non-Hodgkin lymphoma study (NHL-B) who were followed up for the development of heart failure for a median of >3 years. Single-nucleotide polymorphisms (SNPs) were selected from 82 genes with conceivable relevance to ACT. Of 1697 patients, 55 developed acute and 54 developed chronic ACT (cumulative incidence of either form, 3.2%). We detected 5 significant associations with polymorphisms of the NAD(P)H oxidase and doxorubicin efflux transporters. Chronic ACT was associated with a variant of the NAD(P)H oxidase subunit NCF4 (rs1883112, −212A→G; symbols with right-pointing arrows, as edited?‘ odds ratio [OR], 2.5; 95% CI, 1.3 to 5.0). Acute ACT was associated with the His72Tyr polymorphism in the p22phox subunit (rs4673; OR, 2.0; 95% CI, 1.0 to 3.9) and with the variant 7508T→A (rs13058338; OR, 2.6; 95% CI, 1.3 to 5.1) of the RAC2 subunit of the same enzyme. In agreement with these results, mice deficient in NAD(P)H oxidase activity, unlike wild-type mice, were resistant to chronic doxorubicin treatment. In addition, acute ACT was associated with the Gly671Val variant of the doxorubicin efflux transporter multidrug resistance protein 1 (MRP1) (OR, 3.6; 95% CI, 1.6 to 8.4) and with the Val1188Glu-Cys1515Tyr (rs8187694-rs8187710) haplotype of the functionally similar MRP2 (OR, 2.3; 95% CI, 1.0 to 5.4). Polymorphisms in adrenergic receptors previously demonstrated to be predictive of heart failure were not associated with ACT. Conclusions— Genetic variants in doxorubicin transport and free radical metabolism may modulate the individual risk to develop ACT. |
| تدمد: | 1524-4539 0009-7322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ef79f29daf7445017a7d875cab5bdad5Test https://doi.org/10.1161/circulationaha.105.576850Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ef79f29daf7445017a7d875cab5bdad5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244539 00097322 |
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