{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T13:53:41Z","timestamp":1756994021044,"version":"3.37.3"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100006752","name":"Universidade do Porto","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006752","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cardiovasc Toxicol"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Doxorubicin (DOX; also known as adriamycin) serves as a crucial antineoplastic agent in cancer treatment; however, its clinical utility is hampered by its\u2019 intrinsic cardiotoxicity. Although most DOX biotransformation occurs in the liver, a comprehensive understanding of the impact of DOX biotransformation and its\u2019 metabolites on its induced cardiotoxicity remains to be fully elucidated. This study aimed to explore the role of biotransformation and DOX's main metabolites in its induced cardiotoxicity in human differentiated cardiac AC16 cells. A key discovery from our study is that modulating metabolism had minimal effects on DOX-induced cytotoxicity: even so, metyrapone (a non-specific inhibitor of cytochrome P450) increased DOX-induced cytotoxicity at 2\u00a0\u00b5M, while diallyl sulphide (a CYP2E1 inhibitor) decreased the 1\u00a0\u00b5M DOX-triggered cytotoxicity. Then, the toxicity of the main DOX metabolites, doxorubicinol [(DOXol, 0.5 to 10\u00a0\u00b5M), doxorubicinone (DOXone, 1 to 10\u00a0\u00b5M), and 7-deoxydoxorubicinone (7-DeoxyDOX, 1 to 10\u00a0\u00b5M)] was compared to DOX (0.5 to 10\u00a0\u00b5M) following a 48-h exposure. All metabolites evaluated, DOXol, DOXone, and 7-DeoxyDOX caused mitochondrial dysfunction in differentiated AC16 cells, but only at 2\u00a0\u00b5M. In contrast, DOX elicited comparable cytotoxicity, but at half the concentration. Similarly, all metabolites, except 7-DeoxyDOX impacted on lysosomal ability to uptake neutral red. Therefore, the present study showed that the modulation of DOX metabolism demonstrated minimal impact on its cytotoxicity, with the main metabolites exhibiting lower toxicity to AC16 cardiac cells compared to DOX. In conclusion, our findings suggest that metabolism may not be a pivotal factor in mediating DOX's cardiotoxic effects.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s12012-024-09829-6","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T04:30:43Z","timestamp":1707798643000},"page":"266-279","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Comparative In Vitro Study of the Cytotoxic Effects of Doxorubicin\u2019s Main Metabolites on Cardiac AC16 Cells Versus the Parent Drug"],"prefix":"10.1007","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-3147","authenticated-orcid":false,"given":"Ana","family":"Reis-Mendes","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1541-9465","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Vitorino-Oliveira","sequence":"additional","affiliation":[]},{"given":"Mariana","family":"Ferreira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3858-3494","authenticated-orcid":false,"given":"F\u00e9lix","family":"Carvalho","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-5119","authenticated-orcid":false,"given":"Fernando","family":"Remi\u00e3o","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5397-4672","authenticated-orcid":false,"given":"Em\u00edlia","family":"Sousa","sequence":"additional","affiliation":[]},{"given":"Maria","family":"de Lourdes Bastos","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0471-2756","authenticated-orcid":false,"given":"Vera Marisa","family":"Costa","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,2,13]]},"reference":[{"key":"9829_CR1","unstructured":"FDA, U.S. Food and Drug Administration: DOXORUBICIN HYDROCHLORIDE injection, for intravenous use. FDA: Silver Spring, December 2019. (https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2020\/050467s078,050629s030lbl.pdf, Accessed June 20, 2023)"},{"issue":"1","key":"9829_CR2","first-page":"84","volume":"1845","author":"F Yang","year":"2014","unstructured":"Yang, F., et al. (2014). Doxorubicin, DNA torsion, and chromatin dynamics. Biochimica et Biophysica Acta, 1845(1), 84\u201389.","journal-title":"Biochimica et Biophysica Acta"},{"issue":"1","key":"9829_CR3","doi-asserted-by":"publisher","first-page":"15","DOI":"10.2165\/00003088-198815010-00002","volume":"15","author":"PAJ Speth","year":"1988","unstructured":"Speth, P. A. J., van Hoesel, Q. G. C. M., & Haanen, C. (1988). Clinical pharmacokinetics of doxorubicin. Clinical Pharmacokinetics, 15(1), 15\u201331.","journal-title":"Clinical Pharmacokinetics"},{"issue":"6a","key":"9829_CR4","first-page":"1945","volume":"13","author":"DJ Stewart","year":"1993","unstructured":"Stewart, D. J., et al. (1993). Concentrations of doxorubicin and its metabolites in human autopsy heart and other tissues. Anticancer Research, 13(6a), 1945\u20131952.","journal-title":"Anticancer Research"},{"issue":"4","key":"9829_CR5","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/0277-5379(86)90112-4","volume":"22","author":"J Cummings","year":"1986","unstructured":"Cummings, J., Merry, S., & Willmott, N. (1986). Disposition kinetics of adriamycin, adriamycinol and their 7-deoxyaglycones in AKR mice bearing a sub-cutaneously growing ridgway osteogenic sarcoma (ROS). European Journal of Cancer & Clinical Oncology, 22(4), 451\u2013460.","journal-title":"European Journal of Cancer & Clinical Oncology"},{"issue":"1","key":"9829_CR6","first-page":"79","volume":"4","author":"S Takanashi","year":"1976","unstructured":"Takanashi, S., & Bachur, N. R. (1976). Adriamycin metabolism in man. Evidence from urinary metabolites. Drug Metabolism & Disposition, 4(1), 79\u201387.","journal-title":"Drug Metabolism & Disposition"},{"issue":"10","key":"9829_CR7","doi-asserted-by":"publisher","first-page":"2113","DOI":"10.1124\/dmd.108.022251","volume":"36","author":"N Kassner","year":"2008","unstructured":"Kassner, N., et al. (2008). Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver. Drug Metabolism and Disposition, 36(10), 2113\u20132120.","journal-title":"Drug Metabolism and Disposition"},{"key":"9829_CR8","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.cbi.2014.11.010","volume":"234","author":"CM Schaupp","year":"2015","unstructured":"Schaupp, C. M., et al. (2015). Metabolism of doxorubicin to the cardiotoxic metabolite doxorubicinol is increased in a mouse model of chronic glutathione deficiency: A potential role for carbonyl reductase 3. Chemico-Biological Interactions, 234, 154\u2013161.","journal-title":"Chemico-Biological Interactions"},{"issue":"5","key":"9829_CR9","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1021\/tx000013q","volume":"13","author":"S Licata","year":"2000","unstructured":"Licata, S., et al. (2000). Doxorubicin metabolism and toxicity in human myocardium: Role of cytoplasmic deglycosidation and carbonyl reduction. Chemical Research in Toxicology, 13(5), 414\u2013420.","journal-title":"Chemical Research in Toxicology"},{"issue":"6","key":"9829_CR10","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1016\/S0006-2952(03)00442-8","volume":"66","author":"A Mordente","year":"2003","unstructured":"Mordente, A., et al. (2003). Anthracycline secondary alcohol metabolite formation in human or rabbit heart: Biochemical aspects and pharmacologic implications. Biochemical Pharmacology, 66(6), 989\u2013998.","journal-title":"Biochemical Pharmacology"},{"issue":"10","key":"9829_CR11","doi-asserted-by":"publisher","first-page":"3585","DOI":"10.1073\/pnas.85.10.3585","volume":"85","author":"RD Olson","year":"1988","unstructured":"Olson, R. D., et al. (1988). Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci U S A, 85(10), 3585\u20133589.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"9829_CR12","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1016\/0031-6989(85)90113-4","volume":"17","author":"M Del Tacca","year":"1985","unstructured":"Del Tacca, M., et al. (1985). Might adriamycinol contribute to adriamycin-induced cardiotoxicity? Pharmacological Research Communications, 17(11), 1073\u20131084.","journal-title":"Pharmacological Research Communications"},{"issue":"3","key":"9829_CR13","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3390\/biom9030098","volume":"9","author":"A Reis-Mendes","year":"2019","unstructured":"Reis-Mendes, A., et al. (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.","journal-title":"Biomolecules"},{"issue":"1","key":"9829_CR14","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/S0005-2728(99)00011-0","volume":"1411","author":"J Serrano","year":"1999","unstructured":"Serrano, J., et al. (1999). Cardioselective and cumulative oxidation of mitochondrial DNA following subchronic doxorubicin administration. Biochimica et Biophysica Acta, 1411(1), 201\u2013205.","journal-title":"Biochimica et Biophysica Acta"},{"issue":"7","key":"9829_CR15","doi-asserted-by":"publisher","first-page":"3068","DOI":"10.1016\/S0021-9258(17)35747-2","volume":"261","author":"JH Doroshow","year":"1986","unstructured":"Doroshow, J. H., & Davies, K. J. (1986). Redox cycling of anthracyclines by cardiac mitochondria II Formation of superoxide anion, hydrogen peroxide, and hydroxyl radical. Journal of Biological Chemistry, 261(7), 3068\u20133074.","journal-title":"Journal of Biological Chemistry"},{"issue":"5","key":"9829_CR16","doi-asserted-by":"publisher","first-page":"245","DOI":"10.3727\/096504003108748294","volume":"13","author":"J Paw\u0142owska","year":"2003","unstructured":"Paw\u0142owska, J., et al. (2003). Differential ability of cytostatics from anthraquinone group to generate free radicals in three enzymatic systems: NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase. Oncology Research, 13(5), 245\u2013252.","journal-title":"Oncology Research"},{"issue":"10","key":"9829_CR17","first-page":"4543","volume":"43","author":"JH Doroshow","year":"1983","unstructured":"Doroshow, J. H. (1983). Anthracycline antibiotic-stimulated superoxide, hydrogen peroxide, and hydroxyl radical production by NADH dehydrogenase. Cancer Research, 43(10), 4543\u20134551.","journal-title":"Cancer Research"},{"issue":"6","key":"9829_CR18","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1097\/00000421-198212000-00015","volume":"5","author":"AR Dresdale","year":"1982","unstructured":"Dresdale, A. R., et al. (1982). Prospective randomized study of the role of N-acetyl cysteine in reversing doxorubicin-induced cardiomyopathy. American Journal of Clinical Oncology, 5(6), 657\u2013663.","journal-title":"American Journal of Clinical Oncology"},{"issue":"1 Suppl 1","key":"9829_CR19","first-page":"53","volume":"10","author":"C Myers","year":"1983","unstructured":"Myers, C., et al. (1983). A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Seminars in Oncology, 10(1 Suppl 1), 53\u201355.","journal-title":"Seminars in Oncology"},{"issue":"7","key":"9829_CR20","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1096\/fasebj.12.7.541","volume":"12","author":"G Minotti","year":"1998","unstructured":"Minotti, G., et al. (1998). The secondary alcohol metabolite of doxorubicin irreversibly inactivates aconitase\/iron regulatory protein-1 in cytosolic fractions from human myocardium. The FASEB Journal, 12(7), 541\u2013552.","journal-title":"The FASEB Journal"},{"issue":"20","key":"9829_CR21","first-page":"6602","volume":"63","author":"LE Olson","year":"2003","unstructured":"Olson, L. E., et al. (2003). Protection from doxorubicin-induced cardiac toxicity in mice with a null allele of carbonyl reductase 1. Cancer Research, 63(20), 6602\u20136606.","journal-title":"Cancer Research"},{"issue":"1","key":"9829_CR22","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.yjmcc.2005.03.003","volume":"39","author":"MM Davidson","year":"2005","unstructured":"Davidson, M. M., et al. (2005). Novel cell lines derived from adult human ventricular cardiomyocytes. Journal of Molecular and Cellular Cardiology, 39(1), 133\u2013147.","journal-title":"Journal of Molecular and Cellular Cardiology"},{"issue":"2","key":"9829_CR23","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1007\/s00204-021-03204-y","volume":"96","author":"F Dion\u00edsio","year":"2022","unstructured":"Dion\u00edsio, F., et al. (2022). Cardiotoxicity of cyclophosphamide\u2019s metabolites: An in vitro metabolomics approach in AC16 human cardiomyocytes. Archives of Toxicology, 96(2), 653\u2013671.","journal-title":"Archives of Toxicology"},{"issue":"1","key":"9829_CR24","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1021\/jm00367a004","volume":"27","author":"SJ Hays","year":"1984","unstructured":"Hays, S. J., et al. (1984). Structure-activity relationship study of the inhibition of adrenal cortical 11 beta-hydroxylase by new metyrapone analogues. Journal of Medicinal Chemistry, 27(1), 15\u201319.","journal-title":"Journal of Medicinal Chemistry"},{"issue":"39","key":"9829_CR25","doi-asserted-by":"publisher","first-page":"13634","DOI":"10.1021\/ja053809q","volume":"127","author":"H Park","year":"2005","unstructured":"Park, H., Lee, S., & Suh, J. (2005). Structural and dynamical basis of broad substrate specificity, catalytic mechanism, and inhibition of cytochrome P450 3A4. Journal of the American Chemical Society, 127(39), 13634\u201313642.","journal-title":"Journal of the American Chemical Society"},{"issue":"2","key":"9829_CR26","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/0014-4835(92)90202-4","volume":"55","author":"T Asakura","year":"1992","unstructured":"Asakura, T., & Shichi, H. (1992). Cytochrome P450-mediated prostaglandin omega\/omega-1 hydroxylase activities in porcine ciliary body epithelial cells. Experimental Eye Research, 55(2), 377\u2013384.","journal-title":"Experimental Eye Research"},{"issue":"1","key":"9829_CR27","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1124\/dmd.108.024075","volume":"37","author":"CD Linder","year":"2009","unstructured":"Linder, C. D., Renaud, N. A., & Hutzler, J. M. (2009). Is 1-aminobenzotriazole an appropriate in vitro tool as a nonspecific cytochrome P450 inactivator? Drug Metabolism and Disposition, 37(1), 10\u201313.","journal-title":"Drug Metabolism and Disposition"},{"issue":"3","key":"9829_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.78","volume":"4","author":"M Jin","year":"2013","unstructured":"Jin, M., et al. (2013). Regulation of cytochrome P450 2e1 expression by ethanol: Role of oxidative stress-mediated pkc\/jnk\/sp1 pathway. Cell Death & Disease, 4(3), e554.","journal-title":"Cell Death & Disease"},{"issue":"11","key":"9829_CR29","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1211\/0022357991777010","volume":"51","author":"K Behnia","year":"1999","unstructured":"Behnia, K., & Boroujerdi, M. (1999). Inhibition of aldo-keto reductases by phenobarbital alters metabolism, pharmacokinetics and toxicity of doxorubicin in rats. Journal of Pharmacy and Pharmacology, 51(11), 1275\u20131282.","journal-title":"Journal of Pharmacy and Pharmacology"},{"issue":"4","key":"9829_CR30","doi-asserted-by":"publisher","first-page":"339","DOI":"10.2133\/dmpk.DMPK-12-RG-090","volume":"28","author":"Y Deng","year":"2013","unstructured":"Deng, Y., et al. (2013). In vitro inhibition and induction of human liver cytochrome P450 enzymes by gentiopicroside: Potent effect on CYP2A6. Drug Metabolism and Pharmacokinetics, 28(4), 339\u2013344.","journal-title":"Drug Metabolism and Pharmacokinetics"},{"issue":"6","key":"9829_CR31","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1007\/s11095-006-0277-7","volume":"23","author":"JH Lin","year":"2006","unstructured":"Lin, J. H. (2006). CYP induction-mediated drug interactions: In vitro assessment and clinical implications. Pharmaceutical Research, 23(6), 1089\u20131116.","journal-title":"Pharmaceutical Research"},{"issue":"6","key":"9829_CR32","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1007\/s00432-014-1645-z","volume":"140","author":"AS Soares","year":"2014","unstructured":"Soares, A. S., et al. (2014). Combination of Cl-IB-MECA with paclitaxel is a highly effective cytotoxic therapy causing mTOR-dependent autophagy and mitotic catastrophe on human melanoma cells. Journal of Cancer Research and Clinical Oncology, 140(6), 921\u2013935.","journal-title":"Journal of Cancer Research and Clinical Oncology"},{"issue":"7","key":"9829_CR33","first-page":"3417","volume":"43","author":"RF Greene","year":"1983","unstructured":"Greene, R. F., et al. (1983). Plasma pharmacokinetics of adriamycin and adriamycinol: Implications for the design of in vitro experiments and treatment protocols. Cancer Research, 43(7), 3417\u20133421.","journal-title":"Cancer Research"},{"issue":"1","key":"9829_CR34","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1007\/s00204-022-03363-6","volume":"97","author":"A Reis-Mendes","year":"2023","unstructured":"Reis-Mendes, A., et al. (2023). Autophagy (but not metabolism) is a key event in mitoxantrone-induced cytotoxicity in differentiated AC16 cardiac cells. Archives of Toxicology, 97(1), 201\u2013216.","journal-title":"Archives of Toxicology"},{"issue":"7","key":"9829_CR35","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1038\/nprot.2008.75","volume":"3","author":"G Repetto","year":"2008","unstructured":"Repetto, G., del Peso, A., & Zurita, J. L. (2008). Neutral red uptake assay for the estimation of cell viability\/cytotoxicity. Nature Protocols, 3(7), 1125\u20131131.","journal-title":"Nature Protocols"},{"issue":"18","key":"9829_CR36","doi-asserted-by":"publisher","first-page":"4480","DOI":"10.1021\/bi00232a015","volume":"30","author":"M Reers","year":"1991","unstructured":"Reers, M., Smith, T. W., & Chen, L. B. (1991). J-aggregate formation of a carbocyanine as a quantitative fluorescent indicator of membrane potential. Biochemistry, 30(18), 4480\u20134486.","journal-title":"Biochemistry"},{"issue":"1","key":"9829_CR37","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1006\/bbrc.1993.2438","volume":"197","author":"A Cossarizza","year":"1993","unstructured":"Cossarizza, A., et al. (1993). A new method for the cytofluorimetric analysis of mitochondrial membrane potential using the J-aggregate forming lipophilic cation 5,5\u2019,6,6\u2019-tetrachloro-1,1\u2019,3,3\u2019-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Biochemical and Biophysical Research Communications, 197(1), 40\u201345.","journal-title":"Biochemical and Biophysical Research Communications"},{"issue":"2\u20133","key":"9829_CR38","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/S0960-0760(97)00027-7","volume":"62","author":"R Sampath-Kumar","year":"1997","unstructured":"Sampath-Kumar, R., et al. (1997). Metyrapone is a competitive inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 reductase. Journal of Steroid Biochemistry and Molecular Biology, 62(2\u20133), 195\u2013199.","journal-title":"Journal of Steroid Biochemistry and Molecular Biology"},{"issue":"5","key":"9829_CR39","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1007\/s00280-004-0900-4","volume":"55","author":"M Joerger","year":"2005","unstructured":"Joerger, M., et al. (2005). Pharmacokinetics of low-dose doxorubicin and metabolites in patients with AIDS-related Kaposi sarcoma. Cancer Chemotherapy and Pharmacology, 55(5), 488\u2013496.","journal-title":"Cancer Chemotherapy and Pharmacology"},{"issue":"187","key":"9829_CR40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2023.106475","volume":"1","author":"JWH Leow","year":"2023","unstructured":"Leow, J. W. H., et al. (2023). Investigating the relevance of CYP2J2 inhibition for drugs known to cause intermediate to high risk torsades de pointes. European Journal of Pharmaceutical Sciences, 1(187), 106475","journal-title":"European Journal of Pharmaceutical Sciences"},{"issue":"1","key":"9829_CR41","doi-asserted-by":"publisher","first-page":"174","DOI":"10.3892\/mmr.2017.6580","volume":"16","author":"B Zhou","year":"2017","unstructured":"Zhou, B., et al. (2017). Mitochondrial activity and oxidative stress functions are influenced by the activation of AhR-induced CYP1A1 overexpression in cardiomyocytes. Molecular Medicine Reports, 16(1), 174\u2013180","journal-title":"Molecular Medicine Reports"},{"issue":"2","key":"9829_CR42","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.neuro.2007.12.003","volume":"29","author":"MA Lopes","year":"2008","unstructured":"Lopes, M. A., et al. (2008). Doxorubicin induces biphasic neurotoxicity to rat cortical neurons. Neurotoxicology, 29(2), 286\u2013293.","journal-title":"Neurotoxicology"},{"issue":"4","key":"9829_CR43","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1007\/s12012-012-9177-8","volume":"12","author":"AF Branco","year":"2012","unstructured":"Branco, A. F., et al. (2012). Differentiation-dependent doxorubicin toxicity on H9c2 cardiomyoblasts. Cardiovascular Toxicology, 12(4), 326\u2013340.","journal-title":"Cardiovascular Toxicology"},{"issue":"3","key":"9829_CR44","first-page":"2165","volume":"18","author":"B Xiao","year":"2019","unstructured":"Xiao, B., et al. (2019). The true colors of autophagy in doxorubicin-induced cardiotoxicity. Oncology Letters, 18(3), 2165\u20132172.","journal-title":"Oncology Letters"},{"issue":"11","key":"9829_CR45","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.3390\/ph16111613","volume":"16","author":"SR Brand\u00e3o","year":"2023","unstructured":"Brand\u00e3o, S. R., et al. (2023). The metabolic fingerprint of doxorubicin-induced cardiotoxicity in male CD-1 mice fades away with time while autophagy increases. Pharmaceuticals, 16(11), 1613.","journal-title":"Pharmaceuticals"},{"issue":"21","key":"9829_CR46","doi-asserted-by":"publisher","first-page":"8105","DOI":"10.3390\/ijms21218105","volume":"21","author":"RN Montalvo","year":"2020","unstructured":"Montalvo, R. N., et al. (2020). Protection against doxorubicin-induced cardiac dysfunction is not maintained following prolonged autophagy inhibition. International Journal of Molecular Sciences, 21(21), 8105.","journal-title":"International Journal of Molecular Sciences"},{"issue":"4","key":"9829_CR47","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1002\/bdd.2000","volume":"37","author":"KE Parrish","year":"2016","unstructured":"Parrish, K. E., et al. (2016). In vitro and in vivo characterization of CYP inhibition by 1-aminobenzotriazole in rats. Biopharmaceutics & Drug Disposition, 37(4), 200\u2013211.","journal-title":"Biopharmaceutics & Drug Disposition"},{"issue":"5","key":"9829_CR48","doi-asserted-by":"publisher","first-page":"287","DOI":"10.2133\/dmpk.18.287","volume":"18","author":"C Emoto","year":"2003","unstructured":"Emoto, C., et al. (2003). In vitro inhibitory effect of 1-aminobenzotriazole on drug oxidations catalyzed by human cytochrome P450 enzymes: A comparison with SKF-525A and ketoconazole. Drug Metabolism and Pharmacokinetics, 18(5), 287\u2013295.","journal-title":"Drug Metabolism and Pharmacokinetics"},{"issue":"8","key":"9829_CR49","doi-asserted-by":"publisher","first-page":"3437","DOI":"10.1210\/jc.2019-00217","volume":"104","author":"SG Creemers","year":"2019","unstructured":"Creemers, S. G., et al. (2019). Osilodrostat is a potential novel steroidogenesis inhibitor for the treatment of cushing syndrome: an in vitro study. Journal of Clinical Endocrinology and Metabolism, 104(8), 3437\u20133449.","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"issue":"7","key":"9829_CR50","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1021\/acs.biochem.8b01221","volume":"58","author":"I Sevrioukova","year":"2019","unstructured":"Sevrioukova, I. (2019). Interaction of human drug-metabolizing CYP3A4 with small inhibitory molecules. Biochemistry, 58(7), 930\u2013939.","journal-title":"Biochemistry"},{"issue":"1","key":"9829_CR51","first-page":"47","volume":"94","author":"J Aubrecht","year":"1996","unstructured":"Aubrecht, J., et al. (1996). Differential induction of mRNA expression of cytochromes P450 (CYP2B1 and CYP1A1\/2) by metyrapone in primary rat hepatocyte cultures. Research Communications in Molecular Pathology and Pharmacology, 94(1), 47\u201361.","journal-title":"Research Communications in Molecular Pathology and Pharmacology"},{"issue":"6","key":"9829_CR52","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1021\/tx00024a008","volume":"4","author":"JF Brady","year":"1991","unstructured":"Brady, J. F., et al. (1991). Inhibition of cytochrome P-450 2E1 by diallyl sulfide and its metabolites. Chemical Research in Toxicology, 4(6), 642\u2013647.","journal-title":"Chemical Research in Toxicology"},{"issue":"10","key":"9829_CR53","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1007\/s00204-013-1040-6","volume":"87","author":"LG Rossato","year":"2013","unstructured":"Rossato, L. G., et al. (2013). The metabolic profile of mitoxantrone and its relation with mitoxantrone-induced cardiotoxicity. Archives of Toxicology, 87(10), 1809\u20131820.","journal-title":"Archives of Toxicology"},{"issue":"4","key":"9829_CR54","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.3390\/ijms21041279","volume":"21","author":"MKO Grant","year":"2020","unstructured":"Grant, M. K. O., et al. (2020). Sexual dimorphism in doxorubicin-induced systemic inflammation: implications for hepatic cytochrome P450 regulation. International Journal of Molecular Sciences, 21(4), 1279.","journal-title":"International Journal of Molecular Sciences"},{"key":"9829_CR55","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.974123","volume":"9","author":"ML Canale","year":"2022","unstructured":"Canale, M. L., et al. (2022). Women at heart: Introducing gender cardio-oncology. Front Cardiovasc Med, 9, 974123.","journal-title":"Front Cardiovasc Med"},{"issue":"7","key":"9829_CR56","doi-asserted-by":"publisher","first-page":"3564","DOI":"10.3390\/ijms23073564","volume":"23","author":"M Cantiello","year":"2022","unstructured":"Cantiello, M., et al. (2022). Induction by phenobarbital of phase I and II xenobiotic-metabolizing enzymes in bovine liver: An overall catalytic and immunochemical characterization. International Journal of Molecular Sciences, 23(7), 3564.","journal-title":"International Journal of Molecular Sciences"},{"issue":"3","key":"9829_CR57","doi-asserted-by":"publisher","first-page":"197","DOI":"10.3109\/07357900009031824","volume":"18","author":"MG Sturgill","year":"2000","unstructured":"Sturgill, M. G., August, D. A., & Brenner, D. E. (2000). Hepatic enzyme induction with phenobarbital and doxorubicin metabolism and myelotoxicity in the rabbit. Cancer Investigation, 18(3), 197\u2013205.","journal-title":"Cancer Investigation"},{"issue":"18","key":"9829_CR58","first-page":"5158","volume":"60","author":"GL Forrest","year":"2000","unstructured":"Forrest, G. L., et al. (2000). Human carbonyl reductase overexpression in the heart advances the development of doxorubicin-induced cardiotoxicity in transgenic mice1. Cancer Research, 60(18), 5158\u20135164.","journal-title":"Cancer Research"},{"issue":"12","key":"9829_CR59","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1016\/0024-3205(79)90591-5","volume":"25","author":"NW Revis","year":"1979","unstructured":"Revis, N. W., & Marusi\u0107, N. (1979). Effects of doxorubicin and its aglycone metabolite on calcium sequestration by rabbit heart, liver, and kidney mitochondria. Life Sciences, 25(12), 1055\u20131063.","journal-title":"Life Sciences"},{"issue":"12","key":"9829_CR60","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1016\/0020-711X(94)90176-7","volume":"26","author":"PM Sokolove","year":"1994","unstructured":"Sokolove, P. M. (1994). Interactions of adriamycin aglycones with mitochondria may mediate adriamycin cardiotoxicity. International Journal of Biochemistry, 26(12), 1341\u20131350.","journal-title":"International Journal of Biochemistry"},{"issue":"3b","key":"9829_CR61","first-page":"2445","volume":"23","author":"ME Clementi","year":"2003","unstructured":"Clementi, M. E., et al. (2003). Doxorubicin-derived metabolites induce release of cytochrome C and inhibition of respiration on cardiac isolated mitochondria. Anticancer Research, 23(3b), 2445\u20132450.","journal-title":"Anticancer Research"},{"issue":"4","key":"9829_CR62","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/0006-2952(93)90556-C","volume":"46","author":"PM Sokolove","year":"1993","unstructured":"Sokolove, P. M., et al. (1993). Interaction of adriamycin aglycones with isolated mitochondria. Effect of selenium deficiency. Biochemical Pharmacology, 46(4), 691\u2013697","journal-title":"Biochemical Pharmacology"}],"container-title":["Cardiovascular Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12012-024-09829-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12012-024-09829-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12012-024-09829-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,16]],"date-time":"2024-03-16T11:16:39Z","timestamp":1710587799000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12012-024-09829-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,13]]},"references-count":62,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,3]]}},"alternative-id":["9829"],"URL":"https:\/\/doi.org\/10.1007\/s12012-024-09829-6","relation":{},"ISSN":["1530-7905","1559-0259"],"issn-type":[{"type":"print","value":"1530-7905"},{"type":"electronic","value":"1559-0259"}],"subject":[],"published":{"date-parts":[[2024,2,13]]},"assertion":[{"value":"23 December 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 January 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"All authors have agreed with the content of this article and gave their consent to submit for publication.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}}]}}