{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T22:38:28Z","timestamp":1792103908383,"version":"4.4.0"},"reference-count":49,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Regulatory Toxicology and Pharmacology"],"published-print":{"date-parts":[[2023,6]]},"DOI":"10.1016\/j.yrtph.2023.105410","type":"journal-article","created":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T11:46:35Z","timestamp":1684410395000},"page":"105410","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":40,"special_numbering":"C","title":["Revisiting the mutagenicity and genotoxicity of N-nitroso propranolol in bacterial and human in vitro assays"],"prefix":"10.1016","volume":"141","author":[{"given":"Xilin","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Eun","family":"Seo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta A.","family":"Mittelstaedt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nyosha","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Sims","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sruthi T.","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aisar H.","family":"Atrakchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"McGovern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.","family":"Davis-Bruno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Keire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalie K.","family":"Elespuru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Heflich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3501-9014","authenticated-orcid":false,"given":"Nan","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.yrtph.2023.105410_bib1","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1093\/mutage\/geab039","article-title":"Biomarkers of DNA damage response improve in vitro micronucleus assays by revealing genotoxic mode of action and reducing the occurrence of irrelevant positive results","volume":"36","author":"Avlasevich","year":"2021","journal-title":"Mutagenesis"},{"key":"10.1016\/j.yrtph.2023.105410_bib2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.jpeds.2014.08.067","article-title":"Efficacy and safety of high-dose propranolol for the management of infant supraventricular tachyarrhythmias","volume":"166","author":"Barton","year":"2015","journal-title":"J. Pediatr."},{"key":"10.1016\/j.yrtph.2023.105410_bib3","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1093\/carcin\/17.9.2029","article-title":"Cytochrome P450 metabolic dealkylation of nine N-nitrosodialkylamines by human liver microsomes","volume":"17","author":"Bellec","year":"1996","journal-title":"Carcinogenesis"},{"key":"10.1016\/j.yrtph.2023.105410_bib4","doi-asserted-by":"crossref","first-page":"443","DOI":"10.3389\/fphar.2016.00443","article-title":"Comparison of liver cell models using the basel phenotyping cocktail","volume":"7","author":"Berger","year":"2016","journal-title":"Front. Pharmacol."},{"key":"10.1016\/j.yrtph.2023.105410_bib5","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/em.22028","article-title":"\u03b3H2AX and p53 responses in TK6 cells discriminate promutagens and nongenotoxicants in the presence of rat liver S9","volume":"57","author":"Bernacki","year":"2016","journal-title":"Environ. Mol. Mutagen."},{"key":"10.1016\/j.yrtph.2023.105410_bib6","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.mrrev.2006.09.003","article-title":"Genotoxic and carcinogenic risk to humans of drug-nitrite interaction products","volume":"635","author":"Brambilla","year":"2007","journal-title":"Mutat. Res."},{"key":"10.1016\/j.yrtph.2023.105410_bib7","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/0041-008X(89)90253-6","article-title":"Genotoxicity of N-nitrosochlordiazepoxide in cultured mammalian cells","volume":"97","author":"Brambilla","year":"1989","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"10.1016\/j.yrtph.2023.105410_bib8","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.mrgentox.2007.03.002","article-title":"In vitro micronucleus assay scored by flow cytometry provides a comprehensive evaluation of cytogenetic damage and cytotoxicity","volume":"630","author":"Bryce","year":"2007","journal-title":"Mutat. Res."},{"key":"10.1016\/j.yrtph.2023.105410_bib9","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/em.21996","article-title":"Genotoxic mode of action predictions from a multiplexed flow cytometric assay and a machine learning approach","volume":"57","author":"Bryce","year":"2016","journal-title":"Environ. Mol. Mutagen."},{"key":"10.1016\/j.yrtph.2023.105410_bib10","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1093\/mutage\/10.6.517","article-title":"Evaluation of phenobarbital\/beta-naphthoflavone as an alternative S9-induction regime to Aroclor 1254 in the rat for use in in vitro genotoxicity assays","volume":"10","author":"Callander","year":"1995","journal-title":"Mutagenesis"},{"key":"10.1016\/j.yrtph.2023.105410_bib11","author":"Canada"},{"key":"10.1016\/j.yrtph.2023.105410_bib12","first-page":"68","article-title":"Characterization of cytochrome P450s (CYP)-overexpressing HepG2 cells for assessing drug and chemical-induced liver toxicity","volume":"39","author":"Chen","year":"2021","journal-title":"J. Environ. Sci. Health C Toxicol. Carcinog."},{"key":"10.1016\/j.yrtph.2023.105410_bib13","doi-asserted-by":"crossref","first-page":"864753","DOI":"10.3389\/ftox.2022.864753","article-title":"Thymidine kinase(+\/-) mammalian cell mutagenicity assays for assessment of nanomaterials","volume":"4","author":"Chen","year":"2022","journal-title":"Front Toxicol."},{"key":"10.1016\/j.yrtph.2023.105410_bib14","doi-asserted-by":"crossref","first-page":"100186","DOI":"10.1016\/j.comtox.2021.100186","article-title":"Developing structure-activity relationships for N-nitrosamine activity","volume":"20","author":"Cross","year":"2021","journal-title":"Comput. Toxicol."},{"key":"10.1016\/j.yrtph.2023.105410_bib15","unstructured":"FDA, 2018. M7(R1) assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. https:\/\/www.fda.gov\/media\/85885\/download. (Accessed 2 May 2023)."},{"key":"10.1016\/j.yrtph.2023.105410_bib16","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0027-5107(01)00223-8","article-title":"Role of human cytochrome P450 (CYP) in the metabolic activation of N-alkylnitrosamines: application of genetically engineered Salmonella typhimurium YG7108 expressing each form of CYP together with human NADPH-cytochrome P450 reductase","volume":"483","author":"Fujita","year":"2001","journal-title":"Mutat. Res."},{"key":"10.1016\/j.yrtph.2023.105410_bib17","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/0165-1161(94)90037-X","article-title":"Recommendations for the performance of bacterial mutation assays","volume":"312","author":"Gatehouse","year":"1994","journal-title":"Mutat. Res."},{"key":"10.1016\/j.yrtph.2023.105410_bib18","author":"ICH"},{"key":"10.1016\/j.yrtph.2023.105410_bib19","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/0165-1110(88)90023-1","article-title":"A comparative analysis of data on the clastogenicity of 951 chemical substances tested in mammalian cell cultures","volume":"195","author":"Ishidate","year":"1988","journal-title":"Mutat. Res."},{"key":"10.1016\/j.yrtph.2023.105410_bib20","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2174\/1389200221666200414094644","article-title":"Clinical pharmacokinetics of propranolot hydrochloride: a review","volume":"21","author":"Kalam","year":"2020","journal-title":"Curr. Drug Metabol."},{"key":"10.1016\/j.yrtph.2023.105410_bib21","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1081\/DMR-120005668","article-title":"Role of human cytochrome P450 (CYP) in the metabolic activation of nitrosamine derivatives: application of genetically engineered Salmonella expressing human CYP","volume":"34","author":"Kamataki","year":"2002","journal-title":"Drug Metab. Rev."},{"key":"10.1016\/j.yrtph.2023.105410_bib22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0027-5107(87)90019-4","article-title":"Formation of a higly mutagenic diazo compound from the bamethan-nitrite reaction","volume":"177","author":"Kikugawa","year":"1987","journal-title":"Mutat. Res. Fund Mol. Mech. Mutagen"},{"key":"10.1016\/j.yrtph.2023.105410_bib23","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1517\/17425251003674380","article-title":"Human CYPs involved in drug metabolism: structures, substrates and binding affinities","volume":"6","author":"Lewis","year":"2010","journal-title":"Expet Opin. Drug Metabol. Toxicol."},{"key":"10.1016\/j.yrtph.2023.105410_bib24","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/toxsci\/kfaa035","article-title":"Development and application of TK6-derived cells expressing human cytochrome P450s for genotoxicity testing","volume":"175","author":"Li","year":"2020","journal-title":"Toxicol. Sci."},{"key":"10.1016\/j.yrtph.2023.105410_bib25","doi-asserted-by":"crossref","first-page":"111662","DOI":"10.1016\/j.fct.2020.111662","article-title":"Evaluation of pyrrolizidine alkaloid-induced genotoxicity using metabolically competent TK6 cell lines","volume":"145","author":"Li","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"10.1016\/j.yrtph.2023.105410_bib26","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.1007\/s00204-022-03347-6","article-title":"Genotoxicity evaluation of nitrosamine impurities using human TK6 cells transduced with cytochrome P450s","volume":"96","author":"Li","year":"2022","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.yrtph.2023.105410_bib27","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/0027-5107(83)90058-1","article-title":"The superiority of hamster liver microsomal fraction for activating nitrosamines to mutagens in Salmonella typhimurium","volume":"111","author":"Lijinsky","year":"1983","journal-title":"Mutat. Res."},{"key":"10.1016\/j.yrtph.2023.105410_bib28","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/225021a0","article-title":"Nitrosamines as environmental carcinogens","volume":"225","author":"Lijinsky","year":"1970","journal-title":"Nature"},{"key":"10.1016\/j.yrtph.2023.105410_bib29","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.jhazmat.2010.09.062","article-title":"Genotoxic evaluation of the non-halogenated disinfection by-products nitrosodimethylamine and nitrosodiethylamine","volume":"185","author":"Liviac","year":"2011","journal-title":"J. Hazard Mater."},{"key":"10.1016\/j.yrtph.2023.105410_bib30","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0065-230X(08)60079-2","article-title":"Carcinogenic nitroso compounds","volume":"10","author":"Magee","year":"1967","journal-title":"Adv. Cancer Res."},{"key":"10.1016\/j.yrtph.2023.105410_bib31","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/0378-4274(94)90057-4","article-title":"Low clastogenic activity in vivo of the N-nitroso derivatives of 5 beta-adrenergic-blocking drugs proved to be potent genotoxins in vitro","volume":"73","author":"Martelli","year":"1994","journal-title":"Toxicol. Lett."},{"key":"10.1016\/j.yrtph.2023.105410_bib32","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/S0090-9556(25)08435-1","article-title":"Cytochrome P450 isozymes involved in propranolol metabolism in human liver microsomes. The role of CYP2D6 as ring-hydroxylase and CYP1A2 as N-desisopropylase","volume":"22","author":"Masubuchi","year":"1994","journal-title":"Drug Metab. Dispos."},{"key":"10.1016\/j.yrtph.2023.105410_bib33","doi-asserted-by":"crossref","first-page":"503351","DOI":"10.1016\/j.mrgentox.2021.503351","article-title":"Differentiating between micronucleus dose-responses induced by whole cigarette smoke solutions with Benchmark Dose potency ranking","volume":"866","author":"Mittelstaedt","year":"2021","journal-title":"Mutat. Res. Genet. Toxicol. Environ. Mutagen"},{"key":"10.1016\/j.yrtph.2023.105410_bib34","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/em.2860040103","article-title":"Cytotoxicity and mutagenicity of dimethylnitrosamine in mammalian cells (CHO\/HGPRT system); enhancement by calcium phosphate","volume":"4","author":"O'Neill","year":"1982","journal-title":"Environ. Mutagen."},{"key":"10.1016\/j.yrtph.2023.105410_bib35","author":"OECD"},{"key":"10.1016\/j.yrtph.2023.105410_bib36","author":"OECD"},{"key":"10.1016\/j.yrtph.2023.105410_bib37","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1081\/DCT-120024844","article-title":"Genotoxic activities of drug-nitrite interaction products","volume":"26","author":"Ozhan","year":"2003","journal-title":"Drug Chem. Toxicol."},{"key":"10.1016\/j.yrtph.2023.105410_bib38","first-page":"3","article-title":"Occurrence and exposure to N-nitroso compounds and precursors","author":"Preussmann","year":"1984","journal-title":"IARC Sci. Publ."},{"key":"10.1016\/j.yrtph.2023.105410_bib39","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/S0022-3565(25)33652-9","volume":"225","author":"Raisfeld-Danse","year":"1983","journal-title":"J. Pharmacol. Exp. Therapeut."},{"key":"10.1016\/j.yrtph.2023.105410_bib40","first-page":"2273","article-title":"Formation of the N-nitroso derivatives of six beta-adrenergic-blocking agents and their genotoxic effects in rat and human hepatocytes","volume":"51","author":"Robbiano","year":"1991","journal-title":"Cancer Res."},{"key":"10.1016\/j.yrtph.2023.105410_bib41","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.xphs.2022.11.013","article-title":"The landscape of potential small and drug substance related nitrosamines in pharmaceuticals","volume":"112","author":"Schlingemann","year":"2023","journal-title":"J. Pharmaceut. Sci."},{"key":"10.1016\/j.yrtph.2023.105410_bib42","first-page":"583","article-title":"Evaluation of an in vitro three-dimensional HepaRG spheroid model for genotoxicity testing using the high-throughput CometChip platform","volume":"39","author":"Seo","year":"2022","journal-title":"ALTEX"},{"key":"10.1016\/j.yrtph.2023.105410_bib43","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1007\/s00204-019-02406-9","article-title":"Quantitative comparison of in vitro genotoxicity between metabolically competent HepaRG cells and HepG2 cells using the high-throughput high-content CometChip assay","volume":"93","author":"Seo","year":"2019","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.yrtph.2023.105410_bib44","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.jpba.2017.10.035","article-title":"Artifactual degradation of secondary amine-containing drugs during accelerated stability testing when saturated sodium nitrite solutions are used for humidity control","volume":"149","author":"Sluggett","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"10.1016\/j.yrtph.2023.105410_bib45","doi-asserted-by":"crossref","first-page":"105247","DOI":"10.1016\/j.yrtph.2022.105247","article-title":"Use of the bacterial reverse mutation assay to predict carcinogenicity of N-nitrosamines","volume":"135","author":"Trejo-Martin","year":"2022","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"10.1016\/j.yrtph.2023.105410_bib46","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/mutage\/gev085","article-title":"Empirical analysis of BMD metrics in genetic toxicology part I: in vitro analyses to provide robust potency rankings and support MOA determinations","volume":"31","author":"Wills","year":"2016","journal-title":"Mutagenesis"},{"key":"10.1016\/j.yrtph.2023.105410_bib47","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/0027-5107(77)90151-8","article-title":"Mutagenicities of N-nitrosamines on Salmonella","volume":"48","author":"Yahagi","year":"1977","journal-title":"Mutat. Res."},{"key":"10.1016\/j.yrtph.2023.105410_bib48","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1093\/carcin\/13.10.1789","article-title":"Cytochrome P450 2E1 and 2A6 enzymes as major catalysts for metabolic activation of N-nitrosodialkylamines and tobacco-related nitrosamines in human liver microsomes","volume":"13","author":"Yamazaki","year":"1992","journal-title":"Carcinogenesis"},{"key":"10.1016\/j.yrtph.2023.105410_bib49","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1021\/jm00357a027","article-title":"Derivatives of beta-adrenergic antagonists. N-nitrosopropranolol and N-hydroxypropranolol and its aldonitrone","volume":"26","author":"Zhang","year":"1983","journal-title":"J. Med. Chem."}],"container-title":["Regulatory Toxicology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230023000788?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230023000788?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T12:36:03Z","timestamp":1759494963000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0273230023000788"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6]]},"references-count":49,"alternative-id":["S0273230023000788"],"URL":"https:\/\/doi.org\/10.1016\/j.yrtph.2023.105410","relation":{},"ISSN":["0273-2300"],"issn-type":[{"value":"0273-2300","type":"print"}],"subject":[],"published":{"date-parts":[[2023,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Revisiting the mutagenicity and genotoxicity of N-nitroso propranolol in bacterial and human in vitro assays","name":"articletitle","label":"Article Title"},{"value":"Regulatory Toxicology and Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.yrtph.2023.105410","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"105410"}}