{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:49:59Z","timestamp":1792165799190,"version":"4.4.0"},"reference-count":43,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013120","name":"European Medicines Agency","doi-asserted-by":"publisher","award":["EMA\/2020\/46\/L1.02"],"award-info":[{"award-number":["EMA\/2020\/46\/L1.02"]}],"id":[{"id":"10.13039\/501100013120","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Regulatory Toxicology and Pharmacology"],"published-print":{"date-parts":[[2026,5]]},"DOI":"10.1016\/j.yrtph.2026.106036","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T07:40:08Z","timestamp":1768894808000},"page":"106036","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":6,"special_numbering":"C","title":["Nitrosamine drug substance-related impurities cause DNA methylation adducts in vitro and in primary hepatocytes upon Cytochrome P450-dependend metabolic activation"],"prefix":"10.1016","volume":"167","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4814-3900","authenticated-orcid":false,"given":"Matthias","family":"Vogel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max J.","family":"Carlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Skowron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Felske","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhys","family":"Whomsley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5225-2718","authenticated-orcid":false,"given":"J\u00f6rg","family":"Fahrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.yrtph.2026.106036_bib1","doi-asserted-by":"crossref","DOI":"10.1007\/s00204-025-04084-2","article-title":"Molecular dosimetry of estragole and 1'-hydroxyestragole-induced DNA adduct formation, clastogenicity and cytotoxicity in human liver cell models","author":"Ackermann","year":"2025","journal-title":"Arch. Toxicol."},{"issue":"1","key":"10.1016\/j.yrtph.2026.106036_bib2","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0887-2333(02)00118-2","article-title":"Time course of cytochromes P450 decline during rat hepatocyte isolation and culture: effect of L-NAME","volume":"17","author":"Binda","year":"2003","journal-title":"Toxicol. Vitro"},{"key":"10.1016\/j.yrtph.2026.106036_bib3","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/978-1-0716-2788-4_16","article-title":"Analyzing the effects of HDAC inhibitors on DNA damage and associated cytotoxicity in primary hepatocytes","volume":"2589","author":"Carlsson","year":"2023","journal-title":"Methods Mol. Biol."},{"issue":"11","key":"10.1016\/j.yrtph.2026.106036_bib4","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/s41419-022-05446-9","article-title":"p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol","volume":"13","author":"Carlsson","year":"2022","journal-title":"Cell Death Dis."},{"issue":"6","key":"10.1016\/j.yrtph.2026.106036_bib5","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1021\/acs.chemrestox.5c00133","article-title":"The DNA repair protein MGMT protects against the genotoxicity of N-Nitrosodimethylamine, but not N-Nitrosodiethanolamine and N-Nitrosomethylaniline, in human HepG2 liver cells with CYP2E1 expression","volume":"38","author":"Carlsson","year":"2025","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2026.106036_bib6","doi-asserted-by":"crossref","DOI":"10.1021\/acs.oprd.3c00153","article-title":"Formation of N-Nitrosamine drug substance related impurities in medicines: a regulatory perspective on risk factors and mitigation strategies","author":"Cioc","year":"2023","journal-title":"Org. Process Res. Dev."},{"issue":"17","key":"10.1016\/j.yrtph.2026.106036_bib8","doi-asserted-by":"crossref","first-page":"E4061","DOI":"10.1073\/pnas.1712345115","article-title":"PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression","volume":"115","author":"D\u00f6rsam","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"5","key":"10.1016\/j.yrtph.2026.106036_bib7","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1007\/s00204-014-1281-z","article-title":"The eucalyptus oil ingredient 1,8-cineol induces oxidative DNA damage","volume":"89","author":"D\u00f6rsam","year":"2015","journal-title":"Arch. Toxicol."},{"key":"10.1016\/j.yrtph.2026.106036_bib9","series-title":"Questions and Answers for Marketing Authorisation holders\/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726\/2004 Referral on Nitrosamine Impurities in Human Medicinal Products","year":"2025"},{"key":"10.1016\/j.yrtph.2026.106036_bib10","series-title":"Appendix 1 to Questions and Answers for Marketing Authorisation holders\/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726\/2004 Referral on Nitrosamine Impurities in Human Medicinal Products","year":"2025"},{"key":"10.1016\/j.yrtph.2026.106036_bib11","series-title":"Appendix 2 to Questions and Answers for Marketing Authorisation holders\/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726\/2004 Referral on Nitrosamine Impurities in Human Medicinal Products","year":"2025"},{"issue":"5","key":"10.1016\/j.yrtph.2026.106036_bib12","doi-asserted-by":"crossref","DOI":"10.3390\/ijms24054684","article-title":"DNA alkylation damage by nitrosamines and relevant DNA repair pathways","volume":"24","author":"Fahrer","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.yrtph.2026.106036_bib13","article-title":"Control of Nitrosamine impurities in human drugs guidance for industry","year":"2025","journal-title":"Food and Drug Administration"},{"key":"10.1016\/j.yrtph.2026.106036_bib14","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2023.105505","article-title":"Nitrosamine acceptable intakes should consider variation in molecular weight: the implication of stoichiometric DNA damage","volume":"145","author":"Fine","year":"2023","journal-title":"Regul. Toxicol. Pharmacol."},{"issue":"7","key":"10.1016\/j.yrtph.2026.106036_bib15","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1021\/tx049965c","article-title":"Biologically relevant chemical reactions of N7-alkylguanine residues in DNA","volume":"17","author":"Gates","year":"2004","journal-title":"Chem. Res. Toxicol."},{"issue":"4","key":"10.1016\/j.yrtph.2026.106036_bib16","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/em.70009","article-title":"An enhanced metabolization protocol for In vitro genotoxicity assessment of N-Nitrosamines in mammalian cells","volume":"66","author":"Geijer","year":"2025","journal-title":"Environ. Mol. Mutagen."},{"issue":"6","key":"10.1016\/j.yrtph.2026.106036_bib17","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1021\/acs.chemrestox.0c00471","article-title":"Direct alkylation of deoxyguanosine by Azaserine leads to O(6)-Carboxymethyldeoxyguanosine","volume":"34","author":"Geisen","year":"2021","journal-title":"Chem. Res. Toxicol."},{"issue":"6","key":"10.1016\/j.yrtph.2026.106036_bib18","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1021\/tx980005y","article-title":"Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines","volume":"11","author":"Hecht","year":"1998","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2026.106036_bib19","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2024.105709","article-title":"Optimizing the detection of N-nitrosamine mutagenicity in the Ames test","volume":"153","author":"Heflich","year":"2024","journal-title":"Regul. Toxicol. Pharmacol."},{"issue":"2","key":"10.1016\/j.yrtph.2026.106036_bib20","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1021\/tx049847p","article-title":"Cytochrome P450 enzymes as catalysts of metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco specific carcinogen","volume":"18","author":"Jalas","year":"2005","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2026.106036_bib21","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2024.105672","article-title":"Estimation of acceptable daily intake values based on modeling and in vivo mutagenicity of NDSRIs of fluoxetine, duloxetine and atomoxetine","volume":"152","author":"Jolly","year":"2024","journal-title":"Regul. Toxicol. Pharmacol."},{"issue":"8","key":"10.1016\/j.yrtph.2026.106036_bib22","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.dnarep.2007.03.008","article-title":"MGMT: key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents","volume":"6","author":"Kaina","year":"2007","journal-title":"DNA Repair (Amst)"},{"issue":"11","key":"10.1016\/j.yrtph.2026.106036_bib23","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2021.108864","article-title":"Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice","volume":"34","author":"Kay","year":"2021","journal-title":"Cell Rep."},{"issue":"2","key":"10.1016\/j.yrtph.2026.106036_bib24","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1073\/pnas.0811991106","article-title":"O6-methylguanine-induced cell death involves exonuclease 1 as well as DNA mismatch recognition in vivo","volume":"106","author":"Klapacz","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"12","key":"10.1016\/j.yrtph.2026.106036_bib25","doi-asserted-by":"crossref","first-page":"4439","DOI":"10.1002\/j.1460-2075.1992.tb05544.x","article-title":"Expression of the E.coli 3-methyladenine DNA glycosylase I gene in mammalian cells reduces the toxic and mutagenic effects of methylating agents","volume":"11","author":"Klungland","year":"1992","journal-title":"EMBO J."},{"key":"10.1016\/j.yrtph.2026.106036_bib26","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2024.105640","article-title":"Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: development and application of the Carcinogenic Potency Categorization Approach (CPCA)","volume":"150","author":"Kruhlak","year":"2024","journal-title":"Regul. Toxicol. Pharmacol."},{"issue":"9","key":"10.1016\/j.yrtph.2026.106036_bib27","doi-asserted-by":"crossref","DOI":"10.3390\/ijms23095109","article-title":"Metabolism and DNA adduct formation of tobacco-specific N-Nitrosamines","volume":"23","author":"Li","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.yrtph.2026.106036_bib28","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2023.105410","article-title":"Revisiting the mutagenicity and genotoxicity of N-nitroso propranolol in bacterial and human in vitro assays","volume":"141","author":"Li","year":"2023","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"10.1016\/j.yrtph.2026.106036_bib29","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2024.105730","article-title":"Mutagenicity and genotoxicity evaluation of 15 nitrosamine drug substance-related impurities in human TK6 cells","volume":"154","author":"Li","year":"2024","journal-title":"Regul. Toxicol. Pharmacol."},{"issue":"1","key":"10.1016\/j.yrtph.2026.106036_bib30","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1124\/jpet.300.1.105","article-title":"O-Dealkylation of fluoxetine in relation to CYP2C19 gene dose and involvement of CYP3A4 in human liver microsomes","volume":"300","author":"Liu","year":"2002","journal-title":"J. Pharmacol. Exp. Therapeut."},{"issue":"2","key":"10.1016\/j.yrtph.2026.106036_bib31","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1093\/mutage\/geae001","article-title":"N-Nitrosodimethylamine investigations in MutaMouse define point-of-departure values and demonstrate less-than-additive somatic mutant frequency accumulations","volume":"39","author":"Lynch","year":"2024","journal-title":"Mutagenesis"},{"issue":"3","key":"10.1016\/j.yrtph.2026.106036_bib32","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/jsscb.380170307","article-title":"Alkylation of DNA and tissue specificity in nitrosamine carcinogenesis","volume":"17","author":"Montesano","year":"1981","journal-title":"J. Supramol. Struct. Cell. Biochem."},{"issue":"20","key":"10.1016\/j.yrtph.2026.106036_bib33","first-page":"5815","article-title":"Apoptosis induced by DNA damage O6-methylguanine is Bcl-2 and caspase-9\/3 regulated and Fas\/caspase-8 independent","volume":"60","author":"Ochs","year":"2000","journal-title":"Cancer Res."},{"key":"10.1016\/j.yrtph.2026.106036_bib34","doi-asserted-by":"crossref","DOI":"10.4061\/2010\/284935","article-title":"Formation, repair, and genotoxic properties of bulky DNA adducts formed from tobacco-specific nitrosamines","volume":"2010","author":"Peterson","year":"2010","journal-title":"J. Nucleic Acids"},{"issue":"6","key":"10.1016\/j.yrtph.2026.106036_bib35","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1080\/00498250210128675","article-title":"Cytochrome P450 expression in human hepatocytes and hepatoma cell lines: molecular mechanisms that determine lower expression in cultured cells","volume":"32","author":"Rodriguez-Antona","year":"2002","journal-title":"Xenobiotica"},{"key":"10.1016\/j.yrtph.2026.106036_bib36","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2025.105906","article-title":"Genotoxicity evaluation of ten nitrosamine drug substance-related impurities using 2D and 3D HepaRG cell models","volume":"162","author":"Seo","year":"2025","journal-title":"Regul. Toxicol. Pharmacol."},{"issue":"2","key":"10.1016\/j.yrtph.2026.106036_bib37","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1021\/acs.chemrestox.3c00327","article-title":"Mechanisms of nitrosamine mutagenicity and their relationship to rodent carcinogenic potency","volume":"37","author":"Snodin","year":"2024","journal-title":"Chem. Res. Toxicol."},{"issue":"6","key":"10.1016\/j.yrtph.2026.106036_bib38","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1021\/tx050028u","article-title":"Mass spectrometric analysis of relative levels of pyridyloxobutylation adducts formed in the reaction of DNA with a chemically activated form of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone","volume":"18","author":"Sturla","year":"2005","journal-title":"Chem. Res. Toxicol."},{"key":"10.1016\/j.yrtph.2026.106036_bib39","doi-asserted-by":"crossref","DOI":"10.1002\/dta.3874","article-title":"Quantitative investigation of nitrosamine drug substance-related impurities (NDSRIs) under artificial gastric conditions by liquid chromatography-tandem mass spectrometry and structure-activity relationship analysis","author":"Vogel","year":"2025","journal-title":"Drug Test. Anal."},{"issue":"2","key":"10.1016\/j.yrtph.2026.106036_bib40","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/0003-9861(86)90325-5","article-title":"Specific DNA alkylation damage and its repair in carcinogen-treated rat liver and brain","volume":"246","author":"Wani","year":"1986","journal-title":"Arch. Biochem. Biophys."},{"issue":"20","key":"10.1016\/j.yrtph.2026.106036_bib41","doi-asserted-by":"crossref","first-page":"5376","DOI":"10.1021\/ac020235o","article-title":"Quantitative determination of N7-methyldeoxyguanosine and O6-methyldeoxyguanosine in DNA by LC-UV-MS-MS","volume":"74","author":"Yang","year":"2002","journal-title":"Anal. Chem."},{"key":"10.1016\/j.yrtph.2026.106036_bib42","doi-asserted-by":"crossref","first-page":"186","DOI":"10.3389\/fonc.2012.00186","article-title":"Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma","volume":"2","author":"Yoshimoto","year":"2012","journal-title":"Front. Oncol."},{"issue":"11","key":"10.1016\/j.yrtph.2026.106036_bib43","doi-asserted-by":"crossref","first-page":"4665","DOI":"10.1007\/s00204-025-04166-1","article-title":"Quantitative genotoxicity assessment of N-nitrosodimethylamine in mice by error-corrected next-generation sequencing and DNA methylation quantification for toxicity threshold determination","volume":"99","author":"You","year":"2025","journal-title":"Arch. Toxicol."}],"container-title":["Regulatory Toxicology and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230026000097?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0273230026000097?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T01:52:39Z","timestamp":1773971559000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0273230026000097"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":43,"alternative-id":["S0273230026000097"],"URL":"https:\/\/doi.org\/10.1016\/j.yrtph.2026.106036","relation":{},"ISSN":["0273-2300"],"issn-type":[{"value":"0273-2300","type":"print"}],"subject":[],"published":{"date-parts":[[2026,5]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Nitrosamine drug substance-related impurities cause DNA methylation adducts in vitro and in primary hepatocytes upon Cytochrome P450-dependend metabolic activation","name":"articletitle","label":"Article Title"},{"value":"Regulatory Toxicology and Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.yrtph.2026.106036","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Authors. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}],"article-number":"106036"}}