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dc.contributor.authorHölzl-Armstrong, Lisa
dc.contributor.authorMoody, Sarah
dc.contributor.authorKucab, Jill E
dc.contributor.authorZwart, Edwin P
dc.contributor.authorBellamri, Medjda
dc.contributor.authorLuijten, Mirjam
dc.contributor.authorTuresky, Robert J
dc.contributor.authorStratton, Michael R
dc.contributor.authorArlt, Volker M
dc.contributor.authorPhillips, David H
dc.date.accessioned2020-12-13T11:29:18Z
dc.date.available2020-12-13T11:29:18Z
dc.date.issued2020-11-12
dc.identifier.pmid33189884
dc.identifier.doi10.1016/j.fct.2020.111855
dc.identifier.urihttp://hdl.handle.net/10029/624551
dc.description.abstract2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a possible human carcinogen formed in cooked fish and meat. PhIP is bioactivated by cytochrome P450 enzymes to form 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP), a genotoxic metabolite that reacts with DNA leading to the mutation-prone DNA adduct N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhIP). Here, we studied N-OH-PhIP-induced whole genome mutagenesis in human TP53 knock-in (Hupki) mouse embryo fibroblasts (HUFs) immortalised and subjected to whole genome sequencing (WGS). In addition, mutagenicity of N-OH-PhIP in TP53 and the lacZ reporter gene were assessed. TP53 mutant frequency in HUF cultures treated with N-OH-PhIP (2.5 μM for 24 h, n = 90) was 10% while no TP53 mutations were found in untreated controls (DMSO for 24 h, n = 6). All N-OH-PhIP-induced TP53 mutations occurred at G:C base pairs with G > T/C > A transversions accounting for 58% of them. TP53 mutations characteristic of those induced by N-OH-PhIP have been found in human tumours including breast and colorectal, which are cancer types that have been associated with PhIP exposure. LacZ mutant frequency increased 25-fold at 5 μM N-OH-PHIP and up to ~350 dG-C8-PhIP adducts/108 nucleosides were detected by ultra-performance liquid chromatography-electrospray ionisation multistage scan mass spectrometry (UPLC-ESI-MS3) at this concentration. In addition, a WGS mutational signature defined by G > T/C > A transversions was present in N-OH-PhIP-treated immortalised clones, which showed similarity to COSMIC SBS4, 18 and 29 signatures found in human tumours.en_US
dc.language.isoenen_US
dc.rightsCopyright © 2020 Elsevier Ltd. All rights reserved.
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectDNA adductsen_US
dc.subjectDietary carcinogenen_US
dc.subjectMutationen_US
dc.subjectPhIPen_US
dc.subjectTP53en_US
dc.subjectWhole genome sequencingen_US
dc.titleMutagenicity of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) in human TP53 knock-in (Hupki) mouse embryo fibroblasts.en_US
dc.typeArticleen_US
dc.identifier.eissn1873-6351
dc.identifier.journalFood Chem Toxicol 2020; 147:111885en_US
dc.source.journaltitleFood and chemical toxicology : an international journal published for the British Industrial Biological Research Association
dc.source.beginpage111855
dc.source.endpage
dc.source.countryEngland


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