Mutagenicity of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) in human TP53 knock-in (Hupki) mouse embryo fibroblasts
| Autor: | Volker M. Arlt, Robert J. Turesky, Michael R. Stratton, David H. Phillips, Edwin P. Zwart, Sarah Moody, Mirjam Luijten, Lisa Hölzl-Armstrong, Jill E. Kucab, Medjda Bellamri |
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| Rok vydání: | 2020 |
| Předmět: |
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Pyridines Mutant Toxicology medicine.disease_cause 03 medical and health sciences chemistry.chemical_compound Mice 0404 agricultural biotechnology DNA adduct medicine Animals Humans TP53 Gene Knock-In Techniques Carcinogen 030304 developmental biology 0303 health sciences Mutation biology Mutagenicity Tests Mutagenesis Imidazoles DNA adducts Dietary carcinogen Cytochrome P450 04 agricultural and veterinary sciences General Medicine Fibroblasts 040401 food science Molecular biology chemistry Gene Expression Regulation Whole genome sequencing biology.protein Tumor Suppressor Protein p53 DNA PhIP Food Science |
| Zdroj: | Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 147 |
| ISSN: | 1873-6351 |
| Popis: | 2-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. |
| Databáze: | OpenAIRE |
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