Triphenyl phosphate induces clastogenic effects potently in mammalian cells, human CYP1A2 and 2E1 being major activating enzymes.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Ireland NLM ID: 0227276 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7786 (Electronic) Linking ISSN: 00092797 NLM ISO Abbreviation: Chem Biol Interact Subsets: MEDLINE
    • Publication Information:
      Publication: Limerick : Elsevier
      Original Publication: Amsterdam, Elsevier.
    • Subject Terms:
      Mutagens*/toxicity ; Cytochrome P-450 CYP1A2*/genetics; Cricetinae ; Animals ; Humans ; Cricetulus ; Cytochrome P-450 Enzyme System/metabolism ; Cytochrome P-450 CYP2E1/metabolism
    • Abstract:
      As a new-type flame retardant and toxic substance, triphenyl phosphate (TPP) is a ubiquitous pollutant present even in human blood. TPP is transformed by human CYP enzymes to oxidized/dealkylated metabolites. The impact of TPP metabolism on its toxicity, however, remains unclear. In this study, the genotoxicity of TPP in several mammalian cell lines and its relevance to CYP/sulfortransferase (SULT) activities were investigated. The results indicated that TPP induced micronucleus formation at ≥1 μM concentrations in a human hepatoma (C3A, endogenous CYPs being substantial) cell line, which was abolished by 1-aminobenzotriazole (CYPs inhibitor). In cell line HepG2 (parental to C3A with lower CYP expression) TPP was inactive up to 10 μM, while pretreatment with ethanol (CYP2E1 inducer), PCB 126 (CYP1A inducer), or rifampicin (CYP3A inducer) led to micronucleus formation by TPP. In V79-Mz and V79-derived cells expressing human CYP1A1 TPP was inactive (up to 32 μM), and in cells expressing human CYP1B1, 2B6 and 3A4 it induced micronucleus weakly (positive only at 32 μM). However, TPP induced micronucleus potently in V79-derived cells expressing human CYP1A2, while this effect was drastically reduced by human SULT1A1 co-expression; likewise, TPP was inactive in cells expressing both human CYP2E1 and SULT1A1, but became positive with pentachlorophenol (inhibitor of SULT1) co-exposure. Moreover, in C3A cells TPP selectively induced centromere-free micronucleus (immunofluorescent assay), and TPP increased γ-H2AX (by Western blot, indicating double-strand DNA breaks). In conclusion, this study suggests that TPP is potently clastogenic, human CYP1A2 and 2E1 being major activating enzymes while SULT1A1 involved in detoxification.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2022 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Centromere protein B; Clastogenicity; Double-strand DNA breaks; Metabolic activation; Micronuclei; Triphenyl phosphate
    • Accession Number:
      0 (Mutagens)
      EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
      YZE19Z66EA (triphenyl phosphate)
      9035-51-2 (Cytochrome P-450 Enzyme System)
      EC 1.14.13.- (Cytochrome P-450 CYP2E1)
      EC 1.14.14.1 (CYP1A2 protein, human)
    • Publication Date:
      Date Created: 20221113 Date Completed: 20221223 Latest Revision: 20221223
    • Publication Date:
      20221223
    • Accession Number:
      10.1016/j.cbi.2022.110259
    • Accession Number:
      36372259