Ames test-negative carcinogen, ortho-phenyl phenol, binds tubulin and causes aneuploidy in budding yeast

Tatsuo Nunoshiba, Eri Watanabe, Teruhisa Takahashi, Yasukazu Daigaku, Satoko Ishikawa, Masataka Mochizuki, Ayako Ui, Takemi Enomoto, Kazuo Yamamoto

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Ortho-phenyl phenol (OPP) is broad-spectrum of fungicides and antibacterial agents. OPP tested negative in an Ames system and positive with respect to the formation of tumors in the urinary bladder in rats when administered in diet, showing attributes of an Ames test-negative carcinogen. It has also been demonstrated that OPP does not bind or cleave DNA in vivo or in vitro, rather dose-dependent protein binding in OPP-treated rats was observed. OPP, however, generates chromosomal aberrations including aneuploidy. Thus, the steps by which Ames test-negative carcinogens exert their effects need to be elucidated. Here, we used an assay of loss of heterozygosity (LOH) in Saccharomyces cerevisiae to determine the biological effects of OPP and its hepatic metabolite phenyl hydroquinone (PHQ). LOH was found to be induced by OPP and PHQ because of a functional chromosome loss: aneuploidy. PHQ bound to and interfered with the depolymerization of tubulin in vitro and arrested the cell-cycle at M and G1. These results indicate that OPP and PHQ damaged tubulin to cause mis-segregation of chromosome by delaying cell-cycle progression through mitosis, and as a consequence caused aneuploidy.

Original languageEnglish
Pages (from-to)90-97
Number of pages8
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume617
Issue number1-2
DOIs
Publication statusPublished - 2007 Apr 1

Fingerprint

Carcinogenicity Tests
Saccharomycetales
Aneuploidy
Tubulin
Phenol
Loss of Heterozygosity
Cell Cycle
Chromosome Segregation
Mitosis
Protein Binding
Chromosome Aberrations
Saccharomyces cerevisiae
Urinary Bladder
Chromosomes
Anti-Bacterial Agents
Diet

Keywords

  • Ames test-negative carcinogen
  • Aneuploidy
  • O-phenyl phenol
  • Phenyl hydroquinone
  • Yeast

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

Cite this

Ames test-negative carcinogen, ortho-phenyl phenol, binds tubulin and causes aneuploidy in budding yeast. / Nunoshiba, Tatsuo; Watanabe, Eri; Takahashi, Teruhisa; Daigaku, Yasukazu; Ishikawa, Satoko; Mochizuki, Masataka; Ui, Ayako; Enomoto, Takemi; Yamamoto, Kazuo.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 617, No. 1-2, 01.04.2007, p. 90-97.

Research output: Contribution to journalArticle

Nunoshiba, Tatsuo ; Watanabe, Eri ; Takahashi, Teruhisa ; Daigaku, Yasukazu ; Ishikawa, Satoko ; Mochizuki, Masataka ; Ui, Ayako ; Enomoto, Takemi ; Yamamoto, Kazuo. / Ames test-negative carcinogen, ortho-phenyl phenol, binds tubulin and causes aneuploidy in budding yeast. In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2007 ; Vol. 617, No. 1-2. pp. 90-97.
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