title: Ames test-negative carcinogen, ortho-phenyl phenol, binds tubulin and causes aneuploidy in budding yeast.
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.
authors.affiliation: Graduate School of Life Sciences, Tohoku University, Sendai 980-8577, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nunoshiba
authors.forename: Eri
authors.initials: E
authors.lastname: Watanabe
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Takahashi
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Daigaku
authors.forename: Satoko
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Masataka
authors.initials: M
authors.lastname: Mochizuki
authors.forename: Ayako
authors.initials: A
authors.lastname: Ui
authors.forename: Takemi
authors.initials: T
authors.lastname: Enomoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000782:Aneuploidy; D001713:Biphenyl Compounds / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism*; D002455:Cell Division; D015825:Chromosomes, Fungal / Q000235:genetics; D005434:Flow Cytometry; D016193:G1 Phase; D006873:Hydroquinones / Q000378:metabolism*; D019656:Loss of Heterozygosity; D008870:Microtubules / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D014404:Tubulin / Q000378:metabolism*
chemical_list: D001713:Biphenyl Compounds; D002273:Carcinogens; D006873:Hydroquinones; D014404:Tubulin; C004369:2-phenylphenol; C066330:phenylhydroquinone