title: Dose-dependent effects of dietary alpha- and gamma-tocopherols on genetic instability in mouse Mutatect tumors.
abstract: Vitamin E in foodstuffs is a mixture of tocopherols. In mouse Mutatect tumors, a model designed to detect DNA mutations, the hypoxanthine phosphoribosyltransferase (Hprt) gene mutation frequency is associated with the number of tumor-infiltrating neutrophils and both are markedly decreased in mice fed high levels of alpha-tocopherol. Dietary alpha-tocopherol is also associated with a decrease in neutrophil-associated loss of an interleukin 8 (IL-8)-expressing transgene in this tumor model. We examined Hprt gene mutation frequency (expressed as the number of 6-thioguanine-resistant colonies per 10(5) clonable tumor cells), IL-8 transgene loss, and myeloperoxidase activity (an indirect measure of neutrophil number) in tumors from Mutatect mice fed diets supplemented with various concentrations of D-alpha-tocopherol acetate and/or D-gamma-tocopherol acetate or neither tocopherol for 4 weeks. Hprt gene mutation frequency and myeloperoxidase activity were statistically significantly lower in tumor cells from mice fed alpha-tocopherol at 50 or 100 mg/kg body weight per day than in tumor cells from mice fed 0 mg/kg body weight per day alpha-tocopherol (P<.001 for each comparison). IL-8 transgene loss occurred in 28 of 28 tumors (100%; 95% confidence interval [CI] = 86% to 100%) from mice fed alpha-tocopherol at 50 mg or less/kg body weight per day and seven of 18 tumors (39%; 95% CI = 24% to 54%) from mice fed 100 mg/kg body weight per day (P<.001, Fisher's exact test, referent groups [pooled] 0, 25, and 50 mg/kg). gamma-Tocopherol had no detectable effect on any of the three endpoints. Thus, dietary alpha-tocopherol decreases two forms of genetic instability in a dose-dependent manner in this experimental tumor model.
authors.affiliation: Ottawa Regional Cancer Centre and the Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ontario, Canada.
authors.forename: Catherine C-Y
authors.initials: CC
authors.lastname: Soo
authors.forename: Arsalan S
authors.initials: AS
authors.lastname: Haqqani
authors.forename: Nick
authors.initials: N
authors.lastname: Hidiroglou
authors.forename: Joy E
authors.initials: JE
authors.lastname: Swanson
authors.forename: Robert S
authors.initials: RS
authors.lastname: Parker
authors.forename: H Chaim
authors.initials: HC
authors.lastname: Birnboim
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005354:Fibrosarcoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D009195:Peroxidase / Q000378:metabolism; D019076:Transgenes; D014810:Vitamin E / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000494:pharmacology; D024504:gamma-Tocopherol / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D016209:Interleukin-8; D014810:Vitamin E; D024504:gamma-Tocopherol; D009195:Peroxidase; D007041:Hypoxanthine Phosphoribosyltransferase; D024502:alpha-Tocopherol