title: Influence of dietary antioxidants on the mutagenicity of 7,12-dimethylbenz[a]anthracene and bleomycin in female rats.
abstract: Studies on agents that modulate carcinogen-induced genotoxic effects in experimental animals provide end points that can be used for assessing the antimutagenic or anticarcinogenic properties of putative chemopreventive compounds and for predicting their protective efficacy in humans. In this study, we investigated the ability of the dietary antioxidant Vitamins C, E, beta-carotene and the mineral selenium to inhibit the mutant frequency (MF) induced by treatment of rats with 7,12-dimethylbenz[a]anthracene (DMBA), a mammary carcinogen and bleomycin (BLM), an anti-tumor agent that can damage DNA by free radical mechanisms. Both chemicals have been previously shown to be mutagenic in the rat lymphocyte Hprt assay. Adult female Fischer 344 rats were given the antioxidants singly or in a combination 2 weeks prior to mutagen treatment. Antioxidant intake continued for an additional 4 weeks post-mutagen treatment. At sacrifice, spleens were aseptically removed for the isolation of lymphocytes to conduct the mutagenesis assay at the Hprt locus. The DMBA and BLM treatment induced a marked increase in MF, 52.8 x 10(-6) and 19.2 x 10(-6), respectively, over the controls. The MFs seen in the individual antioxidants alone (single or mixture) were relatively similar to the controls, with the exception of Vitamins C and E, that had 1.7- and 1.5-fold increase, respectively. The degree of inhibitory response was dependent on the type of mutagen and the particular antioxidant. BLM/antioxidant combination had inhibitions ranging from 44 to 80%, while DMBA/antioxidant system ranged from 60 to 93%, with Vitamins C and E achieving the highest inhibition in both systems. The mixture displayed low inhibitory responses, 44.6% for BLM/mix and 47% DMBA/mix. On the whole, the results indicate that the dietary constituents tested are antimutagenic; however, because of the gradations seen with the responses, the protective efficacy of these antioxidants may depend on the type of mutagen/carcinogen they encounter. Pending molecular analysis of mitochondrial DNA mutations will also indicate whether there is a shift in the mutational spectra produced by the carcinogens in the presence of antioxidants.
authors.affiliation: Division of Genetic & Reproductive Toxicology, National Center for Toxicological Research, FDA Jefferson Laboratories, Jefferson, AR 72079, USA.
authors.forename: M
authors.initials: M
authors.lastname: Khaidakov
authors.forename: M E
authors.initials: ME
authors.lastname: Bishop
authors.forename: M G
authors.initials: MG
authors.lastname: Manjanatha
authors.forename: L E
authors.initials: LE
authors.lastname: Lyn-Cook
authors.forename: V G
authors.initials: VG
authors.lastname: Desai
authors.forename: J J
authors.initials: JJ
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Aidoo
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology; D001761:Bleomycin / Q000633:toxicity*; D002478:Cells, Cultured; D002999:Clone Cells; D004252:DNA Mutational Analysis; D019587:Dietary Supplements; D004334:Drug Administration Schedule; D005260:Female; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012643:Selenium / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D014810:Vitamin E / Q000494:pharmacology; D019207:beta Carotene / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D019207:beta Carotene; D001761:Bleomycin; D014810:Vitamin E; D015127:9,10-Dimethyl-1,2-benzanthracene; D007041:Hypoxanthine Phosphoribosyltransferase; D012643:Selenium; D001205:Ascorbic Acid