Presentation Abstract

Abstract Number: 3701
Presentation Title: Dimethylbenzanthracene (DMBA) and DMBA dihydrodiol mutagenicity in rat epithelial and fibroblast cell lines, and its inhibition by combinations of nutraceuticals
Presentation Time: Tuesday, Apr 05, 2011, 8:00 AM -12:00 PM
Location: Exhibit Hall A4-C, Poster Section 34
Poster Section: 34
Poster Board Number: 20
Author Block: Peter G. Sacks1, Zhong-Lin Zhao1, Wieslawa Kosinska1, Zhiming He1, P. David Josephy2, Joseph B. Guttenplan3. 1NYU College of Dentistry, New York, NY; 2University of Guelph, Guelph, ON, Canada; 3NYU College of Dentistry and New York University School of Medicine, New York, NY
Abstract Body: 7,12-Dimethylbenzanthracene (DMBA) is a potent mammary carcinogen in rats. Combinations of non-toxic nutraceutical agents, administered at or near physiological levels, were investigated for their abilities to inhibit the mutagenicity of DMBA or DMBA-dihydrodiol (DMBAD, a primary metabolite and proximate mutagen of DMBA) in vitro, in rat mammary epithelial and fibroblast cells derived from a lacI (BigBlue) Fischer rat (McDiarmid, H.M., Douglas, G.R., Coomber, B.L., and Josephy, P.D. Epithelial and fibroblast cell lines cultured from the transgenic BigBlue rat: an in vitro mutagenesis assay. Mutat. Res., 497: 39-47, 2001). In the epithelial cells, DMBA was not appreciably mutagenic at concentrations up to 4 µM, but DMBAD, was significantly mutagenic at ten-fold lower concentrations. These results indicate that the epithelial cells can bioactivate the intermediate, DMBAD, but cannot effect the complete biotransformation of DMBA to its ultimate mutagenic metabolite, DMBA-dihydrodiolepoxide. In the fibroblast cell line, in contrast, DMBA was mutagenic at concentrations as low as 20 nM and DMBAD was even more potent than DMBA. Several combinations of nutraceuticals (dietary components providing health benefits) were tested for their abilities to inhibit mutagenesis in these cell lines; the concentrations tested were based on reported serum concentrations and these were used to establish 1x concentrations. The agents and their 1x concentrations were: resveratrol (Res), 2.4 μM; sulforaphane (Sul), 0.06 μM; antioxidant mix (α- and γ-tocopherol, 30 μM, plus vitamin C, 68 μM - VCE); α-lipoic acid (LA), 2 μM; epigallocatechin gallate (EGCG), 0.7 μM; and N-acetylcysteine (NAC), 12 μM. None of the agents or their combinations, tested at 1 - 3 x concentrations, showed any cytotoxicity. In both epithelial and fibroblast cells, Sul and Res alone slightly inhibited mutagenesis at 2x concentrations; no other agents had observable effects. All binary combinations of Res, LA, and Sul, at 2x concentrations, inhibited mutagenesis; the Res + Sul combination was particularly effective (ca. 50% inhibition). These results suggest a role for fibroblast cells in the bioactivation of carcinogens, implicating the microenvironment, and indicate that combinations of nutraceuticals can inhibit mutagenesis by polycyclic aromatic hydrocarbons. Supported by the Susan Komen Foundation grant # KG080836 (JBG) and NSERC Canada (PDJ).