Cancer Prevention Research A γ-Tocopherol–Rich Mixture of Tocopherols Inhibits Colon Inflammation and Carcinogenesis in Azoxymethane and Dextran Sulfate Sodium–Treated Mice

We investigated the effects of a γ-tocopherol–rich mixture of tocopherols (γ-TmT, containing 57% γ-T, 24% δ-T, and 13% α-T) on colon carcinogenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS)–treated mice. In experiment 1, 6-week-old male CF-1 mice were given a dose of AOM (10 mg/kg body weight, i.p.), and 1 week later, 1.5% DSS in drinking water for 1 week. The mice were maintained on either a γ-TmT (0.3%)–enriched or a standard AIN93M diet, starting 1 week before the AOM injection, until the termination of experiment. In the AOM/DSS–treated mice, dietary γ-TmT treatment resulted in a significantly lower colon inflammation index (52% of the control) on day 7 and number of colon adenomas (9% of the control) on week 7. γ-TmT treatment also resulted in higher apoptotic index in adenomas, lower prostaglandin E2, leukotriene B4, and nitrotyrosine levels in the colon, and lower prostaglandin E2, leukotriene B4, and 8-isoprostane levels in the plasma on week 7. Some of the decreases were observed even on day 7. In experiment 2 with AOM/DSS– treated mice sacrificed on week 21, dietary 0.17% or 0.3% γ-TmT treatment, starting 1 week before the AOM injection, significantly inhibited adenocarcinoma and adenoma formation in the colon (to 17-33% of the control). Dietary 0.3% γ-TmT that was initiated after DSS treatment also exhibited a similar inhibitory activity. The present study showed that γ-TmT effectively inhibited colon carcinogenesis in AOM/DSS–treated mice, and the inhibition may be due to the apoptosis-inducing, anti-inflammatory, antioxidative, and reactive nitrogen species–trapping activities of tocopherols. Tocopherols are a family of phenolic compounds, each containing a chromanol ring system and a 16-carbon phytyl tail. These lipophilic compounds are synthesized by plants to serve as free radical scavengers (i.e., chain-breaking antioxidants) and are an important group of dietary antioxidants for humans (1, 2). γ-Tocopherol (γ-T) and α-tocopherol (α-T) are the major dietary tocopherols present in vegetable oils, such as oils from soybean, corn, and cottonseeds and nuts (3, 4). α-T is trimethylated at the 5-, 7-, and 8-positions of the chroman ring, whereas γ-T is dimethylated at the 7and 8-positions. The structures of these tocopherols are shown in Fig. 1A. Although γ-T is more abundant than α-T in the human diet, the latter is the major tocopherol found in human tissues. α-T has been traditionally considered “the” vitamin E because of its superior activity over other tocopherols in the classic fertility restoration assay (1). However, as pointed out by several reviews, γ-T has stronger antioxidative and anti-inflammatory activities than α-T and may be more effective in the prevention of cardiovascular diseases, neurodegenerative diseases, and cancers (2, 5, 6). In a study with healthy subjects, supplementation with a γ-T–rich mixture of tocopherols was more effective than with α-T at preventing platelet aggregation (7). In the Women's Health Study, supplementation with α-T did not show a protective effect against cardiovascular disease or cancer (8). In another trial, α-T supplementation produced unexpected adverse effects on the occurrence of second primary cancers and on cancer-free survival (9). It is known that excessive intake of α-T decreases blood levels of γ-T because of their competition for tocopherol transfer proteins; γ-T has a lower affinity for this protein and is excreted more extensively (5). One speculation is that the adverse effects of supplementation with large doses of α-T are caused by its lowering of the level of γ-T in the body. Authors' Affiliations: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey and Cancer Institute of New Jersey, New Brunswick, New Jersey Received 05/14/2008; revised 07/18/2008; accepted 08/18/2008. Grant support: Jewels of Charity award to the Cancer Institute of New Jersey and Facility Cores supported by ES05022 and CA72720. Requests for reprints: Chung S. Yang, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020. Phone: 732-445-3400, ext. 248; Fax: 732-445-0687; E-mail: [email protected]. ©2009 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-08-0099 OF1 Cancer Prev Res 2009;2(2) February 2009 www.aacrjournals.org Published Online First on January 20, 2009 as 10.1158/1940-6207.CAPR-08-0099 Cancer Research. on June 19, 2017. © 2009 American Association for cancerpreventionresearch.aacrjournals.org Downloaded from Published OnlineFirst January 20, 2009; DOI: 10.1158/1940-6207.CAPR-08-0099