Evidence for the preventive effect of the polyunsaturated phytol side chain in tocotrienols on 17b-estradiol epoxidation

F-L Yu PhD^a, A Gapor^b, W Bender^a

^aDepartment of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL, United States, ^bAgro Product Unit, Malaysian Palm Oil Board, Kuala Lumpur, Malaysia

AIM: Vitamin E is a family of compounds containing a chromanol ring with a phytol side chain referred to as tocopherols and tocotrienols. Tocopherols possess a saturated phytol side chain where as the phytol side chain in tocotrienols has three unsaturated double-bonds. Vitamin E is a potent antioxidant, a free radical scavenger and is able to prevent chronic diseases associated with oxidative stress, such as: cardiovascular diseases and cancer. The mechanism for the chain-breaking free radical scavenger of vitamin E is well studied, and the chromanol ring is solely involved. Little is known on the functional role of the phytol side chain of either tocopherols or tocotrienols in any biological events. METHODS: A few years ago, we discovered that 17b-estradiol (E2), like many well established chemical carcinogens, could be activated by epoxidation, resulting in its ability to bind to DNA and to inhibit DNA-dependent RNA synthesis. We proposed that E2 epoxidation is the underlying mechanism for the initiation of breast cancer carcinogenesis [Carcinogenesis 17, 1957-1961, 1996]. Based on this new insight, a method to screen chemopreventive agents against breast cancer, at the initiation, was developed [Asia Pacific J Clin Nutr 11(suppl.7), S460-S466, 2002]. RESULTS: Here, we examined the preventive effect of alpha-tocopherol, alpha-, gamma-, and delta-tocotrienols on E2 activation. We found that when any one of these E vitamins were mixed with E2 for epoxidation by the epoxide-forming oxidant dimethyldioxirane (DMDO), alpha-tocotrienols was the most effective and alpha-tocopherol the least against the formation of E2 epoxide as reflected by the loss of the ability of E2 to inhibit nuclear RNA synthesis. This conclusion was further confirmed by the reduced binding of [3H]labeled E2 to nuclear DNA. CONCLUSIONS: Since the only difference between alpha-tocopherol and alpha-tocotrienol is the phytol side chain, and all tocotrienols possess identical unsaturated phytol side chain, we conclude that the unsaturated phytol group plays a key role in the prevention of E2 epoxidation.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 793 (Dietary influences).