Deficiency in systemic vitamin E metabolites is associated with colorectal cancer

A24

The role of vitamin E as a cancer chemopreventive has been investigated though several large epidemiological trials, however, the results have not provided a conclusive link between vitamin E consumption and overall risk reduction. Interestingly, the primary form of supplemental vitamin E comprises alpha-tocopherol, while foods high in vitamin E are comprised of primarily the gamma isoform, yet plasma concentrations of alpha-tocopherol are generally up to five times higher than gamma. Two endogenous processes are primarily responsible for this observation: the presence of an alpha-tocopherol binding protein with a high affinity for the alpha, but not gamma isoforms, and a cytochrome p450(4F2) that has a 50X higher affinity for the omega carboxylation of the gamma versus alpha isoform. The subsequent metabolism of carboxylated gamma isoforms to the water-soluble carboxyethyl-hydroxychroman (CEHC) urinary metabolite has also been shown, however, this alone does not appear to account for the total dietary intake of gamma tocopherol. Given that the strongest cancer chemopreventive evidence for vitamin E comes from studies examining intake based upon diet, our objective was to investigate endogenous vitamin E metabolites, with emphasis on the gamma isoforms, in the serum of colorectal cancer patients and healthy controls using a combination of non-targeted and targeted metabolomic approaches. We report here the discovery of six novel omega-carboxylated gamma-tocopherol/tocotrienol metabolites found to be deficient in the serum of approximately 75% of CRC patients (n>400) from four independent populations including two cross-sectional case-control studies and two longitudinal studies. We show that the deficiency appears to be decoupled from the presence of colorectal tumors based upon a lack of association with tumor stage, and lack of change following surgical treatment. The deficiency may therefore represent an underlying risk factor associated with CRC, and may be useful as a risk stratification screening tool. The findings also shed new light on our understanding of vitamin E metabolism.