Abstract
The natural vitamin E family is composed of 8 members equally divided into 2 classes: tocopherols (TCP) and tocotrienols (TE). A growing body of evidence suggests TE possess potent biological activity not shared by TCP. The primary objective of this work was to determine the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg a-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Eighty participants were studied. Skin and blood vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. Vital organ vitamin E levels were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1–96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. a-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. In prospective liver transplantation patients, oral TE lowered the model for end-stage liver disease (MELD) score in 50% of patients supplemented, whereas only 20% of TCP-supplemented patients demonstrated a reduction in MELD score. This work provides, to our knowledge, the first evidence demonstrating that orally supplemented TE are transported to vital organs of adult humans. The findings of this study, in the context of the current literature, lay the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans. J. Nutr. 142: 513–519, 2012.
Introduction
The natural vitamin E family is composed of eight members equally divided into two classes: TCP11 and TE. TCP are
1 Supported in part by NIH NS42617 (C.K.S.) and the Malaysian Palm Oil Board, an Institution of the Government of Malaysia. V.P. was supported by TL1RR025753 from the National Center for Research Resources, funded by the Office of the Director, NIH (OD) and supported by the NIH Roadmap for Medical Research. Supplement capsules were provided by Carotech Inc.
2 Author disclosures: V. Patel, C. Rink, G. M. Gordillo, S. Khanna, U. Gnyawali, S. Roy, B. Shneker, K. Ganesh, G. Phillips, J. L. Moore, A. Sarkar, R. Kirkpatrick, E. A. Elkhammas, E. Klatte, M. Miller, M. Firstenberg, E. A. Chiocca, and C. K. Sen, no conflicts of interest.
3 This trial was registered at clinicaltrials.gov as NCT00678834.
4 SupplementalFigures1and2andTables1and2areavailablefromthe“Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://jn.nutrition.org.
10 These authors contributed equally.
11 Abbreviations used: TCP, tocopherol; TE, tocotrienol; aTCP, a-tocopherol; gTCP, g-tocopherol; aTE, a-tocotrienol; dTE, d-tocotrienol; gTE, g-tocotrienol; ESLD, end-stage liver disease; MCA, middle cerebral artery; MELD, model for end-stage liver disease.
* To whom correspondence should be addressed. E-mail: chandan.sen@osumc. edu.
characterized by a saturated phytyl side chain with 3 chiral carbons, whereas TE possesses a farnesyl side chain with double bonds at carbons 3, 7, and 11. Within each class, isomers are differentiated by a, b, g, and d according to the position and degree of methylation on the chromanol head (1,2). TCP represent the primary form of vitamin E in green leafy vegetables, whereas TE are found in highest concentrations in seeds of monocotyledons that include wheat, rice, barley, and palm (3).
A growing body of evidence suggests TE possesses potent biological activity not shared by TCP (2). In particular, aTE and gTE have emerged as vitamin E molecules with neuroprotective and anticancer properties that are not exhibited by aTCP (1,4). Importantly, many of the unique therapeutic effects of the TE isomers occur at a concentration range achievable by dietary supplementation. A nanomolar concentration of aTE in brain tissue of spontaneously hypertensive rats was achieved by oral supplementation and attenuated ischemic stroke-induced brain damage (5). Oral administration of dTE significantly increased its concentration in tumors of mice with pancreatic cancer and inhibited tumor growth (6).
TTP selectively transports dietary aTCP into tissues (7). It is commonly held that TTP affinity is a critical determinant for the biological activity of the 8 natural vitamin E family members (8). The affinity of TTP to bind and transport aTE is 12% that of aTCP (9), which has led to the notion that TE biological activity is negligible (8). Interestingly, orally supplemented TE is transported to vital organs and restore fertility in TTP-deficient mice, sugges- ting TTP-independent mechanisms of transport for TE (3). The delivery and concentration of TE in vital organs of humans fol- lowing oral supplementation remain unknown. A series of studies in our laboratory have demonstrated potent in vitro as well as in vivo neuroprotective properties of aTE against neurodegeneration and stroke (5,10–15). Recently, we concluded a randomized, blinded, preclinical trial in canines where orally supplemented TE proved to be substantially effective in protecting against stroke- induced brain lesions as evaluated by high resolution MRI (10). In particular, TE has been shown to significantly reduce hemispher- ical infarct volume and prevent loss of white matter fiber tract connectivity in canines subject to MCA occlusion (10). Addition- ally, a post hoc analysis of cerebral angiograms during MCA occlusion demonstrated that canines supplemented with TE had improved cerebrovascular collateral circulation to the ischemic MCA territory (10). aTE has also been shown to significantly attenuate MCA occlusion-induced stroke in mice (11). As we prepare to test the efficacy of aTE in attenuation of stroke out- comes in clinical trials, we sought to test whether orally supple- mented TE reaches human brain tissue and whether it is safely tolerated at a much higher dose than what is commonly available by diet alone. This study employed daily dietary supplementation to examine the effects of TE or TCP supplementation on tissue vitamin E concentration in vital human organs. To acquire these tissues from orally supplemented humans, surgical patient popu- lations were recruited for long-term oral TE or TCP supplemen- tation.
