*3.3.2. Gender*

in HepG2 cells fivefold [47]. In this study, the cell culture medium has been preconditioned with 100 μmol/L α-TOH for 10 days, as the standard medium was deficient for α-TOH [47]. Further, an indirect approach for the modulation of vitamin E metabolism via the modification of CYP3A4 expression could be realized by triggering PXR, a nuclear receptor that regulates the expression of metabolic enzymes and transporters involved in the metabolism of xenobiotics and endobiotics [101, 102]. Landes and coworkers showed that γ-T3 as well as rifampicin acts as PXR agonists, thus upregulating CYP3A4 mRNA expression in HepG2 liver cells [81]. Given the fact that enhanced mRNA expression of CYP3A4 results in enhanced enzymatic activity, the stimulation of PXR by various pharmacological agonists or antagonists could also modulate the hepatic metabolism of vitamin E. In summary, the direct or indirect regulation of CYP3A4 by various pharmacological means represents an effective way

The handling of vitamin E is also influenced by nonmodifiable factors. These are aging, gen-

The aging process is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication [103]. In particular, the mitochondrial dysfunction leads to higher formation of reactive oxygen species (ROS) and enhanced oxidative damage [104]. Both processes can be diminished by the antioxidant function of vitamin E [105]. Consequently, two questions arise: (i) can vitamin E modulate the aging processes or prevent age-related diseases? This has been subject of several reviews [106–109]. (ii) And how is the concentration, distribution, and function of vitamin E modulated by the aging process? In humans, age-dependent changes of α-TOH plasma concentrations are known. In healthy aged humans, the α-TOH plasma concentrations are higher than in younger individuals [110–113]. However, this might be due to the agerelated increase of plasma cholesterol concentrations, as the age-related increase in α-TOH plasma concentrations disappear after adjustment for cholesterol plasma concentrations [112] or serum lipids [113]. Traber et al. suggested that α-TOH plasma concentrations are more dependent on control mechanisms for plasma lipids rather than on α-TOH absorption [113]. Hospitalized elderly patients [114] as well as older persons with cognitive impairments (dementia or Alzheimer's disease [115, 116]) have low α-TOH plasma concentrations [117]. However, an unfavorable nutrient status of the hospitalized patients was discussed as the

Several studies analyzed the age-dependent changes of α-TOH tissue concentrations and handling in mice [37, 117–119] and rats [120]. In brain [37, 117, 118] and kidney [37, 117], epididymal adipose tissue [117] and aortic vessel wall [120], a consistent increase in α-TOH was found with age. In old rats, however, an age-dependent increase in intestinal absorption was found [121]. This was considered as a "*self-protective age-dependent adaption"* [120], which

der, and individual genetics. Published data in this area are sparse but interesting.

to modify the hepatic vitamin E metabolism.

cause of the lower α-TOH plasma concentrations.

*3.3.1. Aging*

10 Vitamin E in Health and Disease

**3.3. Nonmodifiable factors influencing handling of vitamin E**

The sex-dependent differences in vitamin E handling were described recently by Schmölz et al. [6] and will be summarized here briefly for humans only. While intake of vitamin E in total is higher in men than in women [122], the intake per kcal is higher for women than for men [123]. The absorption of α-TOH seems not to be influenced by sex, but is mainly regulated by downstream regulatory processes (likely by hepatic sorting or metabolism) [113]. The data on serum concentrations of vitamin E are inconsistent: while some researchers reported elevated α-TOH serum concentrations for women compared to men [124, 125], others found contradictory results [123]. Sex-dependent regulation of vitamin E metabolism is specific for the different forms of vitamin E. Women degrade γ-TOH to a higher degree than men, while the metabolism of α-TOH seems to be independent [87]. Two mechanisms may be relevant for sex-dependent regulation of vitamin E metabolism: the hormonal status of individuals and the activation of the CYP enzymes involved in vitamin E metabolism [6]. Further studies could illuminate gender-specific differences in more detail. In the light of the discovery of vitamin E as a factor that limits female fertility, this is of special interest.

### *3.3.3. Genetics*

The influence of genetics on vitamin E handling was summarized in detail in a recent review (for more details, please see [6]). Therefore, only a short overview will be provided here. Interindividual differences in the handling of vitamin E can be caused by individual genetic constitutions. Polymorphisms in genes, which are responsible for vitamin E handling such as CYP4F2 [126], NPC1L1 [127], and CD36 [128] are likely to contribute to variations in vitamin E status. The best-studied gene in this context is α-TTP, as its genetic variability may cause AVED. Two genetic variants are known, which are located in or nearby the proposed tocopherol-binding domain and cause reduced α-TOH serum concentrations [129]. Furthermore, mutations in the promoter region of α-TTP (with increased or decreased activity) were also reported [130]. In summary, vitamin E handling is influenced by several mechanisms, one of which is the variability of genes involved in these processes. This might held responsible for interindividual differences in vitamin E serum concentrations.

formation are crucial factors for NASH development, lowering α-TTP expression by ROS could explain the lower vitamin E levels in NASH patients. In summary, the concentration of vitamin E and other antioxidants is reduced in NASH patients by yet not fully understood molecular mechanisms, potentially involving α-TTP. Nevertheless, recent human intervention trials provide evidence that vitamin E treatment could improve primary NASH outcomes

The Hepatic Fate of Vitamin E

13

http://dx.doi.org/10.5772/intechopen.79445

The current data on vitamin E as a potential agent for cancer therapy are inconsistent. While *in vitro* and early epidemiological studies provided evidence for cell growth-inhibiting, antiproliferative and pro-apoptotic effects of vitamin E in cancer treatment [141–145], more recent investigations reported contradictory results [146–148]. These findings were further sustained by the "Selenium and Vitamin E Cancer Prevention Trial (SELECT)," a randomized intervention study to determine the long-term effect of a supplementation of vitamin E (400 IU/d all-*rac*-α-tocopheryl-acetate) and selenium (200 μg/d L-selenomethionine) on the risk of prostate cancer in healthy men. Interestingly, the authors observed an increased incidence for prostate cancer in subjects supplemented with vitamin E [149]. Beside the investigations on beneficial effects of vitamin E in cancer therapy, almost nothing is known about the influence of cancer on human vitamin E homeostasis. An early study by Knekt, who investigated the association of vitamin E serum concentrations and the risk for different types of female cancer, showed an inverse relation between α-TOH serum concentrations and cancer risk [150]. Thus, women with the lowest α-TOH levels were at enhanced risk for cancer compared to those with higher α-TOH levels. Indeed, this association was restricted to cancer outcomes in tissues and organs, which were not exposed to estrogens [150]. Thus, Knekt hypothesized that low vitamin E levels could represent a potential risk factor for several, but not all types of cancer [150]. Nevertheless, the molecular mechanisms underlying this impairment of vitamin E serum concentrations in cancer patients remain unclear. The enhanced metabolic conversion of vitamin E might represent a mechanistic explanation. In line with this, investigations of tissues from cancer patients showed elevated expression of CYP3A4 [151] and CYP4F2 [152], the two major enzymes of vitamin E catabolism. Unfortunately, vitamin E serum concentrations have not been determined in these studies. Further, *in vitro* studies provided evidence that cancer also affects transporters for vitamin E, such as the tocopherol-associated protein (TAP) [153]. Tissue samples from prostate cancer patients showed significantly lower TAP mRNA expression compared to healthy controls, indicating that cancer may affect the intracellular transport of vitamin E. In addition, the overexpression of TAP in prostate cancer cells leads to a significant reduction of cell growth, while a TAP knockdown by small interfering RNA increased their growth [153]. Interestingly, these effects appeared without additional vitamin E treatment, indicating that TAP not only mediates vitamin E transport but also functions as a vitamin E-independent tumor suppressor gene [153]. In summary, the promising cancer preventive effects of vitamin E shown *in vitro* have not been confirmed in recent *in vivo* trials. Nevertheless, cancer could probably be associated with reduced vitamin E concentrations in the human body, because of an enhanced vitamin E catabolism and/or the alteration of its intracellular transport. However, further investigations are required to validate these results.

(i.e., steatosis, inflammation, hepatocellular ballooning, and fibrosis) [137, 138].

*3.4.2. Cancer*
