Regulatory mechanisms to control tissue α-tocopherol

Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
Free Radical Biology and Medicine (Impact Factor: 5.74). 09/2007; 43(4):610-8. DOI: 10.1016/j.freeradbiomed.2007.05.027
Source: PubMed


To test the hypothesis that hepatic regulation of alpha-tocopherol metabolism would be sufficient to prevent overaccumulation of alpha-tocopherol in extrahepatic tissues and that administration of high doses of alpha-tocopherol would up-regulate extrahepatic xenobiotic pathways, rats received daily subcutaneous injections of either vehicle or 0.5, 1, 2, or 10 mg alpha-tocopherol/100 g body wt for 9 days. Liver alpha-tocopherol increased 15-fold in rats given 10 mg alpha-tocopherol/100 g body wt (mg/100 g) compared with controls. Hepatic alpha-tocopherol metabolites increased with increasing alpha-tocopherol doses, reaching 40-fold in rats given the highest dose. In rats injected with 10 mg/100 g, lung and duodenum alpha-tocopherol concentrations increased 3-fold, whereas alpha-tocopherol concentrations of other extrahepatic tissues increased 2-fold or less. With the exception of muscle, daily administration of less than 2 mg/100 g failed to increase alpha-tocopherol concentrations in extrahepatic tissues. Lung cytochrome P450 3A and 1A levels were unchanged by administration of alpha-tocopherol at any dose. In contrast, lung P-glycoprotein (MDR1) levels increased dose dependently and expression of this xenobiotic transport protein was correlated with lung alpha-tocopherol concentrations (R(2)=0.88, p<0.05). Increased lung MDR1 may provide protection from exposure to environmental toxins by increasing alveolar space alpha-tocopherol.

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    • "At the end of lactation, hepatic levels of α-T incorporation appear dramatically increased in offspring from both supplemented and nonsupplemented mothers, with differences between the two groups larger than at birth; in contrast, brain α-T concentrations show only a slight increment after lactation, with intergroup differences at P21 similar to those observed at P0. By revealing a high hepatic-tocerebral ratio of α-T incorporation in developing rats, such findings are in line with recent evidence in adult rats showing that infusions of pharmacological doses of α-T lead to much larger tocopherol accumulation in liver with respect to extrahepatic tissues [48]. α-T inhibitory effect on PKC activity has been documented in different cellular models in vitro, including neural cells [21–24,40], and confirmed in vivo in the hippocampus of α-T-supplemented adult rats [35]. "
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    ABSTRACT: Vitamin E (α-tocopherol) supplementation has been tested as prophylaxis against gestational disorders associated with oxidative damage. However, recent evidence showing that high maternal α-tocopherol intake can adversely affect offspring development raises concerns on the safety of vitamin E extradosages during pregnancy. Besides acting as an antioxidant, α-tocopherol depresses cell proliferation and modulates cell signaling through inhibiting protein kinase C (PKC), a kinase that is deeply involved in neural maturation and plasticity. Possible effects of α-tocopherol loads in the maturing brain, where PKC dysregulation is associated to developmental dysfunctions, are poorly known. Here, supranutritional doses of α-tocopherol were fed to pregnant and lactating dams to evaluate the effects on PKC signaling and morphofunctional maturation in offspring hippocampus. Results showed that maternal supplementation potentiates hippocampal α-tocopherol incorporation in offspring and leads to marked decrease of PKC phosphorylation throughout postnatal maturation, accompanied by reduced phosphorylation of growth-associated protein-43 and myristoylated alanine-rich C kinase substrate, two PKC substrates involved in neural development and plasticity. Although processes of neuronal maturation, synapse formation and targeting appeared unaffected, offspring of supplemented mothers displayed a marked reduction of long-term synaptic plasticity in juvenile hippocampus. Interestingly, this impairment persisted in adulthood, when a deficit in hippocampus-dependent, long-lasting spatial memory was also revealed. In conclusion, maternal supplementation with elevated doses of α-tocopherol can influence cell signaling and synaptic plasticity in developing hippocampus and promotes permanent adverse effects in adult offspring. The present results emphasize the need to evaluate the safety of supranutritional maternal intake of α-tocopherol in humans.
    Full-text · Article · Apr 2010 · The Journal of nutritional biochemistry
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    • "Genetic factors are now identified to play a role in the physiological control of the intestinal absorption and transfer of vitamin E to chylomicrons and intestinal HDL [47] [48], and thus in the liver uptake and incorporation of vitamin E into nascent VLDL for peripheral tissues distribution [49]. Genetic factors are also at the basis of vitamin E catabolism and biliary elimination by the ABC transporters [50]. Tissue vitamin E delivery and uptake mechanisms in the extra-hepatic tissues remain poorly characterized and appear to be essentially associated to lipoprotein receptor expression and function (reviewed in [43]). "
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    ABSTRACT: Nearly after one century of research and thousands of publications, the physiological function(s) of vitamin E remain unclear. Available evidence suggests a role in cell homeostasis that occurs through the modulation of specific signaling pathways and genes involved in proliferative, metabolic, inflammatory, and antioxidant pathways. Vitamin E presence in the human body is under close metabolic control so that only alpha-tocopherol and, to a lower extent, gamma-tocopherol are retained and delivered to tissues. Other vitamin E forms that are not retained in the body in significant amounts, exhibit responses in vitro that are different form those of alpha-tocopherol and may include tumor cell specific toxicity and apoptosis. These responses provide a therapeutic potential for these minor forms, either as such or metabolically modified, to produce bioactive metabolites. These cellular effects go beyond the properties of lipophilic antioxidant attributed to alpha-tocopherol particularly investigated for its alleged protective role in atherosclerosis or other oxidative stress conditions. Understanding signaling and gene expression effects of vitamin E could help assign a physiological role to this vitamin, which will be discussed in this review. Besides vitamin E signaling, attention will be given to tocotrienols as one of the emerging topics in vitamin E research and a critical re-examination of the most recent clinical trials will be provided together with the potential use of vitamin E in disease prevention and therapy.
    Full-text · Article · Jan 2010 · BioFactors
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    • "Transport of vitamin E is highly dependent on lipid circulation changes in parallel with triglyceride levels (Thurnham et al 1986; Hacquebard & Carpentier 2005). Besides, the concentration of this vitamin in the liver is highly related to the concentration in plasma, the liver being the key organ for storage and regulation of circulating tocopherols (Mustacich et al 2007). In the present study, when diabetic animals were in the early stages of the disease (7 days), it was found that the levels of plasma lipids appeared with relatively low levels of tocopherol per lipid molecule. "
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    ABSTRACT: Type I diabetes in humans and streptozotocin (STZ)-induced diabetes in rats has been associated with oxidative stress, but antioxidant therapy has given contradictory results, in part related to the absence of common conditions used to evaluate in-vivo antioxidant properties. This prompted the study of an experimental model of antioxidant therapy in STZ-treated rats. Adult female rats received STZ (50 mgkg(-1)) and were studied 7 or 14 days later. Adipose tissue weight progressively decreased with the time of treatment, whereas plasma triglycerides increased at 7 days, before returning to control values at 14 days after STZ treatment. STZ diabetic rats had increased plasma thiobarbituric acid reacting substances and alpha-tocopherol levels, but the latter variable was decreased when corrected for total lipids. STZ diabetic rats showed a higher GSSG/GSH ratio at Day 14 and lower GSH + GSSG at Day 7 in liver. To evaluate the effect of short-term antioxidant therapy, rats received 5 doses of vitamins C and E over 3 days before being killed on Day 14. Treatment with antioxidants decreased plasma lactic acid and thiobarbituric acid reacting substances, as well as urine 8-isoprostane, and decreased plasma uric acid in controls. Vitamins increased the plasma alpha-tocopherol/lipids ratio only in control rats, although the plasma and liver alpha-tocopherol concentration increased in both groups. STZ diabetic rats showed moderate oxidative stress and treatment with antioxidant vitamins caused a significant change in a selected group of oxidative stress markers, which reflected an improvement in some of the complications associated with this disease. The present experimental conditions can be used as a sensitive experimental model to study the responsiveness of diabetes to other antioxidant interventions.
    Preview · Article · Aug 2008 · Journal of Pharmacy and Pharmacology
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