Vitamin E activates gene expression via the pregnane X receptor

Landes, Nico; Pfluger, Paul T.; Kluth, Dirk; Birringer, Marc; Rühl, Ralph; Böl, Gaby-Fleur; Glatt, Hansruedi; Brigelius‐Flohé, Regina

doi:10.1016/s0006-2952(02)01520-4

Cited by 217 publications

(155 citation statements)

References 33 publications

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“…Specifically, both CAR (constitutive androstane receptor) and PXR (pregnane × receptor) have been shown to regulate CYP3A; PXR has been shown to regulate MDR1 expression [44,45]. Landes et al [46] demonstrated that various forms of vitamin E activated PXR expressed in HepG2 cells. However, α-tocopherol was one of the least effective of the forms tested.…”

Section: Discussionmentioning

confidence: 99%

Regulatory mechanisms to control tissue α-tocopherol

Mustacich

Elias

et al. 2007

Free Radical Biology and Medicine

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

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Section: Discussionmentioning

confidence: 99%

Regulatory mechanisms to control tissue α-tocopherol

Mustacich

Elias

et al. 2007

Free Radical Biology and Medicine

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“…They can metabolize a large number of drugs. Hence, they will decrease the sensitivity of all those drugs which are metabolized by them [191][192][193]. (4) Genes are indeed fortune tellers of molecular and physiologic activities.…”

Section: Mechanism Of Adverse Actionsmentioning

confidence: 99%

“…Although yet to be established in humans, the in vitro studies on human cell cultures and animal models suggests that vitamin E may increase the production of cytochrome p 450 s and MDRI in liver. Induction of cytochrome p450 3 A4 or Multidrug Resistance Protein -1 (MDRI) may lower the efficacy of any drug metabolized by them [191][192][193]. Very recently, Dotan et al [54] used a very recent statistical method Markov model analysis to analyse the effects of vitamin E supplementation.…”

Section: Inconsistencies: Antioxidant Supplements Are Boon or Banementioning

confidence: 99%

Reconvene and Reconnect the Antioxidant Hypothesis in Human Health and Disease

Singh

Chandra

Mahdi

et al. 2010

Indian J Clin Biochem

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The antioxidants are essential molecules in human system but are not miracle molecules. They are neither performance enhancers nor can prevent or cure diseases when taken in excess. Their supplemental value is debateable. In fact, many high quality clinical trials on antioxidant supplement have shown no effect or adverse outcomes ranging from morbidity to all cause mortality. Several Chochrane Meta-analysis and Markov Model techniques, which are presently best available statistical models to derive conclusive answers for comparing large number of trials, support these claims. Nevertheless none of these statistical techniques are flawless. Hence, more efforts are needed to develop perfect statistical model to analyze the pooled data and further double blind, placebo controlled interventional clinical trials, which are gold standard, should be implicitly conducted to get explicit answers. Superoxide dismutase (SOD), glutathione peroxidase and catalase are termed as primary antioxidants as these scavenge superoxide anion and hydrogen peroxide. All these three enzymes are inducible enzymes, thereby inherently meaning that body increases or decreases their activity as per requirement. Hence there is no need to attempt to manipulate their activity nor have such efforts been clinically useful. SOD administration has been tried in some conditions especially in cancer and myocardial infarction but has largely failed, probably because SOD is a large molecule and can not cross cell membrane. The dietary antioxidants, including nutrient antioxidants are chain breaking antioxidants and in tandem with enzyme antioxidants temper the reactive oxygen species (ROS) and reactive nitrogen species (RNS) within physiological limits. Since body is able to regulate its own requirements of enzyme antioxidants, the diet must provide adequate quantity of non-enzymic antioxidants to meet the normal requirements and provide protection in exigent condition. So far, there is no evidence that human tissues ever experience the torrent of reactive species and that in chronic conditions with mildly enhanced generation of reactive species, the body can meet them squarely if antioxidants defense system in tissues is biochemically optimized. We are not yet certain about optimal levels of antioxidants in tissues. Two ways have been used to assess them: first by dietary intake and second by measuring plasma levels. Lately determination of plasma/serum level of antioxidants is considered better index for diagnostic and prognostic purposes. The recommended levels for vitamin A, E and C and beta carotene are 2.2-2.8 lmol/l; 27.5-30 lmol/l; 40-50 lmol/l and 0.4-0.5 lmol/l, respectively. The requirement and recommended blood levels of other dietary antioxidants are not established. The resolved issues are (1) essential to scavenge excess of radical species (2) participants in redox homeostasis (3) selective antioxidants activity against radical species (4) there is no universal antioxidant and 5) therapeutic value in case of deficiency. The overar...

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“…Homologues to the human CYP3A4 are Cyp3a11 in mice and CYP3A1, 2 and 23 in rats [60]. CYP3A4 and CYP3A5 could indeed be induced in HepG2 cells after treatment with c-tocotrienol and to a weaker extent by a-tocopherol [45]. Induction of CYP3As is mediated by the nuclear pregnane X receptor (PXR), which binds to its responsive element as a heterodimer with RXR [37,47].…”

Section: Vitamin E Is Metabolized Like Xenobioticsmentioning

confidence: 99%

“…Induction of CYP3As is mediated by the nuclear pregnane X receptor (PXR), which binds to its responsive element as a heterodimer with RXR [37,47]. The activation of a PXR-driven CAT reporter in HepG2 cells by different forms of vitamin E has recently been described [45]. The in vivo relevance was demonstrated by an up-regulation of Cyp3a11 by atocopherol in mice [39,75].…”

Section: Vitamin E Is Metabolized Like Xenobioticsmentioning

confidence: 99%

Adverse effects of vitamin E by induction of drug metabolism

Brigelius‐Flohé

2007

Genes Nutr

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Observational studies with healthy persons demonstrated an inverse association of vitamin E with the risk of coronary heart disease or cancer, the outcome of large-scale clinical trials conducted to prove a benefit of vitamin E in the recurrence and/or progression of such disease, however, was disappointing. Vitamin E did not provide benefits to patients with cardiovascular diseases, cancer, diabetes or hypertension. Even harmful events and worsening of pre-existing diseases were reported, which are hard to explain. Since vitamin E is metabolized along the same routes as xenobiotics and induces drug-metabolizing enzymes in rodents, it is hypothesized that a supplementation with high dosages of vitamin E may also lead to an induction of the drug-metabolizing system in patients that depend on drug therapy. Compromising essential therapy might therefore outweigh any benefit of vitamin E in patients. It is recommended to work out at which threshold the drug-metabolizing system can be induced in humans before new trials with high dosages of vitamin E are started.

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Vitamin E activates gene expression via the pregnane X receptor

Cited by 217 publications

References 33 publications

Regulatory mechanisms to control tissue α-tocopherol

Regulatory mechanisms to control tissue α-tocopherol

Reconvene and Reconnect the Antioxidant Hypothesis in Human Health and Disease

Adverse effects of vitamin E by induction of drug metabolism

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