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1
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Mese-Tayfur S, Demirel-Yalcıner T, Migni A, Bartolini D, Galli F, Ozer NK, Sozen E. Modulation of inflammatory signaling by vitamin E metabolites and its therapeutic implications. Free Radic Res 2025; 59:86-101. [PMID: 39764767 DOI: 10.1080/10715762.2024.2449457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/06/2024] [Accepted: 12/28/2024] [Indexed: 01/30/2025]
Abstract
Naturally occurring vitamin E is a lipophilic plant-derived molecule corresponding to the 2 R forms of alpha-tocopherol. A series of natural analogs or tocochromanols are present in nature, including β-, γ- and δ-tocopherol (βT, γT, δT), the corresponding tocotrienols (αTE, βTE, γTE, δTE) and tocomonoenols. Differences between these analogs as lipophilic antioxidants and modulators of molecular processes suggest specific therapeutic properties against various disorders associated with acute and chronic inflammation. However, hepatic metabolism of these compounds via cytochrome P450-initiated side chain ω-oxidation involves the production of long-chain metabolites (LCMs) followed by intermediate (ICMs) and short-chain metabolites (SCMs), respectively. Despite the initial studies indicating these metabolites as catabolic-end products, recent findings identify their importance in providing biological functions. In this scope, LCMs, especially 13'-carboxychromanols (13'-COOHs), have been reported to hold stronger anti-inflammatory capacity than their unmetabolized precursors due to their ability to inhibit 5-lipoxygenase and cyclooxygenase-catalyzed eicosanoid formation, as well as their modulation of the pro-inflammatory transcriptional protein nuclear factor κB (NF-κB). Also, these LCMs have been reported to enhance detoxification and lipid metabolism pathways associated with cellular inflammation by modulating the nuclear receptors peroxisome proliferator-activated receptor-γ (PPARγ) and pregnane x receptor (PXR). These properties of LCMs will be described in this narrative review article focusing on recent information regarding their bioavailability, anti-inflammatory effects, and mechanisms of action in acute and chronic inflammatory disorders.
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Affiliation(s)
- Seher Mese-Tayfur
- Department of Biochemistry, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Institute of Health Sciences, Marmara University, Istanbul, Turkey
| | - Tugce Demirel-Yalcıner
- Department of Biochemistry, Faculty of Medicine, Uskudar University, Istanbul, Turkey
- Metabolic and Inflammatory Diseases Research Center (METIFLAM), Uskudar University, Istanbul, Turkey
| | - Anna Migni
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Desirée Bartolini
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Francesco Galli
- Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy
| | - Nesrin Kartal Ozer
- Department of Biochemistry, Faculty of Medicine, Uskudar University, Istanbul, Turkey
- Metabolic and Inflammatory Diseases Research Center (METIFLAM), Uskudar University, Istanbul, Turkey
| | - Erdi Sozen
- Department of Biochemistry, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
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2
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Jang Y, Kim CY. The Role of Vitamin E Isoforms and Metabolites in Cancer Prevention: Mechanistic Insights into Sphingolipid Metabolism Modulation. Nutrients 2024; 16:4115. [PMID: 39683509 DOI: 10.3390/nu16234115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/27/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Natural forms of vitamin E include four tocopherols and four tocotrienols (α, β, γ, and δ), which are essential as lipophilic antioxidants. Among these eight isoforms, α-tocopherol (αT), the predominant form of vitamin E found in tissues, has traditionally received the most attention in disease prevention research due to its robust antioxidant activity. However, recent studies suggest that other forms of vitamin E exhibit distinct and potentially more potent beneficial activities in disease prevention and treatment. These non-αT forms of vitamin E are metabolized in vivo, producing various metabolites, including 13'-carboxychromanol, though their biological roles remain largely unknown. Notably, sphingolipids, known for their significant roles in cancer biology, may be involved in the anticancer effects of vitamin E through the modulation of sphingolipid metabolism. This review focuses on the diverse biological activities of different vitamin E forms and their metabolites, particularly their anticancer effects, while highlighting the underlying mechanisms, including their novel impact on regulating sphingolipid pathways. By elucidating these interactions, we aim to provide a deeper understanding on the multifaceted roles of vitamin E in cancer prevention and therapy.
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Affiliation(s)
- Yumi Jang
- Department of Food Science and Nutrition, University of Ulsan, Ulsan 44610, Republic of Korea
- Basic-Clinical Convergence Research Institute, University of Ulsan, Ulsan 44610, Republic of Korea
| | - Choon Young Kim
- Department of Food and Nutrition, Yeungnam University, Gyeongsan 38541, Republic of Korea
- Research Institute of Human Ecology, Yeungnam University, Gyeongsan 38541, Republic of Korea
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Mohamad NV. Strategies to Enhance the Solubility and Bioavailability of Tocotrienols Using Self-Emulsifying Drug Delivery System. Pharmaceuticals (Basel) 2023; 16:1403. [PMID: 37895874 PMCID: PMC10610013 DOI: 10.3390/ph16101403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/14/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
Tocotrienols have higher medicinal value, with multiple sources of evidence showing their biological properties as antioxidant, anti-inflammatory, and osteoprotective compounds. However, tocotrienol bioavailability presents an ongoing challenge in its translation into viable products. This is because tocotrienol oil is known to be a poorly water-soluble compound, making it difficult to be absorbed into the body and resulting in less effectiveness. With the potential and benefits of tocotrienol, new strategies to increase the bioavailability and efficacy of poorly absorbed tocotrienol are required when administered orally. One of the proposed formulation techniques was self-emulsification, which has proven its capacity to improve oral drug delivery of poorly water-soluble drugs by advancing the solubility and bioavailability of these active compounds. This review discusses the updated evidence on the bioavailability of tocotrienols formulated with self-emulsifying drug delivery systems (SEDDSs) from in vivo and human studies. In short, SEDDSs formulation enhances the solubility and passive permeability of tocotrienol, thus improving its oral bioavailability and biological actions. This increases its medicinal and commercial value. Furthermore, the self-emulsifying formulation presents a useful dosage form that is absorbed in vivo independent of dietary fats with consistent and enhanced levels of tocotrienol isomers. Therefore, a lipid-based formulation technique can provide an additional detailed understanding of the oral bioavailability of tocotrienols.
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Affiliation(s)
- Nur-Vaizura Mohamad
- Centre for Drug and Herbal Development, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia
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4
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Khallouki F, Saber S, Bouddine T, Hajji L, Elbouhali B, Silvente-Poirot S, Poirot M. In vitro and In vivo oxidation and cleavage products of tocols: From chemical tuners to “VitaminEome” therapeutics. A narrative review. FOOD BIOSCI 2022. [DOI: 10.1016/j.fbio.2022.101839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Zaaboul F, Liu Y. Vitamin E in foodstuff: Nutritional, analytical, and food technology aspects. Compr Rev Food Sci Food Saf 2022; 21:964-998. [PMID: 35181987 DOI: 10.1111/1541-4337.12924] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 11/21/2021] [Accepted: 01/10/2022] [Indexed: 12/16/2022]
Abstract
Vitamin E is a group of isoprenoid chromanols with different biological activities. It comprises eight oil-soluble compounds: four tocopherols, namely, α-, β-, γ-, and δ-tocopherols; and four tocotrienols, namely, α-, β-, γ, and δ-tocotrienols. Vitamin E isomers are well-known for their antioxidant activity, gene-regulation effects, and anti-inflammatory and nephroprotective properties. Considering that vitamin E is exclusively synthesized by photosynthetic organisms, animals can only acquire it through their diet. Plant-based food is the primary source of vitamin E; hence, oils, nuts, fruits, and vegetables with high contents of vitamin E are mostly consumed after processing, including industrial processes and home-cooking, which involve vitamin E profile and content alteration during their preparation. Accordingly, it is essential to identify the vitamin E content and profile in foodstuff to match daily intake requirements. This review summarizes recent advances in vitamin E chemistry, metabolism and metabolites, current knowledge on their contents and profiles in raw and processed plant foods, and finally, their modern developments in analytical methods.
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Affiliation(s)
- Farah Zaaboul
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, People's Republic China
| | - YuanFa Liu
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, People's Republic China
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6
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Jiang Q. Metabolism of natural forms of vitamin E and biological actions of vitamin E metabolites. Free Radic Biol Med 2022; 179:375-387. [PMID: 34785321 PMCID: PMC9018116 DOI: 10.1016/j.freeradbiomed.2021.11.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022]
Abstract
Natural forms of vitamin E comprise four tocopherols and four tocotrienols. During the last twenty years, there have been breakthroughs in our understanding of vitamin E metabolism and biological activities of vitamin E metabolites. Research has established that tocopherols and tocotrienols are metabolized via ω-hydroxylase (CYP4F2)-initiated side chain oxidation to form 13'-hydroxychromanol and 13'-carobyxychromanol (13'-COOH). 13'-COOHs are further metabolized via β-oxidation and sulfation to intermediate carboxychromanols, terminal metabolite carboxyethyl-hydroxychroman (CEHC), and sulfated analogs. Animal and human studies show that γ-, δ-tocopherol and tocotrienols are more extensively metabolized than α-tocopherol (αT), as indicated by higher formation of CEHCs and 13'-COOHs from non-αT forms than those from αT. 13'-COOHs are shown to be inhibitors of cyclooxygenase-1/-2 and 5-lipoxygenase and much stronger than CEHCs for these activities. 13'-COOHs inhibit cancer cell growth, modulate cellular lipids and activate peroxisome proliferator-activated receptor-γ and pregnane X receptor. Consistent with mechanistic findings, αT-13'-COOH or δTE-13'-COOH, respective metabolites of αT or δ-tocotrienol, show anti-inflammatory and cancer-preventive effects, modulates the gut microbiota and prevents β-amyloid formation in mice. Therefore, 13'-COOHs are a new class of bioactive compounds with anti-inflammatory and anti-cancer activities and potentially capable of modulating lipid and drug metabolism. Based on the existing evidence, this author proposes that metabolites may contribute to disease-preventing effects of γ-, δ-tocopherol and tocotrienols. The role of metabolites in αT's actions may be somewhat limited considering controlled metabolism of αT because of its association with tocopherol-transport protein and less catabolism by CYP4F2 than other vitamin E forms.
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Affiliation(s)
- Qing Jiang
- Department of Nutrition Science, Purdue University, IN, 47907, West Lafayette, USA.
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Jiang Q, Im S, Wagner JG, Hernandez ML, Peden DB. Gamma-tocopherol, a major form of vitamin E in diets: Insights into antioxidant and anti-inflammatory effects, mechanisms, and roles in disease management. Free Radic Biol Med 2022; 178:347-359. [PMID: 34896589 PMCID: PMC8826491 DOI: 10.1016/j.freeradbiomed.2021.12.012] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/14/2021] [Accepted: 12/07/2021] [Indexed: 01/03/2023]
Abstract
γ-Tocopherol (γT) is a major form of vitamin E in the US diet and the second most abundant vitamin E in the blood and tissues, while α-tocopherol (αT) is the predominant vitamin E in tissues. During the last >25 years, research has revealed that γT has unique antioxidant and anti-inflammatory activities relevant to disease prevention compared to αT. While both compounds are potent lipophilic antioxidants, γT but not αT can trap reactive nitrogen species by forming 5-nitro-γT, and appears to show superior protection of mitochondrial function. γT inhibits ionophore-stimulated leukotrienes by blocking 5-lipoxygenase (5-LOX) translocation in leukocytes, decreases cyclooxygenase-2 (COX-2)-catalyzed prostaglandins in macrophages and blocks the growth of cancer cells but not healthy cells. For these activities, γT is stronger than αT. Moreover, γT is more extensively metabolized than αT via cytochrome P-450 (CYP4F2)-initiated side-chain oxidation, which leads to formation of metabolites including 13'-carboxychromanol (13'-COOH) and carboxyethyl-hydroxychroman (γ-CEHC). 13'-COOH and γ-CEHC are shown to be the predominant metabolites found in feces and urine, respectively. Interestingly, γ-CEHC has natriuretic activity and 13'-COOH inhibits both COX-1/-2 and 5-LOX activity. Consistent with these mechanistic findings of γT and metabolites, studies show that supplementation of γT mitigates inflammation and disease symptoms in animal models with induced inflammation, asthma and cancer. In addition, supplementation of γT decreased inflammation markers in patients with kidney diseases and mild asthma. These observations support that γT may be useful against inflammation-associated diseases.
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Affiliation(s)
- Qing Jiang
- Department of Nutrition Science, Purdue University, IN, 47907, West Lafayette, USA.
| | - Suji Im
- Department of Nutrition Science, Purdue University, IN, 47907, West Lafayette, USA
| | - James G Wagner
- Department of Pathobiology and Diagnostic Investigation, Michigan State University, USA
| | - Michelle L Hernandez
- Division of Allergy & Immunology, University of North Carolina School of Medicine, USA
| | - David B Peden
- Division of Allergy & Immunology, University of North Carolina School of Medicine, USA
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8
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Liu KY, Nakatsu CH, Jones-Hall Y, Kozik A, Jiang Q. Vitamin E alpha- and gamma-tocopherol mitigate colitis, protect intestinal barrier function and modulate the gut microbiota in mice. Free Radic Biol Med 2021; 163:180-189. [PMID: 33352218 DOI: 10.1016/j.freeradbiomed.2020.12.017] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/02/2020] [Accepted: 12/05/2020] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel diseases (IBDs) including colitis are intestinal disorders characterized by chronic inflammation, barrier dysfunction and dysbiosis. Specific forms of vitamin E have been shown to attenuate colitis, but the mechanisms are not fully understood. The objective of this study is to examine the impact of α-tocopherol (αT) and γ-tocopherol-rich tocopherols (γTmT) on gut inflammation, barrier integrity and microbiota in dextran sulfate sodium (DSS)-induced colitis in mice. We observe that αT and γTmT mitigated DSS-caused fecal bleeding, diarrhea and elevation of IL-6. These vitamin E forms inhibited colitis-induced loss of the tight junction protein occludin, and attenuated colitis-caused elevation of LPS-binding protein in the plasma, a surrogate marker of intestinal barrier dysfunction, suggesting protection of gut barrier integrity. Consistently, αT and γT mitigated TNF-α/IFN-γ-induced impairment of trans-epithelial electrical resistance in human intestinal epithelial Caco-2 cell monolayer. Using 16S rRNA gene sequencing of fecal DNA, we observe that DSS reduced gut microbial evenness and separated microbial composition from healthy controls. In colitis-induced mice, γTmT but not αT separated gut microbial composition from controls, and attenuated DSS-caused depletion of Roseburia, which contains butyrate producing bacteria and is decreased in IBD patients. Canonical correspondence analysis also supports that γTmT favorably altered gut microbial community. In contrast, neither αT nor γTmT affected gut microbes in healthy animals. These results provide evidence supporting protective effects of αT and γT on intestinal barrier function and that γTmT caused favorable changes of the gut microbiota in colitis-induced mice.
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Affiliation(s)
- Kilia Y Liu
- Department of Nutrition Science, Purdue University, West Lafayette, IN, 47907-2059, USA
| | - Cindy H Nakatsu
- Department of Agronomy, Purdue University, West Lafayette, IN, 47907-2059, USA
| | - Yava Jones-Hall
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907-2059, USA
| | - Ariangela Kozik
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907-2059, USA
| | - Qing Jiang
- Department of Nutrition Science, Purdue University, West Lafayette, IN, 47907-2059, USA.
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Wallert M, Börmel L, Lorkowski S. Inflammatory Diseases and Vitamin E-What Do We Know and Where Do We Go? Mol Nutr Food Res 2020; 65:e2000097. [PMID: 32692879 DOI: 10.1002/mnfr.202000097] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 06/26/2020] [Indexed: 12/14/2022]
Abstract
Inflammation-driven diseases and related comorbidities, such as the metabolic syndrome, obesity, fatty liver disease, and cardiovascular diseases cause significant global burden. There is a growing body of evidence that nutrients alter inflammatory responses and can therefore make a decisive contribution to the treatment of these diseases. Recently, the inflammasome, a cytosolic multiprotein complex, has been identified as a key player in inflammation and the development of various inflammation-mediated disorders, with nucleotide-binding domain and leucine-rich repeat pyrin domain (NLRP) 3 being the inflammasome of interest. Here an overview about the cellular signaling pathways underlying nuclear factor "kappa-light-chain-enhancer" of activated B-cells (NF-κB)- and NLRP3-mediated inflammatory processes, and the pathogenesis of the inflammatory diseases atherosclerosis and non-alcoholic fatty liver disease (NAFLD) is provided; next, the current state of knowledge for drug-based and dietary-based interventions for treating cardiovascular diseases and NAFLD is discussed. To date, one of the most important antioxidants in the human diet is vitamin E. Various in vitro and in vivo studies suggest that the different forms of vitamin E and also their derivatives have anti-inflammatory activity. Recent publications suggest that vitamin E-and possibly metabolites of vitamin E-are a promising therapeutic approach for treating inflammatory diseases such as NAFLD.
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Affiliation(s)
- Maria Wallert
- Department of Nutritional Biochemistry and Physiology, Institute of Nutritional Science, Friedrich Schiller University Jena, Jena, 07743, Germany.,Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany
| | - Lisa Börmel
- Department of Nutritional Biochemistry and Physiology, Institute of Nutritional Science, Friedrich Schiller University Jena, Jena, 07743, Germany.,Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany
| | - Stefan Lorkowski
- Department of Nutritional Biochemistry and Physiology, Institute of Nutritional Science, Friedrich Schiller University Jena, Jena, 07743, Germany.,Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD), Halle-Jena-Leipzig, Germany
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10
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Wallert M, Kluge S, Schubert M, Koeberle A, Werz O, Birringer M, Lorkowski S. Diversity of Chromanol and Chromenol Structures and Functions: An Emerging Class of Anti-Inflammatory and Anti-Carcinogenic Agents. Front Pharmacol 2020; 11:362. [PMID: 32372948 PMCID: PMC7187200 DOI: 10.3389/fphar.2020.00362] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 03/10/2020] [Indexed: 12/31/2022] Open
Abstract
Natural chromanols and chromenols comprise a family of molecules with enormous structural diversity and biological activities of pharmacological interest. A recently published systematic review described more than 230 structures that are derived from a chromanol ortpd chromenol core. For many of these compounds structure-activity relationships have been described with mostly anti-inflammatory as well as anti-carcinogenic activities. To extend the knowledge on the biological activity and the therapeutic potential of these promising class of natural compounds, we here present a report on selected chromanols and chromenols based on the availability of data on signaling pathways involved in inflammation, apoptosis, cell proliferation, and carcinogenesis. The chromanol and chromenol derivatives seem to bind or to interfere with several molecular targets and pathways, including 5-lipoxygenase, nuclear receptors, and the nuclear-factor "kappa-light-chain-enhancer" of activated B-cells (NFκB) pathway. Interestingly, available data suggest that the chromanols and chromenols are promiscuitively acting molecules that inhibit enzyme activities, bind to cellular receptors, and modulate mitochondrial function as well as gene expression. It is also noteworthy that the molecular modes of actions by which the chromanols and chromenols exert their effects strongly depend on the concentrations of the compounds. Thereby, low- and high-affinity molecular targets can be classified. This review summarizes the available knowledge on the biological activity of selected chromanols and chromenols which may represent interesting lead structures for the development of therapeutic anti-inflammatory and chemopreventive approaches.
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Affiliation(s)
- Maria Wallert
- Department of Biochemistry and Physiology of Nutrition, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany
| | - Stefan Kluge
- Department of Biochemistry and Physiology of Nutrition, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany
| | - Martin Schubert
- Department of Biochemistry and Physiology of Nutrition, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany
| | - Andreas Koeberle
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
- Michael Popp Research Institute, University of Innsbruck, Innsbruck, Austria
| | - Oliver Werz
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany
| | - Marc Birringer
- Department of Nutrition, Food and Consumer Sciences, University of Applied Sciences Fulda, Fulda, Germany
- Regionales Innovationszentrum Gesundheit und Lebensqualität (RIGL), Fulda, Germany
| | - Stefan Lorkowski
- Department of Biochemistry and Physiology of Nutrition, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany
- Competence Center for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Jena, Germany
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Liu KY, Jiang Q. Tocopherols and Tocotrienols Are Bioavailable in Rats and Primarily Excreted in Feces as the Intact Forms and 13'-Carboxychromanol Metabolites. J Nutr 2020; 150:222-230. [PMID: 31495894 PMCID: PMC7373819 DOI: 10.1093/jn/nxz217] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 07/16/2019] [Accepted: 08/09/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Vitamin E α-, γ-, or δ-tocopherol (αT, γT, δT) and γ- or δ-tocotrienol (γTE, δTE) are metabolized to hydroxychromanols and carboxychromanols including 13'-carboxychromanol (13'-COOH), 11'-COOH, and carboxyethyl hydroxychroman (CEHC), some of which have unique bioactivities compared with the vitamers. However, the bioavailability of these metabolites has not been well characterized. OBJECTIVE We investigated the pharmacokinetics (PK) of vitamin E forms and metabolites in rats. METHODS Six-week-old male Wistar rats received 1-time gavage of γT-rich tocopherols (50 mg/kg) containing γT/δT/αT (57.7%, 21.9%, and 10.9%, respectively) or δTE-rich tocotrienols (35 mg/kg) containing δTE/γTE (8:1). We quantified the time course of vitamin E forms and metabolites in the plasma and their 24-h excretion to the urine and feces. The general linear model repeated measure was used for analyses of the PK data. RESULTS In the rats' plasma, Cmax of γT or δTE was 25.6 ± 9.1 μM (Tmax = 4 h) or 16.0 ± 2.3 μM (Tmax = 2 h), respectively, and sulfated CEHCs and sulfated 11'-COOHs were the predominant metabolites with Cmax of 0.4-0.5 μM (Tmax ∼5-7 h) or ∼0.3 μM (Tmax at 4.7 h), respectively. In 24-h urine, 2.7% of γT and 0.7% of δTE were excreted as conjugated CEHCs. In the feces, 17-45% of supplemented vitamers were excreted as unmetabolized forms and 4.9-9.2% as unconjugated carboxychromanols, among which 13'-COOHs constituted ∼50% of total metabolites and the amount of δTE-derived 13'-COOHs was double that of 13'-COOH derived from γT. CONCLUSIONS PK data of vitamin E forms in rats reveal that γT, δT, γTE, and δTE are bioavailable in the plasma and are mainly excreted as unmetabolized forms and long-chain metabolites including 13'-COOHs in feces, with more metabolites from tocotrienols than from tocopherols.
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Affiliation(s)
- Kilia Y Liu
- Department of Nutrition Science, Interdepartmental Nutrition Program, College of Health and Human Sciences, Purdue University, West Lafayette, IN, USA
| | - Qing Jiang
- Department of Nutrition Science, Interdepartmental Nutrition Program, College of Health and Human Sciences, Purdue University, West Lafayette, IN, USA,Address correspondence to QJ (e-mail: )
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Tang C, Tao G, Wang Y, Liu Y, Li J. Identification of α-Tocopherol and Its Oxidation Products by Ultra-Performance Liquid Chromatography Coupled with Quadrupole Time-of-Flight Mass Spectrometry. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:669-677. [PMID: 31855428 DOI: 10.1021/acs.jafc.9b06544] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
This study aimed to determine α-tocopherol (α-T) and its thermal oxidation products simultaneously. A novel method based on an ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was developed. This approach was achieved by means of a BEH C18 analytical column under gradient elution conditions with eluents of acetonitrile/isopropanol (1:9, v/v) and acetonitrile/water (4:6, v/v). Compounds were elucidated through exact molecular mass and fragmentation ions obtained from the Q-TOF-MS detector. Two oxidation products, α-tocopheryl quinone and 5-formyl-γ-tocopherol, were identified, and one new compound was determined. This approach offered a simple, precise, and reliable method to determine oxidation products of α-T, which may give a way to understand the mechanism of the thermal oxidative process of α-T.
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Affiliation(s)
- Chuanhui Tang
- State Key Laboratory of Food Science and Technology , Jiangnan University , Wuxi 214122 , People's Republic of China
| | - Guanjun Tao
- State Key Laboratory of Food Science and Technology , Jiangnan University , Wuxi 214122 , People's Republic of China
| | - Yue Wang
- State Key Laboratory of Food Science and Technology , Jiangnan University , Wuxi 214122 , People's Republic of China
| | - Yuanfa Liu
- State Key Laboratory of Food Science and Technology , Jiangnan University , Wuxi 214122 , People's Republic of China
| | - Jinwei Li
- State Key Laboratory of Food Science and Technology , Jiangnan University , Wuxi 214122 , People's Republic of China
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He F, Chuang CC, Zhou T, Jiang Q, Sedlock DA, Zuo L. Redox correlation in muscle lengthening and immune response in eccentric exercise. PLoS One 2018; 13:e0208799. [PMID: 30589838 PMCID: PMC6307742 DOI: 10.1371/journal.pone.0208799] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 11/26/2018] [Indexed: 11/19/2022] Open
Abstract
This study was designed to examine the potential involvement of reactive oxygen species in skeletal muscle dysfunction linked with stretching in a mouse model and to explore the effects of combined antioxidant intake on peripheral leukocyte apoptosis following eccentrically-biased downhill runs in human subjects. In the mouse model, diaphragmatic muscle was stretched by 30% of its optimal length, followed by 5-min contraction. Muscle function and extracellular reactive oxygen species release was measured ex vivo. In human models, participants performed two trials of downhill running either with or without antioxidant supplementation, followed by apoptotic assay of inflammatory cells in the blood. The results showed that stretch led to decreased muscle function and prominent ROS increase during muscle contraction. In human models, we observed an elevation in circulating leukocyte apoptosis 24-48 hours following acute downhill runs. However, there is an attenuated leukocyte apoptosis following the second bout of downhill run. Interestingly, the combination of ascorbic acid (vitamin C) and α-tocopherol (vitamin E) supplementation attenuated the decrease in B-cell lymphoma 2 (Bcl-2) at 24 hours following acute downhill running. These data collectively suggest that significant ROS formation can be induced by muscle-lengthening associated with eccentric exercise, which is accompanied by compromised muscle function. The combination of antioxidants supplementation appears to have a protective role via the attenuation of decrease in anti-apoptotic protein.
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Affiliation(s)
- Feng He
- Department of Health and Kinesiology, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States of America
- Department of Kinesiology, California State University-Chico, Chico, CA, United States of America
| | - Chia-Chen Chuang
- Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
- Interdisciplinary Biophysics Graduate Program, The Ohio State University, Columbus, OH, United States of America
| | - Tingyang Zhou
- Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
- Interdisciplinary Biophysics Graduate Program, The Ohio State University, Columbus, OH, United States of America
| | - Qing Jiang
- Department of Nutrition Science, College of Health and Human Science, Purdue University, West Lafayette, IN, United States of America
| | - Darlene A. Sedlock
- Department of Health and Kinesiology, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States of America
- * E-mail: (LZ); (DAS)
| | - Li Zuo
- Radiologic Sciences and Respiratory Therapy Division, School of Health and Rehabilitation Sciences, The Ohio State University College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America
- Interdisciplinary Biophysics Graduate Program, The Ohio State University, Columbus, OH, United States of America
- Molecular Physiology and Biophysics Laboratory, College of Arts and Sciences, University of Maine, Presque Isle, ME, United States of America
- * E-mail: (LZ); (DAS)
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14
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Jiang Q. Natural forms of vitamin E and metabolites-regulation of cancer cell death and underlying mechanisms. IUBMB Life 2018; 71:495-506. [PMID: 30548200 DOI: 10.1002/iub.1978] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/17/2018] [Accepted: 11/02/2018] [Indexed: 12/25/2022]
Abstract
The disappointing results from large clinical studies of α-tocopherol (αT), the major form of vitamin E in tissues, for prevention of chronic diseases including cancer have cast doubt on not only αT but also other forms of vitamin E regarding their role in preventing carcinogenesis. However, basic research has shown that specific forms of vitamin E such as γ-tocopherol (γT), δ-tocopherol (δT), γ-tocotrienol (γTE) and δ-tocotrienol (δTE) can inhibit the growth and induce death of many types of cancer cells, and are capable of suppressing cancer development in preclinical cancer models. For these activities, these vitamin E forms are much stronger than αT. Further, recent research revealed novel anti-inflammatory and anticancer effects of vitamin E metabolites including 13'-carboxychromanols. This review focuses on anti-proliferation and induction of death in cancer cells by vitamin E forms and metabolites, and discuss mechanisms underlying these anticancer activities. The existing in vitro and in vivo evidence indicates that γT, δT, tocotrienols and 13'-carboxychromanols have anti-cancer activities via modulating key signaling or mediators that regulate cell death and tumor progression, such as eicosanoids, NF-κB, STAT3, PI3K, and sphingolipid metabolism. These results provide useful scientific rationales and mechanistic understanding for further translation of basic discoveries to the clinic with respect to potential use of these vitamin E forms and metabolites for cancer prevention and therapy. © 2018 IUBMB Life, 71(4):495-506, 2019.
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Affiliation(s)
- Qing Jiang
- Department of Nutrition Science, Purdue University, West Lafayette, Indiana, 47907, USA
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15
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Pein H, Ville A, Pace S, Temml V, Garscha U, Raasch M, Alsabil K, Viault G, Dinh CP, Guilet D, Troisi F, Neukirch K, König S, Bilancia R, Waltenberger B, Stuppner H, Wallert M, Lorkowski S, Weinigel C, Rummler S, Birringer M, Roviezzo F, Sautebin L, Helesbeux JJ, Séraphin D, Mosig AS, Schuster D, Rossi A, Richomme P, Werz O, Koeberle A. Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. Nat Commun 2018; 9:3834. [PMID: 30237488 PMCID: PMC6148290 DOI: 10.1038/s41467-018-06158-5] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 08/22/2018] [Indexed: 12/19/2022] Open
Abstract
Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13'-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8-49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13'-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13'-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.
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Affiliation(s)
- Helmut Pein
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany
| | - Alexia Ville
- Substances d'Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire, 49070, Beaucouzé, France
| | - Simona Pace
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany
| | - Veronika Temml
- Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria
| | - Ulrike Garscha
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany
| | - Martin Raasch
- Institute of Biochemistry II and Center for Sepsis Control and Care, University Hospital Jena, 07743, Jena, Germany
| | - Khaled Alsabil
- Substances d'Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire, 49070, Beaucouzé, France
| | - Guillaume Viault
- Substances d'Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire, 49070, Beaucouzé, France
| | - Chau-Phi Dinh
- Substances d'Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire, 49070, Beaucouzé, France
| | - David Guilet
- Substances d'Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire, 49070, Beaucouzé, France
| | - Fabiana Troisi
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany
| | - Konstantin Neukirch
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany
| | - Stefanie König
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany
| | - Rosella Bilancia
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131, Naples, Italy
| | - Birgit Waltenberger
- Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria
| | - Hermann Stuppner
- Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria
| | - Maria Wallert
- Chair of Nutritional Biochemistry and Physiology, Institute of Nutrition, Friedrich-Schiller-University Jena, 07743, Jena, Germany
| | - Stefan Lorkowski
- Chair of Nutritional Biochemistry and Physiology, Institute of Nutrition, Friedrich-Schiller-University Jena, 07743, Jena, Germany.,Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD), Halle, Jena and Leipzig, Jena, 07743, Germany
| | - Christina Weinigel
- Institute of Transfusion Medicine, University Hospital Jena, 07747, Jena, Germany
| | - Silke Rummler
- Institute of Transfusion Medicine, University Hospital Jena, 07747, Jena, Germany
| | - Marc Birringer
- Department of Nutritional, Food and Consumer Sciences, Fulda University of Applied Sciences, 36037, Fulda, Germany
| | - Fiorentina Roviezzo
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131, Naples, Italy
| | - Lidia Sautebin
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131, Naples, Italy
| | - Jean-Jacques Helesbeux
- Substances d'Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire, 49070, Beaucouzé, France
| | - Denis Séraphin
- Substances d'Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire, 49070, Beaucouzé, France
| | - Alexander S Mosig
- Institute of Biochemistry II and Center for Sepsis Control and Care, University Hospital Jena, 07743, Jena, Germany
| | - Daniela Schuster
- Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020, Innsbruck, Austria.,Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg, 5020, Salzburg, Austria
| | - Antonietta Rossi
- Department of Pharmacy, School of Medicine, University of Naples Federico II, 80131, Naples, Italy
| | - Pascal Richomme
- Substances d'Origine Naturelle et Analogues Structuraux, SONAS, SFR4207 QUASAV, UNIV Angers, Université Bretagne Loire, 49070, Beaucouzé, France
| | - Oliver Werz
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany.
| | - Andreas Koeberle
- Chair of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany.
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16
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Fujita N, Takenaka A. Testosterone represses urinary excretion of the alpha-tocopherol metabolite alpha-carboxymethylhydroxychroman in rats. J Nutr Biochem 2018; 62:59-64. [PMID: 30253278 DOI: 10.1016/j.jnutbio.2018.08.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 07/06/2018] [Accepted: 08/16/2018] [Indexed: 12/23/2022]
Abstract
In rats, plasma and tissue concentrations of α-tocopherol, a predominant form of vitamin E in mammals, are known to differ between the sexes. In order to examine sex differences in α-tocopherol metabolism, we investigated urinary excretion of the α-tocopherol metabolite α-carboxymethylhydroxychroman (α-CEHC) using Wistar rats. First, we measured α-CEHC in urine of 9-week-old male and female rats in basal and α-tocopherol-administered conditions. We observed that female rats excrete significantly more α-CEHC than male rats via urine. This sex difference was observed in matured 9-week-old rats but not in premature 3-week-old rats, suggesting that the difference may relate to sex hormones. In order to confirm this, we examined the effect of ovariectomy and orchiectomy on female and male rats, respectively. The results of castration clearly demonstrated that orchiectomy enhanced urinary excretion of α-CEHC, supporting the hypothesis that testosterone repressed α-tocopherol metabolism. We then administered testosterone propionate to orchiectomized rats and observed down-regulation of α-CEHC excretion. Taken together, these results indicate that testosterone represses the metabolism and urinary excretion of α-tocopherol in rats. This is the first report to show a sex-dependent difference in urinary excretion rate of an α-tocopherol metabolite and contributes to the understanding of vitamin E metabolism.
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Affiliation(s)
- Naoko Fujita
- Department of Agricultural Chemistry, School of Agriculture, Meiji University, Kawasaki, Kanagawa 214-8571, Japan
| | - Asako Takenaka
- Department of Agricultural Chemistry, School of Agriculture, Meiji University, Kawasaki, Kanagawa 214-8571, Japan.
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17
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Lee MJ, Feng W, Yang L, Chen YK, Chi E, Liu A, Yang CS. Methods for efficient analysis of tocopherols, tocotrienols and their metabolites in animal samples with HPLC-EC. J Food Drug Anal 2018; 26:318-329. [PMID: 29389570 PMCID: PMC9332665 DOI: 10.1016/j.jfda.2017.07.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 07/19/2017] [Accepted: 07/21/2017] [Indexed: 12/14/2022] Open
Abstract
Tocopherols and tocotrienols, collectively known as vitamin E, have received a great deal of attention because of their interesting biological activities. In the present study, we reexamined and improved previous methods of sample preparation and the conditions of high-performance liquid chromatography for more accurate quantification of tocopherols, tocotrienols and their major chain-degradation metabolites. For the analysis of serum tocopherols/tocotrienols, we reconfirmed our method of mixing serum with ethanol followed by hexane extraction. For the analysis of tissue samples, we improved our methods by extracting tocopherols/tocotrienols directly from tissue homogenate with hexane. For the analysis of total amounts (conjugated and unconjugated forms) of side-chain degradation metabolites, the samples need to be deconjugated by incubating with β-glucuronidase and sulfatase; serum samples can be directly used for the incubation, whereas for tissue homogenates a pre-deproteination step is needed. The present methods are sensitive, convenient and are suitable for the determination of different forms of vitamin E and their metabolites in animal and human studies. Results from the analysis of serum, liver, kidney, lung and urine samples from mice that had been treated with mixtures of tocotrienols and tocopherols are presented as examples.
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18
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Abstract
Initial research on vitamin E and cancer has focused on α-tocopherol (αT), but recent clinical studies on cancer-preventive effects of αT supplementation have shown disappointing results, which has led to doubts about the role of vitamin E, including different vitamin E forms, in cancer prevention. However, accumulating mechanistic and preclinical animal studies show that other forms of vitamin E, such as γ-tocopherol (γT), δ-tocopherol (δT), γ-tocotrienol (γTE), and δ-tocotrienol (δTE), have far superior cancer-preventive activities than does αT. These vitamin E forms are much stronger than αT in inhibiting multiple cancer-promoting pathways, including cyclo-oxygenase (COX)- and 5-lipoxygenase (5-LOX)-catalyzed eicosanoids, and transcription factors such as nuclear transcription factor κB (NF-κB) and signal transducer and activator of transcription factor 3 (STAT3). These vitamin E forms, but not αT, cause pro-death or antiproliferation effects in cancer cells via modulating various signaling pathways, including sphingolipid metabolism. Unlike αT, these vitamin E forms are quickly metabolized to various carboxychromanols including 13'-carboxychromanols, which have even stronger anti-inflammatory and anticancer effects than some vitamin precursors. Consistent with mechanistic findings, γT, δT, γTE, and δTE, but not αT, have been shown to be effective for preventing the progression of various types of cancer in preclinical animal models. This review focuses on cancer-preventive effects and mechanisms of γT, δT, γTE, and δTE in cells and preclinical models and discusses current progress in clinical trials. The existing evidence strongly indicates that these lesser-known vitamin E forms are effective agents for cancer prevention or as adjuvants for improving prevention, therapy, and control of cancer.
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Affiliation(s)
- Qing Jiang
- Department of Nutrition Science, Purdue University, West Lafayette, IN
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19
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Alterations of plasma concentrations of lipophilic antioxidants are associated with Guillain-Barre syndrome. Clin Chim Acta 2017; 470:75-80. [PMID: 28476374 DOI: 10.1016/j.cca.2017.05.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/12/2017] [Accepted: 05/01/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy resulting in demyelination in peripheral nervous system. Myelin enriched in lipids is easily oxidized by reactive oxygen species during inflammation. Oxidative stress and lipophilic anti-oxidative capacities in GBS patients have not been fully explored. To evaluate the redox status of GBS patients, we measured malondialdehyde (MDA), myeloperoxidase (MPO), lipophilic antioxidants, and tocopherols concentrations in plasma from GBS patients and age-matched healthy controls. RESULTS Concentrations of γ-tocopherol and δ-tocopherol decreased significantly, and α-carotene significantly increased in GBS patients compared to healthy controls. However, no significant changes in MDA and MPO concentrations were detected. In GBS patients, the γ-tocopherol concentration correlated positively with concentrations of δ-tocopherol, α-tocopherol, lutein, Q10, and γ-CEHC, respectively. Similarly, the δ-tocopherol concentration correlated positively with γ-tocopherol, α-tocopherol, lutein, Q10, δ-CEHC, and γ-CEHC concentrations, respectively. The receiver operating characteristics curve analysis showed that γ-tocopherol may serve as a good predictor for GBS. CONCLUSIONS Diminished lipophilic antioxidant defense, mainly γ-tocopherol and δ-tocopherol, in GBS patients accounting for their lowered resistance to reactive oxygen species is probably associated with pathogenesis of GBS, and potentially useful for the development of therapeutic strategies.
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20
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El Kurdi R, Patra D. Amplification of resonance Rayleigh scattering of gold nanoparticles by tweaking into nanowires: Bio-sensing of α-tocopherol by enhanced resonance Rayleigh scattering of curcumin capped gold nanowires through non-covalent interaction. Talanta 2017; 168:82-90. [PMID: 28391869 DOI: 10.1016/j.talanta.2017.03.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 03/06/2017] [Accepted: 03/07/2017] [Indexed: 12/12/2022]
Abstract
Tuning optical properties by controlling size and shape of the metallic nanoparticles has been of great interest to design novel bio-sensing techniques. Here, as a first example we illustrate that resonance Rayleigh scattering (RRS) signal of Au nanoparticles (NPs) can be amplified >10-fold by growing into Au nanowires (NWs). These thin and long NWs of ~20-25nm diameter and >1µm length can be achieved by suitably manipulating the temperature during green synthesis using curcumin. Interestingly, mixture of Au NWs and NPs or shorter NWs gives a moderate increase in RRS signal suggesting formation of longer NWs is crucial for optimal enhancement of RRS signal. Curcumin along with CTAB act as capping and stabilizing agent for Au NWs/NPs in different temperatures, which is confirmed by XRD, TGA, DSC, EDX and FT-IR data. This amplified RRS signal of Au NWs has been employed to design a new optical biosensor for α-tocopherol (α-TOH), which is among the most biologically active form of vitamin E. Association of α-TOH with Au NWs further enhances the RRS signal of Au NWs, ~10 fold through non-covalent interaction. No interference from other antioxidant substances like ascorbic acid and 6-O-Palmitoyl-L-ascorbic acid is observed. The sensing method is simple, fast and offers remarkable linear dynamic ranges, 12.8-1004µmolL-1, which is larger than reported values. The detection limit for α-TOH estimation has been found to be 50nmolL-1. The biosensor is found to be stable both in the absence and presence of α-TOH and provides an excellent recovery for synthetic samples.
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Affiliation(s)
- Riham El Kurdi
- Department of Chemistry, American University of Beirut, Beirut, Lebanon
| | - Digambara Patra
- Department of Chemistry, American University of Beirut, Beirut, Lebanon.
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21
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Jang Y, Park NY, Rostgaard-Hansen AL, Huang J, Jiang Q. Vitamin E metabolite 13'-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice. Free Radic Biol Med 2016; 95:190-9. [PMID: 27016075 PMCID: PMC4867259 DOI: 10.1016/j.freeradbiomed.2016.03.018] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 02/29/2016] [Accepted: 03/21/2016] [Indexed: 01/01/2023]
Abstract
Vitamin E forms are substantially metabolized to various carboxychromanols including 13'-carboxychromanols (13'-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13'-COOH and δTE-13'-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13'-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13'-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13'-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13'-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13'-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13'-COOH-induced cell death. Further, 13'-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13'-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13'-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents.
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Affiliation(s)
- Yumi Jang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Na-Young Park
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | | | - Jianjie Huang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Qing Jiang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
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22
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Torquato P, Ripa O, Giusepponi D, Galarini R, Bartolini D, Wallert M, Pellegrino R, Cruciani G, Lorkowski S, Birringer M, Mazzini F, Galli F. Analytical strategies to assess the functional metabolome of vitamin E. J Pharm Biomed Anal 2016; 124:399-412. [DOI: 10.1016/j.jpba.2016.01.056] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 01/23/2016] [Accepted: 01/25/2016] [Indexed: 12/24/2022]
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23
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Schmölz L, Birringer M, Lorkowski S, Wallert M. Complexity of vitamin E metabolism. World J Biol Chem 2016; 7:14-43. [PMID: 26981194 PMCID: PMC4768118 DOI: 10.4331/wjbc.v7.i1.14] [Citation(s) in RCA: 135] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/25/2015] [Accepted: 01/19/2016] [Indexed: 02/05/2023] Open
Abstract
Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e., when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant α-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-α-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent ω-hydroxylation followed by five cycles of subsequent β-oxidation, and forms the water-soluble end-product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their side-chain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side-chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a supplement or nutrient. To evaluate individual vitamin E status, the analytical procedures used for detecting and quantifying vitamin E and its metabolites are crucial. The latest methods in analytics are presented.
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24
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Ciffolilli S, Wallert M, Bartolini D, Krauth V, Werz O, Piroddi M, Sebastiani B, Torquato P, Lorkowski S, Birringer M, Galli F. Human serum determination and in vitro anti-inflammatory activity of the vitamin E metabolite α-(13'-hydroxy)-6-hydroxychroman. Free Radic Biol Med 2015; 89:952-62. [PMID: 26454076 DOI: 10.1016/j.freeradbiomed.2015.08.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 08/11/2015] [Accepted: 08/23/2015] [Indexed: 01/14/2023]
Abstract
Cytochrome P450-derived long-chain metabolites are gaining increasing interest as bioactive intermediates of vitamin E. In this study we first report on the HPLC-ECD and GC-MS analysis in human serum of the earliest metabolite of this vitamin, namely α-(13'-hydroxy)-6-hydroxychroman (α-13'-OH). The two chromatographic procedure are sensitive enough (LOQ of 10nM) to measure α-13'-OH after hexane extraction of 1 ml of sample obtained from healthy volunteers supplemented for 1-week with 1000 IU/d (671 mg/d) RRR-α-tocopherol. The observed concentrations ranged between 15 and 50 nM, with minor differences between fasting and 4-hr post-meal state. Baseline (non-supplemented state) levels of 7.2 ± 1.6 nM were observed extracting higher volumes of serum. Biological effects of α-13'-OH investigated for the first time in RAW264.7 murine macrophages involved transcriptional control of inflammatory cytokines, and transcriptional and functional regulation of COX2 and iNOS enzymes in response to lipopolysaccharides. In conclusion, here we present the first quantitative evaluation of serum α-13'-OH also providing early evidence of the anti-inflammatory potential of this metabolite that is worth of further investigation in the area of functional and nutraceutical implications of vitamin E metabolism.
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Affiliation(s)
| | - Maria Wallert
- Institute of Nutrition, Friedrich Schiller University Jena, Germany
| | | | - Verena Krauth
- Institute of Pharmacy, Friedrich Schiller University Jena, Germany
| | - Oliver Werz
- Institute of Pharmacy, Friedrich Schiller University Jena, Germany
| | - Marta Piroddi
- Department of Pharmaceutical Sciences, University of Perugia, Italy
| | | | - Pierangelo Torquato
- Institute of Nutrition, Friedrich Schiller University Jena, Germany; Institute of Nutrition, Friedrich Schiller University Jena, Germany
| | - Stefan Lorkowski
- Institute of Nutrition, Friedrich Schiller University Jena, Germany
| | - Marc Birringer
- Department of Nutritional, Food and Consumer Studies, University of Applied Sciences Fulda, Germany
| | - Francesco Galli
- Department of Pharmaceutical Sciences, University of Perugia, Italy.
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25
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Jiang Q, Xu T, Huang J, Jannasch AS, Cooper B, Yang C. Analysis of vitamin E metabolites including carboxychromanols and sulfated derivatives using LC/MS/MS. J Lipid Res 2015; 56:2217-25. [PMID: 26351363 DOI: 10.1194/jlr.d061663] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Indexed: 11/20/2022] Open
Abstract
Tocopherols and tocotrienols are metabolized via hydroxylation and oxidation of their hydrophobic side chain to generate 13'-hydroxychromanols (13'-OHs) and various carboxychromanols, which can be further metabolized by conjugation including sulfation. Recent studies indicate that long-chain carboxychromanols, especially 13'-carboxychromanol (13'-COOH), appear to be more bioactive than tocopherols in anti-inflammatory and anticancer actions. To understand the potential contribution of metabolites to vitamin E-mediated effects, an accurate assay is needed to evaluate bioavailability of these metabolites. Here we describe an LC/MS/MS assay for quantifying vitamin E metabolites using negative polarity ESI. This assay includes a reliable sample extraction procedure with efficacy of ≥ 89% and interday/intraday variation of 3-11% for major metabolites. To ensure accurate quantification, short-chain, long-chain, and sulfated carboxychromanols are included as external/internal standards. Using this assay, we observed that sulfated carboxychromanols are the primary metabolites in the plasma of rodents fed with γ-tocopherol or δ-tocopherol. Although plasma levels of 13'-COOHs and 13'-OHs are low, high concentrations of these compounds are found in feces. Our study demonstrates an LC/MS/MS assay for quantitation of sulfated and unconjugated vitamin E metabolites, and this assay will be useful for evaluating the role of these metabolites in vivo.
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Affiliation(s)
- Qing Jiang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907
| | - Tianlin Xu
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907
| | - Jianjie Huang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907
| | - Amber S Jannasch
- Metabolite Profiling Facility Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907
| | - Bruce Cooper
- Metabolite Profiling Facility Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907
| | - Chao Yang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907
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26
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Jiang Q. Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy. Free Radic Biol Med 2014; 72:76-90. [PMID: 24704972 PMCID: PMC4120831 DOI: 10.1016/j.freeradbiomed.2014.03.035] [Citation(s) in RCA: 560] [Impact Index Per Article: 50.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 03/25/2014] [Accepted: 03/26/2014] [Indexed: 02/07/2023]
Abstract
The vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol (αT) is the predominant form of vitamin E in tissues and its deficiency leads to ataxia in humans. However, results from many clinical studies do not support a protective role of αT in disease prevention in people with adequate nutrient status. On the other hand, recent mechanistic studies indicate that other forms of vitamin E, such as γ-tocopherol (γT), δ-tocopherol, and γ-tocotrienol, have unique antioxidant and anti-inflammatory properties that are superior to those of αT in prevention and therapy against chronic diseases. These vitamin E forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids, and suppress proinflammatory signaling such as NF-κB and STAT3/6. Unlike αT, other vitamin E forms are significantly metabolized to carboxychromanols via cytochrome P450-initiated side-chain ω-oxidation. Long-chain carboxychromanols, especially 13'-carboxychromanols, are shown to have stronger anti-inflammatory effects than unmetabolized vitamins and may therefore contribute to the beneficial effects of vitamin E forms in vivo. Consistent with mechanistic findings, animal and human studies show that γT and tocotrienols may be useful against inflammation-associated diseases. This review focuses on non-αT forms of vitamin E with respect to their metabolism, anti-inflammatory effects and mechanisms, and in vivo efficacy in preclinical models as well as human clinical intervention studies.
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Affiliation(s)
- Qing Jiang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
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27
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Wallert M, Mosig S, Rennert K, Funke H, Ristow M, Pellegrino RM, Cruciani G, Galli F, Lorkowski S, Birringer M. Long-chain metabolites of α-tocopherol occur in human serum and inhibit macrophage foam cell formation in vitro. Free Radic Biol Med 2014; 68:43-51. [PMID: 24296243 DOI: 10.1016/j.freeradbiomed.2013.11.009] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 11/11/2013] [Accepted: 11/13/2013] [Indexed: 02/07/2023]
Abstract
Despite intensive research the physiological role and molecular mechanisms of action of the lipophilic antioxidant α-tocopherol (α-TOH) are still poorly understood. Hepatic α-TOH catabolism results in intermediate formation of the long-chain metabolites (α-LCMs) α-13'-hydroxy- and α-13'-carboxychromanol (α-13'-OH and α-13'-COOH). We propose that α-LCMs have biological functions that need further exploration. Here we report that α-13'-COOH, as detected by LC/MS Q-TOF, occurs in human serum, providing evidence for its systemic bioavailability. Using semisynthetically derived α-LCMs we performed flow cytometric analyses and found that α-LCMs decrease oxidized LDL (oxLDL) uptake (α-13'-OH, 24±6%, α-13'-COOH, 20±5% vs control) and oxLDL-induced lipid accumulation in human macrophages in vitro (α-13'-OH, 26±4%, α-13'-COOH, 21±9% vs oxLDL), probably owing to α-LCM-mediated reduction in phagocytosis of oxLDL (α-13'-OH, 16±6%, α-13'-COOH, 41±3% vs oxLDL). At the same time, α-LCMs induced expression of CD36, the major scavenger receptor for oxLDL, in human macrophages by about 4.5-fold. Blocking experiments provided evidence that α-LCMs influence oxLDL uptake independent of CD36. A key finding of our study is that bioactivity of the α-LCMs occurs at lower concentrations and with mechanisms distinct from those of their metabolic precursor α-TOH. Our findings shed new light on the mechanistic aspects of α-TOH function in macrophages, which seem to be complicated by circulating α-LCMs. We speculate that α-LCMs represent a new class of regulatory metabolites. Further studies are required to elucidate their physiological role and contribution to cardiovascular disease.
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Affiliation(s)
- Maria Wallert
- Department of Nutritional Biochemistry, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany
| | - Sandy Mosig
- Department of Molecular Hemostaseology, University Hospital Jena, Jena, Germany
| | - Knut Rennert
- Department of Molecular Hemostaseology, University Hospital Jena, Jena, Germany
| | - Harald Funke
- Department of Molecular Hemostaseology, University Hospital Jena, Jena, Germany
| | - Michael Ristow
- Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany
| | - Roberto Maria Pellegrino
- Laboratory of Molecular Modeling and Chemoinformatics, Department of Chemistry, University of Perugia, Perugia, Italy
| | - Gabriele Cruciani
- Laboratory of Molecular Modeling and Chemoinformatics, Department of Chemistry, University of Perugia, Perugia, Italy
| | - Francesco Galli
- Section of Applied Biochemistry and Nutritional Sciences, Department of Internal Medicine, University of Perugia, Perugia, Italy
| | - Stefan Lorkowski
- Department of Nutritional Biochemistry, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany.
| | - Marc Birringer
- Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University Jena, 07743 Jena, Germany.
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28
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Jiang Q, Jiang Z, Hall YJ, Jang Y, Snyder PW, Bain C, Huang J, Jannasch A, Cooper B, Wang Y, Moreland M. Gamma-tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice. Free Radic Biol Med 2013; 65:1069-1077. [PMID: 24013093 PMCID: PMC3859799 DOI: 10.1016/j.freeradbiomed.2013.08.187] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2013] [Revised: 08/11/2013] [Accepted: 08/28/2013] [Indexed: 12/11/2022]
Abstract
Inflammation can promote colon cancer. Mechanistic studies indicate that γ-tocopherol (γT), a major form of vitamin E in diets, has anti-inflammatory and anticancer properties. Here we investigated the effectiveness of γT and a mixture of tocopherols against colitis and colitis-promoted colon tumorigenesis in male BALB/c mice. γT or mixed tocopherols (at 0.1% diet) did not show any effect on colon tumorigenesis induced by azoxymethane (AOM, 10mg/kg) with three cycles of dextran sodium sulfate (DSS at 1.5-2.5%). γT failed to exhibit protection of severe colitis caused by three cycles of DSS at 2.5%. In contrast, when AOM-initiated carcinogenesis was promoted by relatively mild colitis induced by one-cycle DSS (1.5%), γT, but not mixed tocopherols, suppressed total multiplicity of macroscopic adenomas (P=0.06) and large adenomatous polyps (>2mm(2), P<0.05) by 60 and 85%, respectively. γT also significantly decreased tumor multiplicity (>2mm(2)) induced by AOM with two cycles of 1.5% DSS even when dietary supplementation was started after AOM injection. Consistently, γT but not mixed tocopherols attenuated DSS (1.5%)-induced colon inflammation and damage as well as formation of atypical glandular hyperplasia. Mice supplemented with tocopherols had high fecal excretion of 13'-carboxychromanol, a long-chain vitamin E metabolite shown to have potent anti-inflammatory activities. Our study demonstrates that γT is able to alleviate moderate but not severe colitis and its promoted tumorigenesis, and indicates that inflammation severity should be considered in evaluating anticancer effectiveness of chemoprevention agents.
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Affiliation(s)
- Qing Jiang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
| | - Ziying Jiang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Yava Jones Hall
- Department of Comparative Pathology, Purdue University, West Lafayette, IN 47907, USA
| | - Yumi Jang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Paul W Snyder
- Department of Comparative Pathology, Purdue University, West Lafayette, IN 47907, USA
| | - Carol Bain
- Department of Comparative Pathology, Purdue University, West Lafayette, IN 47907, USA
| | - Jianjie Huang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Amber Jannasch
- Metabolite Profiling Facility Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA
| | - Bruce Cooper
- Metabolite Profiling Facility Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA
| | - Yun Wang
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Michelle Moreland
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
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29
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Traber MG. Mechanisms for the prevention of vitamin E excess. J Lipid Res 2013; 54:2295-306. [PMID: 23505319 PMCID: PMC3735929 DOI: 10.1194/jlr.r032946] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Revised: 03/04/2013] [Indexed: 02/07/2023] Open
Abstract
The liver is at the nexus of the regulation of lipoprotein uptake, synthesis, and secretion, and it is the site of xenobiotic detoxification by cytochrome P450 oxidation systems (phase I), conjugation systems (phase II), and transporters (phase III). These two major liver systems control vitamin E status. The mechanisms for the preference for α-tocopherol relative to the eight naturally occurring vitamin E forms largely depend upon the liver and include both a preferential secretion of α-tocopherol from the liver into the plasma for its transport in circulating lipoproteins for subsequent uptake by tissues, as well as the preferential hepatic metabolism of non-α-tocopherol forms. These mechanisms are the focus of this review.
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Affiliation(s)
- Maret G Traber
- Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.
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30
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Marklund M, Landberg R, Andersson R, Aman P, Kamal-Eldin A. Alkylresorcinol metabolism in Swedish adults is affected by factors other than intake of whole-grain wheat and rye. J Nutr 2012; 142:1479-86. [PMID: 22739366 DOI: 10.3945/jn.112.159244] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The urinary alkylresorcinol (AR) metabolites, 3,5-dihydroxybenzoic acid (DHBA) and 3-(3,5-dihydroxyphenyl)-propanoic acid (DHPPA), could potentially serve as biomarkers for intake of whole-grain (WG) wheat and rye. Excretion of AR metabolites is largely dependent on the intake of AR but may also be influenced by other factors. This study aimed to investigate the validity of free and conjugated AR metabolites as biomarkers for WG intake of wheat and rye and to identify potential determinants of AR metabolites in urine. We quantified free aglycones and conjugates of AR metabolites in 24-h urine collections from 52 free-living Swedish adults and calculated correlation coefficients between urinary AR metabolite excretion and self-reported WG intake. We used partial least-squares regression to identify possible determinants of urinary AR metabolites. Approximately 50% of urinary AR metabolites were found as conjugates. Excretions of individually quantified free and conjugated AR metabolites and their sums were correlated to self-reported intake of WG rye and wheat (r = 0.50-0.68; P < 0.001). Excretion of urinary AR metabolites was mainly dependent on intake of 2 major dietary AR homologs, C19:0 and C21:0. Sex, BMI, and vitamin C intake were identified as determinants of the proportion of free and glucuronidated DHPPA in the present study. Urinary AR metabolites may be useful in reflecting short-term to medium-term intake of WG, but urine samples should be deconjugated prior to quantification. Anthropometric and dietary factors affecting the proportion of conjugated AR metabolites in urine may to some extent influence AR elimination and thereby the performance of urinary AR metabolites as biomarkers.
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Affiliation(s)
- Matti Marklund
- Department of Food Science, BioCenter, Swedish University of Agricultural Sciences, Uppsala, Sweden.
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31
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Uchida T, Nomura S, Ichikawa T, Abe C, Ikeda S. Tissue distribution of vitamin E metabolites in rats after oral administration of tocopherol or tocotrienol. J Nutr Sci Vitaminol (Tokyo) 2012; 57:326-32. [PMID: 22293209 DOI: 10.3177/jnsv.57.326] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
We previously found that 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxychroman (γCEHC), a metabolite of the vitamin E isoforms γ-tocopherol or γ-tocotrienol, accumulated in the rat small intestine. The aim of this study was to evaluate tissue distribution of vitamin E metabolites. A single dose of α-tocopherol, γ-tocopherol or a tocotrienol mixture containing α- and γ-tocotrienol was orally administered to rats. Total amounts of conjugated and unconjugated metabolites in the tissues were measured by HPLC with an electrochemical detector, and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox) was used as an internal standard. Twenty-four hours later, the vitamin E isoforms were detected in most tissues and in the serum. However, 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman (αCEHC), a metabolite of α-tocopherol or α-tocotrienol, and γCEHC accumulated in the serum and in some tissues including the liver, small intestine and kidney. Administration of α-tocopherol increased the γCEHC concentration in the small intestine, suggesting that α-tocopherol enhances γ-tocopherol catabolism. In contrast, ketoconazole, an inhibitor of cytochrome P450 (CYP)-dependent vitamin E catabolism, markedly decreased the γCEHC concentration. These data indicate that vitamin E metabolite accumulates not only in the liver but also in the small intestine and kidney. We conclude that some dietary vitamin E is catabolized to carboxyethyl-hydroxychroman in the small intestine and is secreted into the circulatory system.
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Affiliation(s)
- Tomono Uchida
- Department of Nutritional Sciences, Nagoya University of Arts and Sciences, Nisshin, Japan
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32
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Traber MG, Labut EM, Leonard SW, Lebold KM. α-Tocopherol injections in rats up-regulate hepatic ABC transporters, but not cytochrome P450 enzymes. Free Radic Biol Med 2011; 51:2031-40. [PMID: 21945367 PMCID: PMC3208783 DOI: 10.1016/j.freeradbiomed.2011.08.033] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Revised: 08/25/2011] [Accepted: 08/26/2011] [Indexed: 12/11/2022]
Abstract
The role of hepatic xenobiotic regulatory mechanisms in modulating hepatic α-tocopherol concentrations during excess vitamin E administration remains unclear. We hypothesized that increased hepatic α-tocopherol would cause a marked xenobiotic response. Thus, we assessed cytochrome P450 oxidation systems (phase I), conjugation systems (phase II), and transporters (phase III) after daily α-tocopherol injections (100mg/kg body wt) for up to 9days in rats. α-Tocopherol injections increased hepatic α-tocopherol concentrations nearly 20-fold, along with a 10-fold increase in the hepatic α-tocopherol metabolites α-CEHC and α-CMBHC. Expression of phase I (CYP3A2, CYP3A1, CYP2B2) and phase II (SULT2A1) proteins and/or mRNAs was variably affected by α-tocopherol injections; however, expression of phase III transporter genes was consistently changed by α-tocopherol. Two liver efflux transporter genes, ABCB1b and ABCG2, were up-regulated after α-tocopherol injections, whereas OATP, a liver influx transporter, was down-regulated. Thus, an overload of hepatic α-tocopherol increases its own metabolism and increases expression of genes of transporters that are postulated to lead to increased excretion of both vitamin E and its metabolites.
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Affiliation(s)
- Maret G Traber
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
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33
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Enzymatic sulfation of tocopherols and tocopherol metabolites by human cytosolic sulfotransferases. Biosci Biotechnol Biochem 2011; 75:1951-6. [PMID: 21979065 DOI: 10.1271/bbb.110352] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tocopherols are essential micronutrients for mammals widely known as potent lipid-soluble antioxidants that are present in cell membranes. Recent studies have demonstrated that most of the carboxychromanol (CEHC), a tocopherol metabolite, in the plasma exists primarily in sulfate- and glucuronide-conjugated forms. To gain insight into the enzymatic sulfation of tocopherols and their metabolites, a systematic investigation was performed using all 14 known human cytosolic sulfotransferases (SULTs). The results showed that the members of the SULT1 family displayed stronger sulfating activities toward tocopherols and their metabolites. These enzymes showed a substrate preference for γ-tocopherol over α-tocopherol and for γ-CEHC over other CEHCs. Using A549 human lung epithelial cells in a metabolic labeling study, a similar trend in the sulfation of tocopherols and CEHCs was observed. Collectively, the results obtained indicate that SULT-mediated enzymatic sulfation of tocopherols and their metabolites is a significant pathway for regulation of the homeostasis and physiological functions of these important compounds.
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34
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Wang Y, Moreland M, Wagner JG, Ames BN, Illek B, Peden DB, Jiang Q. Vitamin E forms inhibit IL-13/STAT6-induced eotaxin-3 secretion by up-regulation of PAR4, an endogenous inhibitor of atypical PKC in human lung epithelial cells. J Nutr Biochem 2011; 23:602-8. [PMID: 21764283 DOI: 10.1016/j.jnutbio.2011.03.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2010] [Revised: 02/24/2011] [Accepted: 03/02/2011] [Indexed: 10/17/2022]
Abstract
Eotaxin-3 (CCL-26), a potent chemokine for eosinophil recruitment and contributing significantly to the pathogenesis of asthma, is secreted by lung epithelial cells in response to T helper 2 cytokines including interleukin 13 (IL-13). Here we showed that vitamin E forms, but not their metabolites, differentially inhibited IL-13-stimulated generation of eotaxin-3 in human lung epithelial A549 cells. The relative inhibitory potency was γ-tocotrienol (γ-TE) (IC50 ~15 μM)>γ-tocopherol, δ-tocopherol (IC50 ~25-50 μM)>α-tocopherol. Consistent with suppression of eotaxin, γ-TE treatment impaired IL-13-induced phosphorylation of STAT6, the key transcription factor for activation of eotaxin expression, and consequently blocked IL-13-stimulated DNA-binding activity of STAT6. In search of the upstream target of γTE by using inhibitor and siRNA approaches, we discovered that the atypical protein kinase C (aPKC) signaling, instead of classical PKC, p38 MAPK, JNK or ERK, played a critical role in IL-13-stimulated eotaxin generation and STAT6 activation. While showing no obvious effect on aPKC expression or phosphorylation, γ-TE treatment resulted in increased expression of prostate-apoptosis-response 4 (PAR4), an endogenous negative regulator of aPKCs. Importantly, γ-TE treatment led to enhanced formation of aPKC/PAR4 complex that is known to reduce aPKC activity via protein-protein crosstalk. Our study demonstrated that γ-TE inhibited IL-13/STAT6-activated eotaxin secretion via up-regulation of PAR4 expression and enhancement of aPKC-PAR4 complex formation. These results support the notion that specific vitamin E forms may be useful anti-asthmatic agents.
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Affiliation(s)
- Yun Wang
- Department of Foods and Nutrition, Purdue University, Stone Hall, West Lafayette, IN 47907, USA
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35
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Jiang Z, Yin X, Jiang Q. Natural forms of vitamin E and 13'-carboxychromanol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium influx and suppressing 5-lipoxygenase activity, respectively. THE JOURNAL OF IMMUNOLOGY 2010; 186:1173-9. [PMID: 21169551 DOI: 10.4049/jimmunol.1002342] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Leukotrienes generated by 5-lipoxygenase (5-LOX)-catalyzed reaction are key regulators of inflammation. In ionophore-stimulated (A23187; 1-2.5 μM) human blood neutrophils or differentiated HL-60 cells, vitamin E forms differentially inhibited leukotriene B(4) (LTB(4)) with an IC(50) of 5-20 μM for γ-tocopherol, δ-tocopherol (δT), and γ-tocotrienol, but a much higher IC(50) for α-tocopherol. 13'-Carboxychromanol, a long-chain metabolite of δT, suppressed neutrophil- and HL-60 cell-generated LTB(4) with an IC(50) of 4-7 μM and potently inhibited human recombinant 5-LOX activity with an IC(50) of 0.5-1 μM. In contrast, vitamin E forms had no effect on human 5-LOX activity but impaired ionophore-induced intracellular calcium increase and calcium influx as well as the subsequent signaling including ERK1/2 phosphorylation and 5-LOX translocation from cytosol to the nucleus, a key event for 5-LOX activation. Further investigation showed that δT suppressed cytosolic Ca(2+) increase and/or LTB(4) formation triggered by ionophores, sphingosine 1-phosphate, and lysophosphatidic acid but not by fMLP or thapsigargin, whereas 13'-carboxychromanol decreased cellular production of LTB(4) regardless of different stimuli, consistent with its strong inhibition of the 5-LOX activity. These observations suggest that δT does not likely affect fMLP receptor-mediated signaling or store depletion-induced calcium entry. Instead, we found that δT prevented ionophore-caused cytoplasmic membrane disruption, which may account for its blocking of calcium influx. These activities by vitamin E forms and long-chain carboxychromanol provide potential molecular bases for the differential anti-inflammatory effects of vitamin E forms in vivo.
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Affiliation(s)
- Ziying Jiang
- Department of Foods and Nutrition, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN 47907, USA
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36
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Abstract
Vitamin E is known as the most important lipid antioxidant and is widely used to prevent age-associated diseases. Despite increasing knowledge about human vitamin E metabolism, little is known to justify its widespread use. As meta-analyses revealed even harmful effects of high vitamin E doses, a profound understanding of vitamin E metabolism is mandatory. By recent advances in analytical methodology, new metabolites with distinct physicochemical and biological properties were discovered. This review covers current methods to analyze vitamin E metabolites in biological samples. Special emphasis is laid on analytical applications for the identification and quantification of metabolites with a modified hydroxychromanol ring or a truncated side chain.
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Affiliation(s)
- Marc Birringer
- Department of Human Nutrition, Institute of Nutrition, Friedrich Schiller University, Jena, Germany.
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37
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Gao D, Wei H, Guo GS, Lin JM. Microfluidic Cell Culture and Metabolism Detection with Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometer. Anal Chem 2010; 82:5679-85. [DOI: 10.1021/ac101370p] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Dan Gao
- The Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China, and State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Huibin Wei
- The Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China, and State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Guang-Sheng Guo
- The Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China, and State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China
| | - Jin-Ming Lin
- The Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China, and State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China
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Ju J, Picinich SC, Yang Z, Zhao Y, Suh N, Kong AN, Yang CS. Cancer-preventive activities of tocopherols and tocotrienols. Carcinogenesis 2010; 31:533-42. [PMID: 19748925 PMCID: PMC2860705 DOI: 10.1093/carcin/bgp205] [Citation(s) in RCA: 174] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2009] [Revised: 07/31/2009] [Accepted: 08/10/2009] [Indexed: 02/07/2023] Open
Abstract
The cancer-preventive activity of vitamin E has been studied. Whereas some epidemiological studies have suggested a protective effect of vitamin E against cancer formation, many large-scale intervention studies with alpha-tocopherol (usually large doses) have not demonstrated a cancer-preventive effect. Studies on alpha-tocopherol in animal models also have not demonstrated robust cancer prevention effects. One possible explanation for the lack of demonstrable cancer-preventive effects is that high doses of alpha-tocopherol decrease the blood and tissue levels of delta-tocopherols. It has been suggested that gamma-tocopherol, due to its strong anti-inflammatory and other activities, may be the more effective form of vitamin E in cancer prevention. Our recent results have demonstrated that a gamma-tocopherol-rich mixture of tocopherols inhibits colon, prostate, mammary and lung tumorigenesis in animal models, suggesting that this mixture may have a high potential for applications in the prevention of human cancer. In this review, we discuss biochemical properties of tocopherols, results of possible cancer-preventive effects in humans and animal models and possible mechanisms involved in the inhibition of carcinogenesis. Based on this information, we propose that a gamma-tocopherol-rich mixture of tocopherols is a very promising cancer-preventive agent and warrants extensive future research.
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Affiliation(s)
- Jihyeung Ju
- Department of Chemical Biology
- Department of Pharmaceutics
- Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
- Present address: Department of Food and Nutrition, College of Human Ecology, Chungbuk National University, 410 Sungbong-Ro, Heungduk-Gu, Cheongju 361-763, Korea
| | - Sonia C. Picinich
- Department of Chemical Biology
- Department of Pharmaceutics
- Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
| | - Zhihong Yang
- Department of Chemical Biology
- Department of Pharmaceutics
- Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
| | - Yang Zhao
- Department of Chemical Biology
- Department of Pharmaceutics
- Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
| | - Nanjoo Suh
- Department of Chemical Biology
- Department of Pharmaceutics
- Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
| | - Ah-Ng Kong
- Department of Chemical Biology
- Department of Pharmaceutics
- Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
| | - Chung S. Yang
- Department of Chemical Biology
- Department of Pharmaceutics
- Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
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Traber MG. Regulation of xenobiotic metabolism, the only signaling function of α-tocopherol? Mol Nutr Food Res 2010; 54:661-8. [DOI: 10.1002/mnfr.200900440] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Beattie JR, Schock BC. Identifying the spatial distribution of vitamin E, pulmonary surfactant and membrane lipids in cells and tissue by confocal Raman microscopy. Methods Mol Biol 2010; 579:513-35. [PMID: 19763493 DOI: 10.1007/978-1-60761-322-0_26] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2023]
Abstract
Every organ compromises of several different cell types. When studying the effects of a chosen compound within this organ or tissue uptake, localisation, metabolism, and the effect itself can be expected to differ between cells. Using the example of Vitamin E in pulmonary tissue we introduce confocal Raman Microscopy as a superior method to localise lipid-soluble compounds within tissues and cells. We describe the analyses of vitamin E, its oxidation products, and metabolites as well as pulmonary surfactant phospholipids in fixed lung tissue sections. Examples of main structural membrane lipids (PC, cholesterol) and an example of a lipid-signalling molecule (ceramide) are also included. Confocal Raman microscopy is a non-destructive optical method of analysing chemical and physical composition of solids, liquids, gases, gels, and solutions. The method is rich in information allowing discrimination of chemically similar molecules (including geometric isomers) and sensitive monitoring of subtle physical interactions. Additionally, Raman spectroscopy is relatively insensitive to water allowing the analysis of aqueous solutions and suspensions typical in biochemistry. In contrast, Raman spectroscopy is sensitive to non-polar molecules making it ideal for lipidomics research.
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Affiliation(s)
- J Renwick Beattie
- School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, UK
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41
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Yang WC, Regnier FE, Jiang Q, Adamec J. In vitro stable isotope labeling for discovery of novel metabolites by liquid chromatography-mass spectrometry: Confirmation of gamma-tocopherol metabolism in human A549 cell. J Chromatogr A 2009; 1217:667-75. [PMID: 20006340 DOI: 10.1016/j.chroma.2009.12.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2009] [Revised: 11/02/2009] [Accepted: 12/01/2009] [Indexed: 10/20/2022]
Abstract
A general approach for discovering novel catabolic metabolites from a parent biocompound was developed and validated on the metabolism of gamma-tocopherol in human A549 cell. The method is based on LC-MS analysis of in vitro stable isotope-labeled metabolites and assumes that a parent compound and its metabolites share a common functional group that can be derivatized by well-documented reagents. In this method, two equal aliquots of extracted metabolites are separately derivatized with isotope-coded (heavy) and non-isotope-coded (light) form of derivatizing reagent, mixed at 1:1 ratio and analyzed using LC-MS. The metabolites with common functional group are then easily recognized by determination of a chromatographically co-eluted pair of isotopomers (MS doublet peaks) with similar peak intensities and mass difference corresponding to the mass difference between heavy and light form of derivatization reagent. The feasibility of this approach was demonstrated and validated by the identification of products of gamma-tocopherol catabolism in human A549 cell culture media using N-methyl-nicotinic acid N-hydroxysuccinimide ester (C1-NANHS) and N-methyl-d3-nicotinic acid N-hydroxysuccinimide ester (C1-d3-NANHS) derivatizing reagent. Overall four gamma-tocopherol metabolites were identified including 9'-COOH, 11'-COOH, 13'-COOH and 13'-OH. In addition, the developed LC-MS method can also be used for the fast and sensitive quantitative analysis of gamma-tocopherol and other forms of vitamin E related compounds.
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Affiliation(s)
- Wen-Chu Yang
- Bindley Bioscience Center, Purdue University, 1203 W. State Street, West Lafayette, IN 47907, USA
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42
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Jiang Q, Moreland M, Ames BN, Yin X. A combination of aspirin and gamma-tocopherol is superior to that of aspirin and alpha-tocopherol in anti-inflammatory action and attenuation of aspirin-induced adverse effects. J Nutr Biochem 2009; 20:894-900. [PMID: 18993050 PMCID: PMC2799192 DOI: 10.1016/j.jnutbio.2008.08.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Revised: 08/08/2008] [Accepted: 08/13/2008] [Indexed: 11/29/2022]
Abstract
Nonsteroidal anti-inflammatory drugs such as aspirin are used for pain relief and chemoprevention against cancer, but frequently cause gastric mucosal injury. We examined whether combinations of aspirin and alpha-tocopherol (alphaT) or aspirin and gamma-tocopherol (gammaT), with alphaT and gammaT being the two major forms of vitamin E, are better anti-inflammatory agents than aspirin alone, and whether these combinations alleviate aspirin-associated side effects. In the carrageenan-induced air-pouch inflammation model in the rat, aspirin (150 mg/kg) or a combination of aspirin and gammaT (33 mg/kg) inhibited proinflammatory prostaglandin E(2) (PGE(2)) by 70% (P<.02) at the inflammation site 6 h after inflammation was initiated. However, at 18 h, only the combination decreased exudate volume (15%; P<.05) and showed modest inhibition of PGE(2) (40%; P<.07) and lactate dehydrogenase activity (30%; P=.07) in the fluid collected at the inflammation site. gammaT, but not alphaT, spared aspirin-induced reduction in food intake, partially reversed aspirin-depressed gastric PGE(2) and attenuated stomach lesions. Surprisingly, the combination of aspirin and alphaT (33 mg/kg) did not show more benefits than aspirin alone, but worsened gastric injury and food intake reduction. Our study demonstrated that a combination of aspirin and gammaT, but not a combination of aspirin and alphaT, has some advantage over aspirin alone in terms of anti-inflammatory effects and attenuation of aspirin-induced adverse effects. This combination may be useful in complementing aspirin in the treatment of chronic inflammatory conditions and cancer.
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Affiliation(s)
- Qing Jiang
- Department of Foods and Nutrition, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN 47907, USA.
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Mustacich DJ, Gohil K, Bruno RS, Yan M, Leonard SW, Ho E, Cross CE, Traber MG. Alpha-tocopherol modulates genes involved in hepatic xenobiotic pathways in mice. J Nutr Biochem 2009; 20:469-76. [PMID: 18789671 PMCID: PMC2720758 DOI: 10.1016/j.jnutbio.2008.05.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2008] [Revised: 05/02/2008] [Accepted: 05/08/2008] [Indexed: 12/11/2022]
Abstract
Hepatic proteins involved in xenobiotic pathways (Phases I, II and III) are responsible for the metabolism and disposition of endogenous and exogenous compounds including dietary phytochemicals. To test the hypothesis that elevated alpha-tocopherol intakes alter gene expression of hepatic xenobiotic pathways, mice were fed diets supplemented with either 1000 IU (+E) or 35 IU (E) all-rac-alpha-tocopheryl acetate for 4 months; liver RNA was isolated, and gene expression was determined using both whole genome microarray and real-time quantitative polymerase chain reaction analyses. Hepatic alpha-tocopherol (173+/-18 vs. 21+/-1 nmol/g, mean+/-S.E.) and its metabolite (2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman, 0.232+/-0.046 vs. 0.031+/-0.019 nmol/g) concentrations were approximately eightfold higher following the +E dietary treatment. In +E relative to E mice, gene expression of Phase I enzymes, P450 oxidoreductase and cytochrome P450 3a11 increased 1.6- and 4.0-fold, respectively; two Phase II genes, sulfotransferase 2a and glutathione S-transferase mu 3, increased 10.8- and 1.9-fold respectively, and a Phase III biliary transporter, Abcb1a, doubled. Thus, consumption of high-level dietary alpha-tocopherol simultaneously coordinated Phase I, II and III gene expression. These data demonstrate that increased hepatic alpha-tocopherol modulates its own concentrations through increasing xenobiotic metabolism, a process that may alter metabolism of other foreign compounds, such as therapeutic drugs and phytochemicals, in humans.
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Affiliation(s)
| | - Kishorchandra Gohil
- Department of Internal Medicine, Division of Pulmonary and Critical Care, Genome and Biomedical Sciences Facility, University of California, Davis, CA
| | | | - Michelle Yan
- Linus Pauling Institute, Oregon State University, Corvallis, OR
| | | | - Emily Ho
- Linus Pauling Institute, Oregon State University, Corvallis, OR
| | - Carroll E. Cross
- Department of Internal Medicine, Division of Pulmonary and Critical Care, Genome and Biomedical Sciences Facility, University of California, Davis, CA
| | - Maret G. Traber
- Linus Pauling Institute, Oregon State University, Corvallis, OR
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Freiser H, Jiang Q. Optimization of the enzymatic hydrolysis and analysis of plasma conjugated gamma-CEHC and sulfated long-chain carboxychromanols, metabolites of vitamin E. Anal Biochem 2009; 388:260-5. [PMID: 19250920 PMCID: PMC2712927 DOI: 10.1016/j.ab.2009.02.027] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2008] [Revised: 02/18/2009] [Accepted: 02/19/2009] [Indexed: 01/28/2023]
Abstract
Natural forms of vitamin E are metabolized by omega-hydroxylation and beta-oxidation of the hydrophobic side chain to generate urinary-excreted 2-(beta-carboxyethyl)-6-hydroxychroman (CEHC) and CEHC conjugates (sulfate, glucuronide, or glucoside). We recently showed that sulfated long-chain carboxychromanols, the conjugated intermediate beta-oxidation products, are formed from tocopherols and tocotrienols in human cells and in rats. CEHC conjugates have been quantified after being converted to its unconjugated counterpart by sulfatase/glucuronidase. Although the enzymatic hydrolysis is critical for appropriate quantification of conjugated CEHC, it is not clear whether brief incubation of the plasma with sulfatases/glucuronidases results in complete deconjugation of conjugated CEHC. Here we show that quantitative hydrolysis of the conjugated vitamin E metabolites in the plasma requires an extraction procedure using methanol/hexane (2 ml/5 ml) and an overnight sulfatase/glucuronidase hydrolysis. Using this procedure, we demonstrate that conjugated gamma-CEHC and some sulfated long-chain carboxychromanols are fully deconjugated. In contrast, direct enzymatic hydrolysis of the whole plasma underestimates the conjugated metabolites by at least threefold. This protocol may be also useful for the analysis of other conjugated phenolic compounds in complicated biological matrices such as plasma.
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Affiliation(s)
- Helene Freiser
- Department of Foods and Nutrition, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN 47907, USA.
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Freiser H, Jiang Q. Gamma-tocotrienol and gamma-tocopherol are primarily metabolized to conjugated 2-(beta-carboxyethyl)-6-hydroxy-2,7,8-trimethylchroman and sulfated long-chain carboxychromanols in rats. J Nutr 2009; 139:884-9. [PMID: 19297424 PMCID: PMC2714389 DOI: 10.3945/jn.108.103309] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The metabolism of gamma-tocotrienol (gamma-TE) and gamma-tocopherol (gamma-T) was investigated in human A549 cells and in rats. Similar to gamma-T, A549 cells metabolized gamma-TE to sulfated 9'-, 11'-, and 13'-carboxychromanol and their unconjugated counterparts. After 72-h incubation with the cells, 90% of long-chain carboxychromanols in the culture media from gamma-TE, but <45% from gamma-T, were in the sulfated form. The formation of these metabolites was further investigated in rats gavaged by gamma-TE at 10 or 50 mg/kg, gamma-T at 10 mg/kg, or tocopherol-stripped corn oil in controls. Six hours after a single dosing, the supplemented rats had increased plasma concentrations of 13'-carboxychromanol and sulfated 9'-, 11'-, 13'-carboxychromanol, whereas none of these metabolites were detectable in the controls. Sulfated 11'-carboxychromanol was the most abundant long-chain metabolite in gamma-TE-supplemented rats. Sulfatase/glucuronidase hydrolysis revealed for the first time that >88% 2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), the terminal beta-oxidation metabolite, was in the conjugated form in the plasma. In all groups, conjugated gamma-CEHC accounted for >75% of total metabolites, whereas free CEHC was a minor metabolite. At 10 mg/kg, the plasma concentrations of total metabolites from gamma-TE-supplemented rats were higher (P < 0.05) than those from gamma-T-fed rats. These results demonstrate that in rats, conjugation such as sulfation occurs parallel to beta-oxidation in the liver and is quantitatively important to vitamin E metabolism. Conjugated long-chain carboxychromanols may be novel excreted metabolites during supplementation. Our data also provide in vivo evidence that gamma-TE is more extensively metabolized than gamma-T.
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Affiliation(s)
- Helene Freiser
- Department of Foods and Nutrition, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN 47907, USA
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46
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Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. Proc Natl Acad Sci U S A 2008; 105:20464-9. [PMID: 19074288 DOI: 10.1073/pnas.0810962106] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Cyclooxygenase (COX-1/COX-2)-catalyzed eicosanoid formation plays a key role in inflammation-associated diseases. Natural forms of vitamin E are recently shown to be metabolized to long-chain carboxychromanols and their sulfated counterparts. Here we find that vitamin E forms differentially inhibit COX-2-catalyzed prostaglandin E(2) in IL-1beta-stimulated A549 cells without affecting COX-2 expression, showing the relative potency of gamma-tocotrienol approximately delta-tocopherol > gamma-tocopherol >> alpha- or beta-tocopherol. The cellular inhibition is partially diminished by sesamin, which blocks the metabolism of vitamin E, suggesting that their metabolites may be inhibitory. Consistently, conditioned media enriched with long-chain carboxychromanols, but not their sulfated counterparts or vitamin E, reduce COX-2 activity in COX-preinduced cells with 5 microM arachidonic acid as substrate. Under this condition, 9'- or 13'-carboxychromanol, the vitamin E metabolites that contain a chromanol linked with a 9- or 13-carbon-length carboxylated side chain, inhibits COX-2 with an IC(50) of 6 or 4 microM, respectively. But 13'-carboxychromanol inhibits purified COX-1 and COX-2 much more potently than shorter side-chain analogs or vitamin E forms by competitively inhibiting their cyclooxygenase activity with K(i) of 3.9 and 10.7 microM, respectively, without affecting the peroxidase activity. Computer simulation consistently indicates that 13'-carboxychromanol binds more strongly than 9'-carboxychromanol to the substrate-binding site of COX-1. Therefore, long-chain carboxychromanols, including 13'-carboxychromanol, are novel cyclooxygenase inhibitors, may serve as anti-inflammation and anticancer agents, and may contribute to the beneficial effects of certain forms of vitamin E.
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Li YJ, Luo SC, Lee YJ, Lin FJ, Cheng CC, Wein YS, Kuo YH, Huang CJ. Isolation and identification of alpha-CEHC sulfate in rat urine and an improved method for the determination of conjugated alpha-CEHC. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2008; 56:11105-11113. [PMID: 18991451 DOI: 10.1021/jf802459d] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
2,5,7,8-Tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC), the water-soluble metabolite of alpha-tocopherol (alpha-TOH) with a shortened side chain but an intact hydroxychroman structure, has been identified in human urine and are thought to be produced in significant amount at excess intake of alpha-TOH. In previous studies, CEHCs in biological specimens were measured by HPLC, GC-MS or LC-MS, preceded by a hydrolysis procedure using either enzyme or methanolic HCl. In an attempt to analyze alpha-CEHC in rat urine accordingly, we observed that enzyme hydrolysis was relatively inefficient in releasing alpha-CEHC compared to high concentrations of HCl. The HCl releasable alpha-CEHC conjugate was isolated and chemically identified as 6-O-sulfated alpha-CEHC (alpha-CEHC sulfate). Using the synthetic alpha-CEHC sulfate standard, it was found that sulfatase could not hydrolyze to a significant extent. On the other hand, pretreatment with HCl at 60 degrees C in the presence of ascorbate, followed by a one-step ether extraction, not only hydrolyzed the sulfate conjugate completely but also extracted alpha-CEHC with high recovery. The inclusion of ascorbate minimized the conversion of alpha-CEHC to alpha-tocopheronolactone in the HCl pretreatment. A complete procedure for the quantitative analysis of alpha-CEHC including HCl hydrolysis, ether extraction and reverse phase isocratic HPLC-ECD was thus established. In conclusion, alpha-CEHC sulfate was isolated and identified as the HCl-releasable conjugate of alpha-CEHC in rat urine. A rapid and sensitive method with high reproducibility for the determination of free, conjugated and total alpha-CEHC is then established.
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Affiliation(s)
- Yi-Jen Li
- Institute of Microbiology and Biochemistry, National Taiwan University, Taipei, Taiwan
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Wiser J, Alexis NE, Jiang Q, Wu W, Robinette C, Roubey R, Peden DB. In vivo gamma-tocopherol supplementation decreases systemic oxidative stress and cytokine responses of human monocytes in normal and asthmatic subjects. Free Radic Biol Med 2008; 45:40-9. [PMID: 18405673 PMCID: PMC2492672 DOI: 10.1016/j.freeradbiomed.2008.03.002] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2007] [Revised: 03/03/2008] [Accepted: 03/03/2008] [Indexed: 12/30/2022]
Abstract
We have recently reported that gamma-tocopherol (gammaT) reduces allergen- and zymosan-induced inflammation using rodent models. As an initial step in extending these observations to humans, we conducted an open-label, Phase I dosing study of two doses (one or two capsules daily for 1 week) of a gamma-tocopherol-rich preparation containing 623 mg of gamma-tocopherol, 61.1 mg of d-alpha-tocopherol, 11.1 mg of d-beta-tocopherol (11.1 mg), and 231 mg of d-sigma-tocopherol per capsule. Endpoints for this study include serum levels of 5-nitro-gamma-tocopherol, as a marker of oxidative stress, and changes in serum gamma-, alpha-, and delta-tocopherol and gamma-2'-carboxyethyl-6-hydroxychroman (CEHC) 6 and 24 h after the first dose and after 1 week of treatment. To assess the biological activity of this treatment, we obtained peripheral blood mononuclear cells at baseline and after 1 week of treatment with two capsules of a gamma-tocopherol-rich preparation/day and examined the inflammatory cytokine response of these cells in culture to ex vivo endotoxin/LPS (0.01 ng/ml) challenge. We also monitored a number of safety endpoints to examine how well this preparation is tolerated in eight normal volunteers (four allergic and four nonallergic) and eight allergic asthmatics. We further obtained human monocytes from a subset of these volunteers and treated them ex vivo with gammaT, alphaT, gamma-CEHC, and alpha-CEHC and assessed their actions on LPS-induced degradation of IkappaBalpha and JNK signaling and ROS generation. As detailed herein, this open-label study demonstrates that gamma-tocopherol-enriched supplementation decreased systemic oxidative stress, increased serum levels of gamma-tocopherol, and inhibited monocyte responses to LPS without any adverse health effects. Further, in vitro treatment of human monocytes with gamma-CEHC and alpha-CEHC inhibits ROS generation and LPS-induced degradation of IkappaB and JNK activation.
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Affiliation(s)
| | - Neil E. Alexis
- The Center for Environmental Medicine, Asthma and Lung Biology, the University of North Carolina School of Medicine, Chapel Hill, NC
| | - Qing Jiang
- Department of Foods and Nutrition, College of Consumer and Family Science, Purdue University, West Lafayette, IN
| | - Weidong Wu
- The Center for Environmental Medicine, Asthma and Lung Biology, the University of North Carolina School of Medicine, Chapel Hill, NC
| | - Carole Robinette
- The Center for Environmental Medicine, Asthma and Lung Biology, the University of North Carolina School of Medicine, Chapel Hill, NC
| | - Robert Roubey
- The Center for Environmental Medicine, Asthma and Lung Biology, the University of North Carolina School of Medicine, Chapel Hill, NC
| | - David B. Peden
- The Center for Environmental Medicine, Asthma and Lung Biology, the University of North Carolina School of Medicine, Chapel Hill, NC
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Abstract
All of the naturally occurring vitamin E forms, as well as those of synthetic all-rac-alpha-tocopherol, have relatively similar antioxidant properties, so why does the body prefer alpha-tocopherol as its unique form of vitamin E? We propose the hypothesis that all of the observations concerning the in vivo mechanism of action of alpha-tocopherol result from its role as a potent lipid-soluble antioxidant. The purpose of this review then is to describe the evidence for alpha-tocopherol's in vivo function and to make the claim that alpha-tocopherol's major vitamin function, if not only function, is that of a peroxyl radical scavenger. The importance of this function is to maintain the integrity of long-chain polyunsaturated fatty acids in the membranes of cells and thus maintain their bioactivity. That is to say that these bioactive lipids are important signaling molecules and that changes in their amounts, or in their loss due to oxidation, are the key cellular events that are responded to by cells. The various signaling pathways that have been described by others to be under alpha-tocopherol regulation appear rather to be dependent on the oxidative stress of the cell or tissue under question. Moreover, it seems unlikely that these pathways are specifically under the control of alpha-tocopherol given that various antioxidants other than alpha-tocopherol and various oxidative stressors can manipulate their responses. Thus, virtually all of the variation and scope of vitamin E's biological activity can be seen and understood in the light of protection of polyunsaturated fatty acids and the membrane qualities (fluidity, phase separation, and lipid domains) that polyunsaturated fatty acids bring about.
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Affiliation(s)
- Maret G Traber
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512, USA.
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