Tocopherol Metabolism Using Thermochemolysis: Chemical and Biological Properties of γ-Tocopherol, γ-Carboxyethyl-hydroxychroman, and Their Quinones
- 13 May 2005
- journal article
- Published by American Chemical Society (ACS) in Chemical Research in Toxicology
- Vol. 18 (6) , 1018-1025
- https://doi.org/10.1021/tx0496441
Abstract
Identification and quantitative estimation of quinone metabolites of γ-tocopherol (γ-T) and its derivative γ-carboxyethyl hydroxychroman (γ-CEHC) are complicated by their functions as arylating electrophiles. We hypothesize that their biological properties are expressed through arylating quinone electrophile addition (Michael reaction) with thiol nucleophiles in cells and tissues. Glutathione (GSH) reacted with γ-tocopheryl quinone (γ-TQ) to form the hydroquinone adduct, which was identified by electrospray time-of-flight MS (ESI-TOF-MS). Tetramethylammonium hydroxide (TMAH) thermochemolysis reduced and methylated quinones and cleaved and methylated thioether adducts. These relatively nonpolar derivatives were readily separated by GC and identified by MS fragmentation patterns. γ-CEHC was synthesized and oxidized to a product identified as the quinone lactone (γ-CEHC-QL). TMAH methylated both γ-CEHC-QL and its GSH adduct without opening the lactone ring, and these products were separated by GC and identified by MS fragmentation patterns. γ-CEHC-QL reacted with both the cysteinyl enzyme papain and fetal bovine serum, and TMAH thermochemolysis showed that each product mixture contained unreacted precursor and thioether adduct. Cytotoxicities of phenolic precursors, γ-T and γ-CEHC, and their quinones, γ-TQ and γ-CEHC-QL, respectively, were compared in COS1, NT2, 3T3, and N2a cell lines. Phenolic precursor γ-T had a small effect only with NT2 and 3T3 cells while γ-CEHC had no effect in any cell line. Arylating quinones were highly cytotoxic in all cell lines with γ-TQ showing a significantly greater cytotoxicity than γ-CEHC-QL. These data are consistent with our arylating electrophile hypothesis as an explanation for some biological activities of Ts through their quinone metabolites.Keywords
This publication has 13 references indexed in Scilit:
- The Cytotoxicity of Vitamin E Is Both Vitamer- and Cell-Specific and Involves a Selectable TraitJournal of Nutrition, 2004
- The effect of α- and γ-tocopherol and their carboxyethyl hydroxychroman metabolites on prostate cancer cell proliferationArchives of Biochemistry and Biophysics, 2004
- New perspectives on vitamin E: γ-tocopherol and carboxyethylhydroxychroman metabolites in biology and medicinePublished by Elsevier ,2003
- γ‐Tocopherol, but not α‐tocopherol, decreases proinflammatory eicosanoids and inflammation damage in ratsThe FASEB Journal, 2003
- γ‐Tocopherol inhibits human cancer cell cycle progression and cell proliferation by down‐regulation of cyclinsThe FASEB Journal, 2002
- Quantification of the α- and γ-Tocopherol Metabolites 2,5,7,8-Tetramethyl-2-(2′-carboxyethyl)-6-hydroxychroman and 2,7,8-Trimethyl-2-(2′-carboxyethyl)-6-hydroxychroman in Human SerumAnalytical Biochemistry, 1999
- Urinary excretion of 2,7,8-trimethyl-2-(β-carboxyethyl)-6-hydroxychroman is a major route of elimination of γ-tocopherol in humansJournal of Lipid Research, 1999
- Molecular mechanisms of quinone cytotoxicityChemico-Biological Interactions, 1991
- Deficiency of vitamin E in the alveolar fluid of cigarette smokers. Influence on alveolar macrophage cytotoxicity.Journal of Clinical Investigation, 1986
- Alpha- and Gamma-Tocopherol in the Rat: in vitro and in vivo Tissue Uptake and MetabolismJournal of Nutrition, 1971