Mutagenicity of Tocopheryl Quinones: Evolutionary Advantage of Selective Accumulation of Dietary a-Tocopherol

Cornwell, David G.; Williams, Marshall V.; Wani, Altaf A.; Wani, Gulzar; Shen, Elaine; Jones, Kenneth H.

doi:10.1207/s15327914nc431_13

Cited by 37 publications

(41 citation statements)

References 49 publications

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“…Interestingly, tocopherol congeners, which are precursors of arylating quinones, ␤-, ␥-, and ␦-T, are the major components of most vegetable oils, including corn (85%), soy (95%), f lax (99%), and borage (98%) (38). Animals, however, selectively retain the only phenolic antioxidant precursor in the vitamin E family that produces a nonarylating quinone, ␣-T, as Ϸ85% of tissue tocopherol (39,40). We showed in this work that arylating quinones have profound biologic effects, ER stress and cytotoxicity, in animal cells.…”

Section: Discussionmentioning

confidence: 72%

See 1 more Smart Citation

Mechanism of arylating quinone toxicity involving Michael adduct formation and induction of endoplasmic reticulum stress

Wang¹,

Thomas

Sachdeva

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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154

128

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Quinones permeate our biotic environment, contributing to both homeostasis and cytotoxicity. All quinones generate reactive oxygen species through redox cycling, while partially substituted quinones also undergo arylation (Michael adduct formation) yielding covalent bonds with nucleophiles such as cysteinyl thiols. In contrast to reactive oxygen species, the role of arylation in quinone cytotoxicity is not well understood. We found that the arylating quinones, including unsubstituted 1,4-benzoquinone (1,4-BzQ) and partially substituted vitamin E congener ␥-tocopherol quinone (␥-TQ), were cytotoxic, with ␥-TQ > 1,4-BzQ, whereas the fully substituted nonarylating vitamin E congener ␣-tocopherol quinone was not. In vitro, both arylating quinones formed Michael adducts with the thiol nucleophile N-acetylcysteine (NAC) at rates where 1,4-BzQ > ␥-TQ. In cultured cells, concurrent addition of NAC eliminated 1,4-BzQ caused toxicity, but preincubation was required for the same NAC detoxification effect on ␥-TQ. These data clearly established the role of arylation in quinone toxicity and revealed that arylating quinone structure affects cytotoxicity by governing detoxification through the rate of adduct formation. Furthermore, arylating quinones induced endoplasmic reticulum (ER) stress by activating the pancreatic ER kinase (PERK) signaling pathway including elF2␣, ATF4, and C͞EBP homologous protein (CHOP). Detoxification by NAC greatly attenuates CHOP induction in arylating quinone-treated cells, suggesting that ER stress is a cellular mechanism for arylating quinone cytotoxicity.quinone adduction ͉ thiol nucleophiles ͉ tocopherols ͉ CHOP ͉ cytotoxicity Q uinones and their phenolic precursors are present throughout the biotic environment and include polyphenols and tocopherols in the diet, drugs in medicine, environmental pollutants such as polycyclic aromatic hydrocarbons, and their metabolic products (1-8). They are involved in a wide variety of biological and chemical processes, including electron transport in animals and plants, photosynthesis, posttranslational modification of proteins, metabolism of cellular signaling molecules such as estrogens and catecholamines, metabolism of antioxidant and signaling tocopherol congeners (vitamin E), and the elimination of polycyclic aromatic hydrocarbons introduced by combustion processes associated with our petroleum-based chemical environment.Quinones are a class of highly reactive compounds. Although all quinones are redox cycling agents that generate reactive oxygen species (ROS), partially substituted quinones also function as arylating agents (1-3, 5, 6). The arylating quinones react with cellular nucleophiles such as thiols on cysteine residues of proteins, glutathione (GSH), and detoxifying agents such as N-acetylcysteine (NAC), forming covalently linked quinonethiol Michael adducts (1-3, 5, 6) that retain the ability to function as redox cycling agents (4, 9). In contrast to well studied ROS generation and consequent oxidative stress in living cells (1-3), the role o...

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Section: Discussionmentioning

confidence: 72%

“…The role of ER stress in the pathogenesis of various diseases has been revealed by many studies (21)(22)(23)(24)(25)41). Is it possible, as we have suggested (40), that the selection of the nonarylating quinone precursor ␣-T confers an evolutionary benefit in animal cells? Cell Lines and Culture.…”

Section: Discussionmentioning

confidence: 90%

Mechanism of arylating quinone toxicity involving Michael adduct formation and induction of endoplasmic reticulum stress

Wang¹,

Thomas

Sachdeva

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

154

128

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“…The biological activities have since been found to be dependent upon specific regulatory functions that serve to enrich the body with α-tocopherol and to increase excretion of other non-α-tocopherols that are present in the diet. Thus, there are mechanisms to accumulate α-tocopherol, likely because of its peroxyl scavenging antioxidant activity [20], as well as the propensity of non-α-tocopherols to form adducts [21]. …”

Section: Studies On the Biological Action Of Vitamin Ementioning

confidence: 99%

A History of Vitamin E

Niki¹,

2012

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Vitamin E (α-tocopherol) was discovered nearly 100 years ago because it was required to prevent fetal resorption in pregnant, vitamin E-deficient rats fed lard-containing diets that were easily oxidizable. The human diet contains eight different vitamin E-related molecules synthesized by plants; despite the fact that all of these molecules are peroxyl radical scavengers, the human body prefers α-tocopherol. The biological activity of vitamin E is highly dependent upon regulatory mechanisms that serve to retain α-tocopherol and excrete the non-α-tocopherol forms. This preference is dependent upon the combination of the function of α-tocopherol transfer protein (α-TTP) to enrich the plasma with α-tocopherol and the metabolism of non-α-tocopherols. α-TTP is critical for human health because mutations in this protein lead to severe vitamin E deficiency characterized by neurologic abnormalities, especially ataxia and eventually death if vitamin E is not provided in large quantities to overcome the lack of α-TTP. α-Tocopherol serves as a peroxyl radical scavenger that protects polyunsaturated fatty acids in membranes and lipoproteins. Although specific pathways and specific molecular targets have been sought in a variety of studies, the most likely explanation as to why humans require vitamin E is that it is a fat-soluble antioxidant.

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“…However, the biological response of this molecule (or its potential oxidation products) in comparison with a-tocopherol is yet not known. The in vivo preference for a-tocopherol in comparison with other natural occurring tocopherol analogues forms may also rest on the potential ''toxic'' activity of the analogues, for example, non-a-tocopherols may generate cytotoxic adducts (Cornwell et al 2002;Wang et al 2006). …”

Section: Experiments With Rat Liver Mitochondria and Cultured Cellsmentioning

confidence: 99%

α-Tocopherol incorporation in mitochondria and microsomes upon supranutritional vitamin E supplementation

Lauridsen

Jensen

2012

Genes Nutr

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Vitamin E (a-tocopherol) is a major lipid-soluble chain-breaking antioxidant in humans and mammals and plays an important role in normal development and physiology. The localization of a-tocopherol within the highly unsaturated phospholipid bilayer of cell membranes provides a means of controlling lipid oxidation at the initiation site. Mitochondria are the site for major oxidative processes and are important in fat oxidation and energy production, but a side effect is leakage of reactive oxygen species. Thus, incorporation of a-tocopherol and other antioxidants into mitochondria and other cellular compartments is important in order to maintain oxidative stability of the membranebound lipids and prevent damage from the reactive oxygen species. Many studies regarding mitochondrial disease and dysfunction have been performed in relation to deficiency of vitamin E and other antioxidants, whereas relatively sparse information is available regarding the eventual beneficial effects of antioxidant-enriched mitochondria in terms of health and function. This may be due to the fact that only little scientific information is available concerning the effect of supranutritional supplementation with antioxidants on their incorporation into mitochondria and other cellular membranes. The purpose of this review is therefore to briefly summarize experimental data performed with dietary vitamin E treatments in relation to the deposition of a-tocopherol in mitochondria and microsomes.

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Mutagenicity of Tocopheryl Quinones: Evolutionary Advantage of Selective Accumulation of Dietary a-Tocopherol

Cited by 37 publications

References 49 publications

Mechanism of arylating quinone toxicity involving Michael adduct formation and induction of endoplasmic reticulum stress

Mechanism of arylating quinone toxicity involving Michael adduct formation and induction of endoplasmic reticulum stress

A History of Vitamin E

α-Tocopherol incorporation in mitochondria and microsomes upon supranutritional vitamin E supplementation

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