The antioxidant and anti-inflammatory activities of tocopherols are independent of Nrf2 in mice.
The present study investigated the antioxidant and anti-inflammatory actions of tocopherols in mice and determined whether the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is involved in these activities. A mixture of tocopherols (γ-TmT) that is rich in γ-tocopherol was used. Nrf2 knockout (Nrf2 -/-) and wild-type mice were maintained on 0.03, 0.1, or 0.3% γ-TmT-enriched diet starting 2 weeks before the administration of dextran sulfate sodium (DSS) in drinking water (for 1 week, to induce colonic inflammation), until the termination of the experiment at 3 days after the DSS treatment. Dietary γ-TmT dose dependently lowered the levels of 8-oxo-deoxyguanosine, nitrotyrosine, inflammation index, and leukocyte infiltration in colon tissues, as well as 8-isoprostane and prostaglandin E2 in the serum, in both Nrf2 (-/-) and wild-type mice. No significant difference on the inhibitory actions of γ-TmT between the Nrf2 (-/-) and the wild-type mice was observed. The γ-TmT treatment significantly increased the serum levels of γ- and δ-tocopherols. Interestingly, the serum levels of tocopherol metabolites, specifically the γ- and δ-forms of carboxymethylbutyl hydroxychroman and carboxyethyl hydroxychroman, in Nrf2 (-/-) mice were significantly higher than those in wild-type mice. These findings suggest that the antioxidant and anti-inflammatory activities of γ-TmT in the colon are mostly due to the direct action of tocopherols in trapping reactive oxygen and nitrogen species, independent of the antioxidant enzymes and anti-inflammatory proteins that are regulated by Nrf2; however, Nrf2 knockout appears to affect the serum levels of tocopherol metabolites.
Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Guangxun
G
Li
Mao-Jung
MJ
Lee
Anna Ba
AB
Liu
Zhihong
Z
Yang
Yong
Y
Lin
Weichung Joe
WJ
Shih
Chung S
CS
Yang
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D060766:Drinking Water; D005260:Female; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D024504:gamma-Tocopherol / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D060766:Drinking Water; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C075750:8-epi-prostaglandin F2alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D024504:gamma-Tocopherol; D015237:Dinoprost; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; D003849:Deoxyguanosine