title: In vivo gamma-tocopherol supplementation decreases systemic oxidative stress and cytokine responses of human monocytes in normal and asthmatic subjects.
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.
authors.affiliation: The Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7310, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wiser
authors.forename: Neil E
authors.initials: NE
authors.lastname: Alexis
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiang
authors.forename: Weidong
authors.initials: W
authors.lastname: Wu
authors.forename: Carole
authors.initials: C
authors.lastname: Robinette
authors.forename: Robert
authors.initials: R
authors.lastname: Roubey
authors.forename: David B
authors.initials: DB
authors.lastname: Peden
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001249:Asthma / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood* / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D006262:Health; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010703:Phorbol Esters / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D024504:gamma-Tocopherol / Q000097:blood / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D010703:Phorbol Esters; D017382:Reactive Oxygen Species; D024504:gamma-Tocopherol; D051550:I-kappa B Kinase