gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells

Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11494-9. doi: 10.1073/pnas.200357097.

Abstract

Cyclooxygenase-2 (COX-2)-catalyzed synthesis of prostaglandin E(2) (PGE(2)) plays a key role in inflammation and its associated diseases, such as cancer and vascular heart disease. Here we report that gamma-tocopherol (gammaT) reduced PGE(2) synthesis in both lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and IL-1beta-treated A549 human epithelial cells with an apparent IC(50) of 7.5 and 4 microM, respectively. The major metabolite of dietary gammaT, 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), also exhibited an inhibitory effect, with an IC(50) of approximately 30 microM in these cells. In contrast, alpha-tocopherol at 50 microM slightly reduced (25%) PGE(2) formation in macrophages, but had no effect in epithelial cells. The inhibitory effects of gammaT and gamma-CEHC stemmed from their inhibition of COX-2 activity, rather than affecting protein expression or substrate availability, and appeared to be independent of antioxidant activity. gamma-CEHC also inhibited PGE(2) synthesis when exposed for 1 h to COX-2-preinduced cells followed by the addition of arachidonic acid (AA), whereas under similar conditions, gammaT required an 8- to 24-h incubation period to cause the inhibition. The inhibitory potency of gammaT and gamma-CEHC was diminished by an increase in AA concentration, suggesting that they might compete with AA at the active site of COX-2. We also observed a moderate reduction of nitrite accumulation and suppression of inducible nitric oxide synthase expression by gammaT in lipopolysaccharide-treated macrophages. These findings indicate that gammaT and its major metabolite possess anti-inflammatory activity and that gammaT at physiological concentrations may be important in human disease prevention.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arachidonic Acids / metabolism
  • Cell Line
  • Cyclooxygenase Inhibitors / pharmacology*
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Epithelial Cells / metabolism
  • Humans
  • Interleukin-1 / pharmacology
  • Isomerism
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects*
  • Macrophages / enzymology
  • Macrophages / metabolism
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Nitrites / metabolism
  • Reactive Oxygen Species
  • Vitamin E / chemistry
  • Vitamin E / pharmacology*

Substances

  • Arachidonic Acids
  • Cyclooxygenase Inhibitors
  • Interleukin-1
  • Lipopolysaccharides
  • Nitrites
  • Reactive Oxygen Species
  • Vitamin E
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II