Effects of tocopherols and 2,2'-carboxyethyl hydroxychromans on phorbol-ester-stimulated neutrophils.
Tocopherol vitamers [e.g., alpha-, gamma- and delta-tocopherol (alpha-TOC, gamma-TOC and delta-TOC, respectively)] and their water-soluble 2,2'-carboxyethyl hydroxychroman metabolites (e.g., alpha-, gamma- and delta-CEHC) all possess antioxidant properties. As a consequence, and similarly to other natural antioxidants, vitamin E compounds may be useful in preventing inflammatory and oxidative-stress-mediated diseases. In this study, we investigated the concentration-dependent effect of tocopherols and water-soluble metabolites on a key event in oxidative stress, for example, the oxidative burst in neutrophils. It was found that not only alpha-TOC but also gamma-TOC and delta-TOC as well as alpha-, gamma- and delta-CEHC at physiological concentrations inhibit superoxide anion (O2(*-)) production in phorbol-ester-stimulated neutrophils. This effect was mediated by the inhibition of the translocation and activation of protein kinase C (PKC) enzyme, which is the key event in the phorbol-ester signaling. Importantly, CEHCs were stronger inhibitors of PKC as compared with the vitamer precursors, and the gamma forms of both tocopherol and CEHC showed the highest inhibitory activities. Tocopherols, but not CEHCs, directly inhibit the fully activated nicotine-adenine-dinucleotide phosphate (NADPH) oxidase. However, none of the test compounds was able to directly scavenge O2(*-) when tested in a cell-free system. In conclusion, vitamin E compounds can control the neutrophil oxidative burst through the negative modulation of PKC-related signaling and NADPH oxidase activity. As an original finding, we observed that CEHC metabolites might contribute to regulate PKC activity in these cells. These results may have important implications in the anti-inflammatory and antioxidant role of vitamin E compounds.
First Department of Medicine, Health and Medical Science Centre, University of Debrecen, P.O. Box 19, H-4012 Debrecen, Hungary. vargazs@internal.med.unideb.hu
Zsuzsa
Z
Varga
Eszter
E
Kosaras
Edina
E
Komodi
Monika
M
Katko
Istvan
I
Karpati
Jozsef
J
Balla
Gyorgy
G
Paragh
Maria C
MC
Aisa
Francesco
F
Galli
D000975:Antioxidants / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity; D002478:Cells, Cultured; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D013997:Time Factors; D024505:Tocopherols / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014527:Uric Acid / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000975:Antioxidants; D002273:Carcinogens; D002839:Chromans; C483420:carboxyethyl-hydroxychroman; D013481:Superoxides; D014527:Uric Acid; D045304:Cytochromes c; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D024505:Tocopherols