Effect of silybin on phorbol myristate actetate-induced protein kinase C translocation, NADPH oxidase activity and apoptosis in human neutrophils.
Mechanism of the action of silybin (1) and its derivatives (2-4), possessing different lipid solubility in PMA-stimulated neutrophils was evaluated. Silybin (1) inhibited the calcium, phosphatidylserine- and diacylglycerol-dependent protein kinase C translocation and the NADPH oxidase activity in PMA-stimulated neutrophils and resulted in decreased apoptosis. Furthermore, silybin (1) inhibited xanthine oxidase activity and hem-mediated oxidative degradation of low-density lipoprotein, as well. Its derivatives (2-4), possessing different lipid-solubility, affected all the studied parameters. The lipid solubility of silybin (1) was enhanced by methylation (5'7'4''trimethylsilybin: 2), whereas a decrease in lipid-solubility by acetylation of compound 2 (5',7,'4"-trimethylsilybin-acetate: 3) or all the hydroxyl groups of silybin (peracetyl-silybin: 4) attenuated the antioxidant capacity by decreasing the inhibition in PKC translocation and NADPH oxidase activation. All the derivatives of silybin (2-4) showed no inhibition in cell free systems; e.g. did not alter the xanthine oxidase activity and the hem-mediated oxidative degradation of LDL. In conclusion, the antioxidant activity of (1) might be due to its ability to inhibit PKC translocation and NADPH oxidase activation in PMA-stimulated neutrophils. The increase of lipid solubility of silybin (1) supports its penetration through cell membrane and enhances its inhibitory effects. This structural modification of (1) might have pharmacological consequences.
Varga
Zs
Z
Ist Department of Medicine, Medical and Health Science Centre, Debrecen, Hungary. vargazs@ibel.dote.hu
Ujhelyi
L
L
Kiss
A
A
Balla
J
J
Czompa
A
A
Antus
S
S
D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020944:Silybum marianum; D019255:NADPH Oxidases / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011493:Protein Kinase C / Q000187:drug effects; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
D000975:Antioxidants; D010936:Plant Extracts; D012838:Silymarin; D000077385:Silybin; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D011493:Protein Kinase C