Re-evaluation of cyclooxygenase-2-inhibiting activity of vanillin and guaiacol in macrophages stimulated with lipopolysaccharide.
Phytophenols such as para-substituted 2-methoxyphenols exhibit antioxidant and anti-inflammatory activities, however, their biological activities are concentration-dependent, possibly due to their dual property of being both antioxidant and prooxidant. Eugenol (2-allyl-2-methoxyphenol) and isoeugenol (4-propenyl-2-methoxyphenol) did not reveal cyclooxygenase-2 (COX-2)-inhibiting activity in macrophages stimulated with lipopolysaccharide (LPS). In contrast, vanillin (2-hydroxy-3-methoxybenzaldehyde) and guaiacol (2-methoxyphenol), especially the former, inhibited LPS-stimulated nuclear factor kappa B (NF-kappaB) activation and cyclooxygenase (COX)-2 gene expression in cells of the RAW 264.7 murine macrophage cell line. Among the 2-methoxyphenols, vanillin demonstrated a potent anti-inflammatory activity. The phenolic O-H bond dissociation enthalpy (BDE) and molecular orbital energies (chemical hardness [eta], electronegativity [chi], and electrophilicity [omega]) were examined to clarify the mechanism responsible for inhibition of COX-2 expression. The BDE, chi, and omega values for vanillin were significantly higher than the corresponding values for the other 2-methoxyphenols. The anti-inflammatory activity of 2-methoxyphenols depended on the BDE and the phenol function was crucial for eliciting this activity. In addition, the anti-inflammatory activity depended on the chi and omega. These findings make vanillin attractive as a candidate therapeutic agent.
Murakami
Yukio
Y
Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan. ymura@dent.meikai.ac.jp
Hirata
Atsushi
A
Ito
Shigeru
S
Shoji
Masao
M
Tanaka
Shoji
S
Yasui
Toshikazu
T
Machino
Mamoru
M
Fujisawa
Seiichiro
S
D000818:Animals; D001547:Benzaldehydes / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D006139:Guaiacol / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation
D001547:Benzaldehydes; D052246:Cyclooxygenase 2 Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D006139:Guaiacol; C100058:vanillin; D051546:Cyclooxygenase 2