Antioxidant and cyclooxygenase-2-inhibiting activity of 4,4'-biphenol, 2,2'-biphenol and phenol.
The anthropogenic substance 4,4'-biphenol and its analogues are estrogenic and cytotoxic. It has been previously found that synthesized ortho-dimers of phenolic compounds possess potent antioxidative and anti-inflammatory activity. To clarify the relationships between radical-scavenging and anti-inflammatory activities, the radical-scavenging activities of 4,4'-biphenol, 2,2'-biphenol and phenol were investigated by using differential scanning calorimetry to measure the induction period for polymerization of methyl methacrylate initiated by thermal decomposition of 2,2'-azobisisobutyronitrile. We also investigated tThe inhibitory effects of these compounds on lipopolysaccharide (LPS)-stimulated cyclooxygenase-2 (COX-2) mRNA and protein expression and on binding of activator-protein-1 (AP-1) and nuclear factor kappa-B (NF-kappaB) to their respective consensus sequences were also investigated in RAW 264.7 cells. Furthermore, theoretical parameters such as phenolic-OH bond dissociation enthalpy (BDE) and ionization potential (IP(koopman)) were calculated at the density functional theory (DFT)/B3LYP levels. Cytotoxicity declined in the order 4,4'-biphenol > 2,2'-biphenol >> phenol. 2,2'-Biphenol, but not 4,4'-biphenol, showed inhibitory effects on LPS-stimulated COX-2 expression and on AP-1 and NF-kappaB binding to their consensus sequences at 1-10 muM. Expression of COX-2 in RAW cells was enhanced by 4,4'-biphenol plus LPS, possibly because of radical-mediated transformation of 4,4'-biphenol to the cytotoxic diphenylquinone, as judged by the stoichiometric factor (n value) of 3.429 and low IP(koopman) value of this biphenol. In contrast, the anti-inflammatory activity of 2,2'-biphenol may be the result of the formation of a dimer derived from oxidation of this compound, as suggested by its n value close to 1. Phenol showed anti-inflammatory activity but did not completely inhibit COX-2 expression, even at higher concentrations.
Murakami
Yukio
Y
Division of Oral Diagnosis, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry, Sakado-City, Saitama 350-0283, Japan. ymura@dent.meikai.ac.jp
Ishii
Hiroaki
H
Hoshina
Syuhei
S
Takada
Naoki
N
Ueki
Ayako
A
Tanaka
Shoji
S
Kadoma
Yoshinori
Y
Ito
Shigeru
S
Machino
Mamoru
M
Fujisawa
Seiichiro
S
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D008264:Macrophages / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D019800:Phenol / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*
D000975:Antioxidants; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D010636:Phenols; D019800:Phenol; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; C038764:2,2'-biphenol; C027439:4,4'-dihydroxybiphenyl