Modulation of the activity of pro-inflammatory enzymes, COX-2 and iNOS, by chrysin derivatives

Heeyeong Cho, Cheol Won Yun, Woo Kyu Park, Jae Yang Kong, Kyoung Soon Kim, Youmie Park, Sanghyun Lee, Bak Kwang Kim

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

Chrysin, a natural flavone compound found in plants, has anti-inflammatory activity that has been previously explained in part by the suppression of promoter activities of pro-inflammatory enzymes, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Here we present evidence that several chrysin derivatives modulate the activities, as well as the expression, of COX-2 and iNOS enzymes. Nitrate production triggered by lipopolysaccharide (LPS) was suppressed by treatment of cultured Raw264.7 cells (mice macrophage/monocyte) with chrysin, 5-hydroxy-7-methoxyflavone (Ch-2), and 5,7-diacetylflavone (Ch-4). Interestingly, COX-2 enzyme was strongly inhibited by Ch-4 (IC50=2.7μM) but not by other derivatives. Furthermore, the inhibition of COX enzyme by Ch-4 was selective for COX-2 over COX-1. Three-dimensional modeling showed that Ch-4 fits well into the binding pocket of COX-2. The modeling suggested that a hydrogen bond exists between the oxygen of the ketone group at the 7-position of Ch-4 and the hydroxyl group of Tyr355. Docking Ch-4 into the V523I mutant of COX-2 indicated that Ile523 of COX-1 might contribute to the selectivity of COX-2 over COX-1. Ch-4 showed no effect on iNOS activity. Chrysin and Ch-2 weakly inhibited iNOS enzyme activity in the hemoglobin assay, but the underlying mechanisms of inhibition of iNOS by chrysin are not understood.

Original languageEnglish
Pages (from-to)37-43
Number of pages7
JournalPharmacological Research
Volume49
Issue number1
DOIs
Publication statusPublished - 2004 Jan

Keywords

  • 5,7-Diacetylflavone (Ch-4)
  • COX-2
  • Chrysin
  • Selectivity
  • iNOS

ASJC Scopus subject areas

  • Pharmacology

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