Inhibition of the arachidonic acid cascade by norathyriol via blockade of cyclooxygenase and lipoxygenase activity in neutrophils

  • Mei-Feng Hsu
  • Chun-Nan Lin
  • Min-Chi Lu
  • Jih-Pyang Wang
Original Article
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Abstract

Recent studies have suggested that dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LO) may be more beneficial in the treatment of inflammatory diseases in which platelet-leukocyte interaction dominates the underlying inflammatory process, than inhibitors of COX or LO alone. In this study, we examined oxygenated xanthones, shown previously to inhibit platelet and neutrophil activation, with respect to the potency of COX inhibition. 1,3,6,7-Tetrahydroxyxanthone (norathyriol) was the most potent. Norathyriol suppressed thromboxane B2 (TXB2) and leukotriene B4 (LTB4) formation in calcium ionophore (A23187)- and formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated rat neutrophils. Norathyriol was 3–4 times more active against LTB4 formation than against TXB2 formation (IC50 about 2.8 vs. 10 µM, respectively). Norathyriol also inhibited prostaglandin D2 (PGD2) formation in A23187-stimulated rat mast cells (IC50 3.0±1.2 µM) and in arachidonic acid (AA)-activated mast cell lysate. Norathyriol was a more effective inhibitor of 5-LO activity than of COX, as shown also by analyses of enzyme activities in a cell-free system, of COX and 5-LO metabolic capacity in neutrophils and of ex vivo TXB2 and LTB4 formation in A23187-stimulated neutrophils. Moreover, norathyriol inhibited COX-2 and 12-LO with IC50 values (19.6±1.5 and 1.2±0.1 µM, respectively) similar to those required for the inhibition of COX-1 and 5-LO (16.2±1.5 and 1.8±0.4 µM, respectively). Inhibition of 15-LO by norathyriol was slightly less active. Norathyriol had no effect on A23187-induced AA release from neutrophils and did not affect phospholipase A2 (PLA2) activity in a cell-free system. These results indicate that norathyriol inhibits the formation of PGs and LTs in neutrophils probably through direct blockade of COX and 5-LO activities. Norathyriol, a single molecule with multiple targets, might provide a potential therapeutic benefit in the treatment of inflammatory diseases.

Keywords

Neutrophils Norathyriol Cyclooxygenase Lipoxygenase Phospholipase A2 Arachidonic acid release 
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Notes

Acknowledgements

This work was supported by grants from the National Science Council (NSC92-2320-B-075A-001), Taichung Veterans General Hospital (TCVGH-927303C) and China Medical University (CMC83-010, CMC91-M-14 and CMU92-M-07), Taiwan, Republic of China.

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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Mei-Feng Hsu
    • 2
  • Chun-Nan Lin
    • 3
  • Min-Chi Lu
    • 4
  • Jih-Pyang Wang
    • 1
  1. 1.Department of Education and ResearchTaichung Veterans General HospitalTaichungRepublic of China
  2. 2.Department of BiochemistryChina Medical UniversityTaichungRepublic of China
  3. 3.College of PharmacyKaohsiung Medical UniversityKaohsiungRepublic of China
  4. 4.Department of Internal MedicineChung Shan Medical University HospitalTaichungRepublic of China

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