PMID- 15083266
OWN - NLM
STAT- MEDLINE
DCOM- 20041209
LR  - 20181113
IS  - 0028-1298 (Print)
IS  - 0028-1298 (Linking)
VI  - 369
IP  - 5
DP  - 2004 May
TI  - Inhibition of the arachidonic acid cascade by norathyriol via blockade of 
      cyclooxygenase and lipoxygenase activity in neutrophils.
PG  - 507-15
AB  - 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 B(2) (TXB(2)) and leukotriene B(4) (LTB(4)) formation in 
      calcium ionophore (A23187)- and formyl-methionyl-leucyl-phenylalanine 
      (fMLP)-stimulated rat neutrophils. Norathyriol was 3-4 times more active against 
      LTB(4) formation than against TXB(2) formation (IC(50) about 2.8 vs. 10 microM, 
      respectively). Norathyriol also inhibited prostaglandin D(2) (PGD(2)) formation 
      in A23187-stimulated rat mast cells (IC(50) 3.0+/-1.2 microM) 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 TXB(2) and LTB(4) formation in A23187-stimulated neutrophils. Moreover, 
      norathyriol inhibited COX-2 and 12-LO with IC(50) values (19.6+/-1.5 and 
      1.2+/-0.1 microM, respectively) similar to those required for the inhibition of 
      COX-1 and 5-LO (16.2+/-1.5 and 1.8+/-0.4 microM, 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 A(2) 
      (PLA(2)) 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.
FAU - Hsu, Mei-Feng
AU  - Hsu MF
AD  - Department of Biochemistry, China Medical University, Taichung, Taiwan 404, 
      Republic of China.
FAU - Lin, Chun-Nan
AU  - Lin CN
FAU - Lu, Min-Chi
AU  - Lu MC
FAU - Wang, Jih-Pyang
AU  - Wang JP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20040409
PL  - Germany
TA  - Naunyn Schmiedebergs Arch Pharmacol
JT  - Naunyn-Schmiedeberg's archives of pharmacology
JID - 0326264
RN  - 0 (Cyclooxygenase Inhibitors)
RN  - 0 (Xanthenes)
RN  - 27YG812J1I (Arachidonic Acid)
RN  - 3542-72-1 (norathyriol)
RN  - EC 1.13.11.12 (Lipoxygenase)
RN  - EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases)
RN  - RXY07S6CZ2 (Prostaglandin D2)
SB  - IM
MH  - Animals
MH  - Arachidonic Acid/*antagonists & inhibitors/metabolism
MH  - Cells, Cultured
MH  - Cyclooxygenase Inhibitors/*pharmacology
MH  - Lipoxygenase/*metabolism
MH  - Mast Cells/drug effects/metabolism
MH  - Mice
MH  - Neutrophils/*drug effects/enzymology/metabolism
MH  - Prostaglandin D2/biosynthesis
MH  - Prostaglandin-Endoperoxide Synthases/*metabolism
MH  - Rats
MH  - Xanthenes/*pharmacology
EDAT- 2004/04/15 05:00
MHDA- 2004/12/16 09:00
CRDT- 2004/04/15 05:00
PHST- 2003/11/24 00:00 [received]
PHST- 2004/02/21 00:00 [accepted]
PHST- 2004/04/15 05:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/04/15 05:00 [entrez]
AID - 10.1007/s00210-004-0922-9 [doi]
PST - ppublish
SO  - Naunyn Schmiedebergs Arch Pharmacol. 2004 May;369(5):507-15. doi: 
      10.1007/s00210-004-0922-9. Epub 2004 Apr 9.