PMID- 7929234
OWN - NLM
STAT- MEDLINE
DCOM- 19941117
LR  - 20210212
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 269
IP  - 41
DP  - 1994 Oct 14
TI  - Phorbol myristate acetate stimulates the formation of 
      5-oxo-6,8,11,14-eicosatetraenoic acid by human neutrophils by activating NADPH 
      oxidase.
PG  - 25373-80
AB  - We have shown previously that human neutrophil microsomes contain a highly 
      specific dehydrogenase which, in the presence of NADP+, converts 
      5S-hydroxy-6,8,11,14-eicosatetraenoic acid (5S-HETE) to its 5-oxo metabolite, 
      5-oxo-ETE, a potent agonist of these cells. However, intact neutrophils convert 
      5S-HETE principally to its omega-oxidation product, 5,20-diHETE, and to only 
      small amounts of 5-oxo-ETE. Phorbol myristate acetate (PMA) dramatically shifts 
      the metabolism of 5S-HETE by intact cells so that 5-oxo-ETE is the major 
      metabolite. The objective of this investigation was to determine the mechanism 
      for the stimulatory effect of PMA on 5-oxo-ETE formation. The possibility that 
      oxidants released in response to PMA nonenzymatically oxidized 5S-HETE was ruled 
      out, since PMA did not appreciably stimulate the formation of 5-oxo-ETE from 
      5R-HETE. On the other hand, inhibition of NADPH oxidase either by diphenylene 
      iodonium or by mild heating nearly completely prevented the stimulatory effect of 
      PMA on the formation of 5-oxo-ETE. The possibility that this effect was mediated 
      by superoxide seems unlikely, since it was still observed, although somewhat 
      attenuated, in the presence of superoxide dismutase. Moreover, superoxide 
      generated by another mechanism (xanthine/xanthine oxidase) did not appreciably 
      affect the formation of 5-oxo-ETE by neutrophils. However, phenazine 
      methosulfate, which can nonenzymatically convert NADPH to NADP+, mimicked the 
      effect of PMA on 5-oxo-ETE formation by intact neutrophils. It is concluded that 
      PMA acts by activating NADPH oxidase, resulting in conversion of NADPH to NADP+, 
      which enhances the formation of 5-oxo-ETE and reduces the formation of 
      5,20-diHETE. Serum-treated zymosan has an effect on the metabolism of 5S-HETE 
      similar to that of PMA in that it also stimulates the formation of 5-oxo-ETE and 
      inhibits that of 5,20-diHETE.
FAU - Powell, W S
AU  - Powell WS
AD  - Meakins-Christie Laboratories, Department of Medicine, McGill University, 
      Montreal, Quebec, Canada.
FAU - Gravelle, F
AU  - Gravelle F
FAU - Gravel, S
AU  - Gravel S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Arachidonic Acids)
RN  - 0 (Azides)
RN  - 0 (Hydroxyeicosatetraenoic Acids)
RN  - 0 (Prostaglandins B)
RN  - 107373-23-9 (5,20-dihydroxy-6,8,11,14-eicosatetraenoic acid)
RN  - 11062-77-4 (Superoxides)
RN  - 126432-17-5 (5-oxo-6,8,11,14-eicosatetraenoic acid)
RN  - 467RNW8T91 (5-hydroxy-6,8,11,14-eicosatetraenoic acid)
RN  - 53-59-8 (NADP)
RN  - 9010-72-4 (Zymosan)
RN  - AE28F7PNPL (Methionine)
RN  - BIU61O9T9T (prostaglandin B2)
RN  - EC 1.6.- (NADH, NADPH Oxidoreductases)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Arachidonic Acids/*biosynthesis
MH  - Azides/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activation
MH  - Humans
MH  - Hydroxyeicosatetraenoic Acids/analysis/*metabolism
MH  - Methionine/pharmacology
MH  - Microsomes/metabolism
MH  - Models, Biological
MH  - NADH, NADPH Oxidoreductases/*metabolism
MH  - NADP/metabolism
MH  - NADPH Oxidases
MH  - Neutrophils/drug effects/enzymology/*metabolism
MH  - Oxidation-Reduction
MH  - Prostaglandins B/analysis
MH  - Superoxides/metabolism
MH  - Tetradecanoylphorbol Acetate/*pharmacology
MH  - Zymosan/pharmacology
EDAT- 1994/10/14 00:00
MHDA- 1994/10/14 00:01
CRDT- 1994/10/14 00:00
PHST- 1994/10/14 00:00 [pubmed]
PHST- 1994/10/14 00:01 [medline]
PHST- 1994/10/14 00:00 [entrez]
AID - S0021-9258(18)47259-6 [pii]
PST - ppublish
SO  - J Biol Chem. 1994 Oct 14;269(41):25373-80.