Inhibition of human neutrophil leukotriene B4 synthesis in essential fatty acid deficiency: role of leukotriene A hydrolase.
A female subject dependent on long-term total parenteral nutrition developed an aversion and noncompliance to a prescribed weekly lipid infusion designed to meet essential fatty acid (EFA) requirements. Fatty acids (FA) in the subject's plasma and isolated peripheral blood neutrophils were analyzed in search of biochemical evidence of EFA deficiency. Neutrophil 5-lipoxygenase metabolism was examined to assess the possible effects of EFA deficiency on neutrophil eicosanoid metabolism. EFA deficiency was confirmed by marked depletion of linoleic acid (18:2n-6) and accumulation of eicosatrienoic acid (ETrA; 20:3n-9) in plasma and neutrophil phospholipids. In the neutrophils, ETrA comprised 5.2% of phospholipid FA (normal reference values < 0.1%), and arachidonic acid (AA; 20:4n-6) comprised 8.6% of phospholipid FA (normal reference range 10-16%). When stimulated by A23187 in vitro on three separate occasions, the subject's neutrophils displayed impaired synthesis of leukotriene B4 (LTB4), but produced normal amounts of 5-hydroxy-eicosatetraenoic acid and all-trans isomers of LTB4 formed nonenzymatically from leukotriene A4 (LTA4). This pattern of synthesis suggested inhibition of LTA hydrolase and was also seen in neutrophils from healthy subjects by addition of exogenous ETrA in vitro. Comparative studies of the effects of ETrA and eicosapentaenoic acid (20:5n-3) on neutrophils in vitro suggested that ETrA is the more potent inhibitor. Accumulation of ETrA, rather than depletion of AA, appears principally responsible for the observed impairment of neutrophil LTB4 synthesis seen in this EFA-deficient subject.
Cleland
L G
LG
Rheumatology Unit, Royal Adelaide Hospital, Australia.
James
M J
MJ
Proudman
S M
SM
Neumann
M A
MA
Gibson
R A
RA
D000328:Adult; D000001:Calcimycin / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005228:Fatty Acids, Essential / Q000172:deficiency* / Q000276:immunology* / Q000494:pharmacology; D005260:Female; D006801:Humans; D006880:Hydroxy Acids / Q000378:metabolism; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010289:Parenteral Nutrition, Total
D005227:Fatty Acids; D005228:Fatty Acids, Essential; D006880:Hydroxy Acids; D007975:Leukotriene B4; D000001:Calcimycin; D015118:Eicosapentaenoic Acid; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase