Oxidation of 20-hydroxyleukotriene B4 to 20-carboxyleukotriene B4 by human neutrophil microsomes. Role of aldehyde dehydrogenase and leukotriene B4 omega-hydroxylase (cytochrome P-450LTB omega) in leukotriene B4 omega-oxidation.
Leukotriene B4 (LTB4), a potent chemoattractant for leukocytes, is catabolized by human neutrophils via omega-oxidation. Neutrophil microsomes are known to oxidize 20-hydroxy-LTB4 (20-OH-LTB4) to its 20-oxo and 20-carboxy derivatives in the presence of NADPH. This activity has been ascribed to LTB4 omega-hydroxylase (cytochrome P-450LTB omega), a conclusion supported by our finding of the reversal of carbon monoxide inhibition by 450 nm light and by competitive inhibition studies. The oxidation of 20-oxo-LTB4 to 20-carboxy-LTB4 is also catalyzed by microsomes fortified with 1 mM NAD+, and this activity is not affected by cytochrome P-450LTB omega inhibitors. The evidence is compatible with involvement of a disulfiram-insensitive aldehyde dehydrogenase in this second oxidation pathway. Interaction of the two pathways is evidenced by facilitation of NADPH-dependent oxidation of 20-OH-LTB4 by the addition of NAD+. This synergism may be explained by removal of the aldehyde intermediate by the NAD(+)-dependent aldehyde dehydrogenase. Taken together with the finding that the NAD(+)-dependent activity is severalfold higher than the NADPH-dependent one, the dehydrogenase may be important in the oxidation of 20-OH-LTB4 to 20-carboxy-LTB4.
Sumimoto
H
H
Department of Biochemistry, Kyushu University School of Medicine, Fukuoka, Japan.
Minakami
S
S
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; D004357:Drug Synergism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D007975:Leukotriene B4 / Q000378:metabolism* / Q000031:analogs & derivatives; D008861:Microsomes / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009243:NAD / Q000494:pharmacology; D009249:NADP / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology* / Q000648:ultrastructure; D010084:Oxidation-Reduction; D010777:Photochemistry; D013053:Spectrophotometry
D006893:Hydroxyeicosatetraenoic Acids; D009243:NAD; D007975:Leukotriene B4; D009249:NADP; C031571:5,12,20-trihydroxy-6,8,10,14-eicosatetraenoic acid; C031911:20-carboxyleukotriene B4; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000072470:Cytochrome P450 Family 4; C040780:leukotriene B4 20-hydroxylase; D000444:Aldehyde Dehydrogenase