Oxidation of 20-hydroxyleukotriene B₄ to 20-carboxyleukotriene B₄ by human neutrophil microsomes. Role of aldehyde dehydrogenase and leukotriene B₄ ω-hydroxylase (cytochrome P-450(LTBω)) in leukotriene B₄ ω-oxidation

Leukotriene B₄ (LTB₄), a potent chemoattractant for leukocytes, is catabolized by human neutrophils via ω-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 ω-hydroxylase (cytochrome P-450(LTBω)), 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-450(LTBω) 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.