Effect of structural modification at carbon atom 1 of leukotriene B 4 on the chemotactic and metabolic response of human neutrophils

Abstract

Human neutrophils biosynthesize the chemoattractant leukotriene B 4 (LTB 4) and metabolize LTB 4 to omega oxidative products 20-hydroxy-LTB 4 (20-OH-LTB 4) and 20-carboxy-LTB 4 (20-COOH-LTB 4). In this study, we prepared the C-1 methyl ester and N-methyl amide of LTB 4 and then examined neutrophil chemotaxis and metabolism of these derivatives of LTB 4. The results show that chemical modification of LTB 4 at carbon atom 1 dramatically affects metabolism of the lipid molecule. The free acid form of LTB 4 was taken up and metabolized by human neutrophils, while the methyl ester and N-methyl amide derivatives were poor substrates for omega oxidation. Although human neutrophils were poorly attracted to the methyl ester of LTB 4, the amide derivative was a complete agonist of the neutrophil chemotactic response and displayed an ED 50 for chemotaxis identical to that of LTB 4. Therefore, we concluded that omega oxidation is not a requirement for the neutrophil chemotactic response induced by LTB 4. These results also indicate that the N-methyl amide of LTB 4 may be a useful ligand for the elucidation of molecular mechanisms operative in neutrophil chemotaxis to LTB 4, since the C-1 derivative is not further metabolized. Two separate responses of human neutrophils are elicited by LTB 4, resulting in both cellular activation and generation of omega oxidation products. It appears that putative receptors on the neutrophils can distinguish between LTB 4 and certain derivatives that are structurally identical except for modification at the C-1 position (i.e., the methyl ester). LTB 4 derivatives modified at the C-1 position do not undergo conversion to omega oxidation products by the neutrophil.