Serhan C N, Maddox J F, Petasis N A, Akritopoulou-Zanze I, Papayianni A, Brady H R, Colgan S P, Madara J L
Department of Anesthesia, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Biochemistry. 1995 Nov 7;34(44):14609-15. doi: 10.1021/bi00044a041.
Lipoxins (LX) are bioactive eicosanoids that carry a tetraene structure and serve as regulators of inflammation, in part by inhibiting neutrophil migration and adhesion. Lipoxin A4 is rapidly regulated by conversion to inactive LX metabolites via local metabolism that involves dehydrogenation as the predominant route. Here, several LXA4 analogs were designed that resisted rapid conversion by both differentiated HL-60 cells and recombinant 15-hydroxyprostaglandin dehydrogenase, systems where native LXA4 is degraded within minutes. The rank order of conversion by recombinant dehydrogenase was LXA4 methyl ester > PGE2 approximately PGE2 methyl ester > LXA4 >>> the novel LXA4 analogs. In addition, 15(R/S)-methyl-LXA4, 15-cyclohexyl-LXA4, and 16-phenoxy-LXA4 proved to retain LXA4 bioactivity and inhibited neutrophil transmigration across polarized epithelial cell monolayers as well as adhesion to vascular endothelial cells. These results indicate that LXA4 analogs can be designed using these criteria to resist rapid transformation and to retain biological actions of native LXA4. Moreover, the results suggest that LXA4 stable analogs can be useful tools both in vitro and in vivo to evaluate LXA4 actions and therapeutic potential.
脂氧素（LX）是一类具有生物活性的类二十烷酸，其具有四烯结构，部分通过抑制中性粒细胞迁移和黏附来发挥炎症调节作用。脂氧素A4可通过局部代谢迅速转化为无活性的LX代谢产物，这种局部代谢以脱氢作为主要途径。在此，设计了几种脂氧素A4类似物，它们在分化的HL-60细胞和重组15-羟基前列腺素脱氢酶系统中均能抵抗快速转化，在这些系统中天然脂氧素A4会在数分钟内降解。重组脱氢酶催化转化的顺序为：脂氧素A4甲酯＞前列腺素E2≈前列腺素E2甲酯＞脂氧素A4 >>>新型脂氧素A4类似物。此外，15（R/S）-甲基-脂氧素A4、15-环己基-脂氧素A4和16-苯氧基-脂氧素A4被证明保留了脂氧素A4的生物活性，并且抑制中性粒细胞跨极化上皮细胞单层的迁移以及对血管内皮细胞的黏附。这些结果表明，可以依据这些标准设计脂氧素A4类似物，使其抵抗快速转化并保留天然脂氧素A4的生物学作用。此外，结果表明脂氧素A4稳定类似物在体外和体内均可作为评估脂氧素A4作用和治疗潜力的有用工具。
