Tagari P, Foster A, Delorme D, Girard Y, Rokach J
Dept. of Pharmacology, Merck Frosst Canada Inc., Dorval, Québec.
Prostaglandins. 1989 Jun;37(6):629-40. doi: 10.1016/0090-6980(89)90101-9.
Four novel omega- and beta-oxidation (from the omega end) products of peptide leukotrienes, 20-hydroxy and 20-carboxy-LTE4, 18-carboxy-19, 20-dinor-LTE4 and 16-carboxy-17,18,19,20-tetranor-14,15-dihydro-LTE4 were prepared by total synthesis and used as standards for identification of biliary and urinary metabolites in the cynomolgus monkey. After intravenous administration 14, 15-[3H] leukotriene C4 (10 microCi kg-1) was partially metabolized in and rapidly cleared from the vascular circulation. This resulted, within 24 hours, in significant urinary excretion (14.8 +/- 2.1%, n = 4), consisting largely of material more polar than LTE4 (61% of urinary excretion) as shown by reverse phase HPLC. The polar fraction demonstrated two predominant metabolites which coeluted in several HPLC solvent systems with synthetic 16-carboxytetranordihydro-LTE4 (major component) and 18-carboxydinor-LTE4 (minor component). Characterization of the major polar metabolite as 16-carboxytetranordihydro-LTE4 was substantiated by conversion to its N-acetylated derivative. The absence of the 14, 15 double bond was confirmed by product analysis of oxidative ozonolysis. In a single animal, the bile duct was cannulated, with significant biliary excretion of radioactivity demonstrated over 4 hours (58.6% recovery). The predominant polar biliary metabolites were also identified as the 18-carboxydinor and 16-carboxytetranordihydro derivatives of LTE4 mentioned above. These data suggest that beta-oxidation products generated from the omega-carboxyl end of the 20-carboxy-LTE4 are important products of [3H] LTC4 metabolism in the monkey. Quantitation of these urinary metabolites may be an important index of in vivo leukotriene production.
通过全合成制备了四种新型的肽白三烯ω-和β-氧化（从ω端开始）产物，即20-羟基和20-羧基-LTE4、18-羧基-19,20-二去甲-LTE4以及16-羧基-17,18,19,20-四去甲-14,15-二氢-LTE4，并将其用作食蟹猴胆汁和尿液代谢物鉴定的标准品。静脉注射14,15-[³H]白三烯C4（10微居里/千克）后，其在血管循环中部分代谢并迅速清除。这导致在24小时内出现显著的尿液排泄（14.8±2.1%，n = 4），如反相高效液相色谱所示，排泄物质主要比LTE4极性更强（占尿液排泄量的61%）。极性部分显示出两种主要代谢物，它们在几种高效液相色谱溶剂系统中与合成的16-羧基四去甲二氢-LTE4（主要成分）和18-羧基二去甲-LTE4（次要成分）共洗脱。通过转化为其N-乙酰化衍生物证实了主要极性代谢物为16-羧基四去甲二氢-LTE4。通过氧化臭氧化产物分析证实了14,15双键的缺失。在一只动物中，胆管被插管，4小时内显示出显著的放射性胆汁排泄（回收率58.6%）。主要的极性胆汁代谢物也被鉴定为上述LTE4的18-羧基二去甲和16-羧基四去甲二氢衍生物。这些数据表明，20-羧基-LTE4的ω-羧基端产生的β-氧化产物是猴体内[³H] LTC4代谢的重要产物。对这些尿液代谢物的定量可能是体内白三烯生成的重要指标。
