Huber M, Müller J, Leier I, Jedlitschky G, Ball H A, Moore K P, Taylor G W, Williams R, Keppler D
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Federal Republic of Germany.
Eur J Biochem. 1990 Nov 26;194(1):309-15. doi: 10.1111/j.1432-1033.1990.tb19458.x.
The proinflammatory cysteinyl leukotrienes are inactivated in primates by (a) intravascular degradation, (b) hepatic and renal uptake from the blood circulation, (c) intracellular metabolism of leukotriene E4 (LTE4), and (d) biliary and renal excretion of LTC4 degradation products. We have analyzed cysteinyl leukotriene metabolites excreted into bile and urine of the monkey Macaca fascicularis and of man. In both species, hepatobiliary leukotriene elimination predominated over renal excretion. In a representative healthy human subject at least 25% of the administered radioactivity were recovered from bile and 20% from urine within 24 h. In monkey and man intravenous administration of 14,15-3H2-labeled LTC4 resulted in the biliary and urinary excretion of labeled LTE4, omega-hydroxy-LTE4, omega-carboxy-LTE4, omega-carboxy-dinor-LTE4, and omega-carboxy-tetranor-dihydro-LTE4. Small amounts of N-acetyl-LTE4 were detected in human urine only. Oxidative metabolism of LTE4 proceeded more rapidly in the monkey resulting in the formation of higher relative amounts of omega-oxidized leukotrienes in this species as compared to man. [3H]H2O amounted to less than 2% of the administered dose in monkey and human bile and urine samples. Incubation of isolated human hepatocytes with [3H2]LTC4, [3H2]LTD4, and [3H2]LTE4 showed that only [3H2]LTE4 underwent intracellular oxidative metabolism resulting in the formation of omega- and beta-oxidation products. N-Acetylated LTE4 derivatives were not detected as products formed by human hepatocytes. By a combination of reversed-phase high-performance liquid chromatography and radioimmunoassay, endogenous LTE4 and N-acetyl-LTE4 were detected in human urine in concentrations of 220 +/- 40 and 24 +/- 3 pM, corresponding to 12 +/- 1 and 1.5 +/- 0.2 nmol/mol creatinine, respectively (mean +/- SEM; n = 10). Endogenous LTD4 and LTE4 were detected in human bile (n = 3) in concentrations between 0.2-0.9 nM. Our results demonstrate that LTD4 and LTE4 are major LTC4 metabolites in human bile and/or urine and may serve as index metabolites for the measurement of endogenously generated cysteinyl leukotrienes. Moreover, omega-oxidation and subsequent beta-oxidation from the omega-end contribute to the metabolic degradation of LTE4 not only in monkey but also in man.
在灵长类动物中，促炎半胱氨酰白三烯通过以下方式失活：(a) 血管内降解；(b) 从血液循环中被肝脏和肾脏摄取；(c) 白三烯E4（LTE4）的细胞内代谢；以及(d) LTC4降解产物的胆汁和肾脏排泄。我们分析了排泄到猕猴和人类胆汁及尿液中的半胱氨酰白三烯代谢产物。在这两个物种中，肝胆系统对白三烯的清除作用比肾脏排泄更为显著。在一名有代表性的健康人类受试者中，在24小时内至少25%的给药放射性物质从胆汁中回收，20%从尿液中回收。在猕猴和人类中，静脉注射14,15-3H2标记的LTC4导致标记的LTE4、ω-羟基-LTE4、ω-羧基-LTE4、ω-羧基去甲-LTE4和ω-羧基四去甲二氢-LTE4从胆汁和尿液中排泄。仅在人类尿液中检测到少量的N-乙酰-LTE4。与人类相比，猕猴中LTE4的氧化代谢进行得更快，导致该物种中ω-氧化白三烯的相对生成量更高。在猕猴和人类的胆汁及尿液样本中，[3H]H2O占给药剂量的比例不到2%。用[3H2]LTC4、[3H2]LTD4和[3H2]LTE4孵育分离的人类肝细胞表明，只有[3H2]LTE4经历细胞内氧化代谢，产生ω-和β-氧化产物。未检测到N-乙酰化LTE4衍生物是人类肝细胞形成的产物。通过反相高效液相色谱法和放射免疫测定法相结合，在人类尿液中检测到内源性LTE4和N-乙酰-LTE4，其浓度分别为220±40和24±3 pM，分别相当于12±1和1.5±0.2 nmol/mol肌酐（平均值±标准误；n = 10）。在人类胆汁（n = 3）中检测到内源性LTD4和LTE4，浓度在0.2 - 0.9 nM之间。我们的结果表明，LTD4和LTE4是人类胆汁和/或尿液中的主要LTC4代谢产物，可作为测量内源性生成的半胱氨酰白三烯的指标性代谢产物。此外，ω-氧化以及随后从ω端开始的β-氧化不仅在猕猴中，而且在人类中都有助于LTE4的代谢降解。
