Jedlitschky G, Mayatepek E, Keppler D
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Adv Enzyme Regul. 1993;33:181-94. doi: 10.1016/0065-2571(93)90017-8.
Degradation of the cysteinyl leukotrienes LTE4 and N-acetyl-LTE4, and of LTB4 by beta-oxidation from the omega-end has been recognized as an important pathway in the inactivation of these mediators. The contribution of peroxisomes to leukotriene degradation and inactivation was studied in isolated hepatocytes, in isolated liver peroxisomes, and in patients with inherited peroxisome deficiency. (1) Isolated hepatocytes from rats pretreated with the peroxisome proliferator clofibrate produced highly increased amounts of beta-oxidation products derived from omega-carboxy-LTB4 and omega-carboxy-N-acetyl-LTE4 as compared to normal hepatocytes. (2) Isolated peroxisomes purified from normal and clofibrate-treated liver produced omega-carboxy-dinor-LTB4 and omega-carboxy-tetranor-LTB3 when nucleotide cofactors, including CoA, ATP, NAD+, FAD, and NADPH, were added. beta-Oxidation of the cysteinyl leukotriene omega-carboxy-N-acetyl-LTE4 was observed only with isolated peroxisomes together with a microsome fraction providing an acyl-CoA synthetase activity. (3) Peroxisomal leukotriene-binding proteins were identified by photo-affinity labeling with omega-carboxy-[3H]leukotrienes and precipitation of labeled polypeptides with antibodies against enzymes of the peroxisomal beta-oxidation system. (4) Peroxisomal degradation of leukotrienes in humans was studied by analyses of endogenous leukotrienes and their catabolites in urine from patients with an inherited peroxisomal deficiency disorder (Zellweger syndrome) and healthy infant controls. Urinary LTE4, relative to creatinine, was increased 10-fold in the patients, whereas the beta-oxidation product omega-carboxy-tetranor-LTE3 was only detectable in healthy infants. In addition, LTB4 was exclusively detected in the urine of patients with peroxisome deficiency. The increased levels of biologically active, proinflammatory mediators might be of pathophysiological significance. In addition, the altered pattern of leukotriene metabolites in urine may be of diagnostic value. The measurements in these patients underline the essential role of peroxisomes in the catabolism and inactivation of leukotrienes in humans.
半胱氨酰白三烯LTE4和N - 乙酰 - LTE4以及LTB4通过从ω端进行β氧化而降解，这已被认为是这些介质失活的重要途径。在分离的肝细胞、分离的肝过氧化物酶体以及患有遗传性过氧化物酶体缺乏症的患者中，研究了过氧化物酶体对白三烯降解和失活的作用。（1）与正常肝细胞相比，用过氧化物酶体增殖剂氯贝丁酯预处理的大鼠分离肝细胞产生的源自ω - 羧基 - LTB4和ω - 羧基 - N - 乙酰 - LTE4的β氧化产物量大幅增加。（2）从正常和经氯贝丁酯处理的肝脏中纯化的分离过氧化物酶体在添加包括辅酶A、ATP、NAD +、FAD和NADPH在内的核苷酸辅因子时，会产生ω - 羧基 - 二降 - LTB4和ω - 羧基 - 四降 - LTB3。仅在分离的过氧化物酶体与提供酰基辅酶A合成酶活性的微粒体部分一起时，才观察到半胱氨酰白三烯ω - 羧基 - N - 乙酰 - LTE4的β氧化。（3）用过氧化物酶体β氧化系统的酶抗体沉淀标记多肽，通过用ω - 羧基 - [3H]白三烯进行光亲和标记来鉴定过氧化物酶体白三烯结合蛋白。（4）通过分析患有遗传性过氧化物酶体缺乏症（脑肝肾综合征）的患者和健康婴儿对照尿液中的内源性白三烯及其分解代谢产物，研究了人类过氧化物酶体对白三烯的降解作用。相对于肌酐，患者尿液中的LTE4增加了10倍，而β氧化产物ω - 羧基 - 四降 - LTE3仅在健康婴儿中可检测到。此外，仅在过氧化物酶体缺乏症患者的尿液中检测到LTB4。生物活性促炎介质水平的升高可能具有病理生理学意义。此外，尿液中白三烯代谢产物模式的改变可能具有诊断价值。对这些患者的测量结果强调了过氧化物酶体在人类白三烯分解代谢和失活中的重要作用。
