Peroxisomal leukotriene degradation: biochemical and clinical implications

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.