IMPAIRED DEGRADATION OF PROSTAGLANDINS AND THROMBOXANE IN ZELLWEGER-SYNDROME

Cyclooxygenase products are metabolized by omega-oxidation as well as beta-oxidation. Children with Zellweger syndrome (ZS) are characterized by peroxisome deficiency. To evaluate the role of peroxisomal beta-oxidation on cyclooxygenase metabolites, the degradation of endogenous prostanglandin (PG) E(2), prostacyclin, and thromboxane (Tx) A(2) was assessed in children with ZS (n = 7) and in healthy children (n = 7). PGE(2), prostacyclin, TxB(2), and their major urinary metabolites 7 alpha-hydroxy-5,11-dioxo-tetranor-prosta-1,16-dioic acid, 2,3-dinor-6-oxo-PGF(1 alpha), and 2,3-dinor-TxB(2), respectively, were measured in urine by gas chromatography-mass spectrometry/mass spectrometry. The median excretion of healthy children was 17.9 ng of 7 alpha-hydroxy-5,11-dioxo-tetranor-prosta-1,16-dioic acid/mg creatinine (interquartile range, 6.3 to 19.4 ng/mg), 0.38 ng of 2,3-dinor-6-oxo-PGF(1 alpha)/mg creatinine (interquartile range, 0.34 to 0.70 ng/mg), and 0.36 ng of 2,3-dinor-TxB(2)/mg creatinine (interquartile range, 0.14 to 0.54 ng/mg). In contrast, none of these metabolites could be detected in urine of children with ZS (p < 0.002). However, we identified in the urine of these children a new metabolite of PGE(2) as 11-hydroxy-9,15-dioxo-prost-5-en-1,20-dioic acid by gas chromatography-mass spectrometry, and we confirmed the presence of 9,11-dihydroxy-15-oxo-prost-5-en-1,20-dioic acid the main urinary metabolite of PGF(2 alpha) in ZS. Importantly, these two metabolites were only detectable in urine of children with ZS. Furthermore, we found highly elevated amounts of PGE(2), 6-oxo-PGF(1 alpha), and TxB(2) in urine from children with ZS compared with the amounts eliminated by healthy children (all parameters, p < 0.002). The present findings demonstrate an impaired degradation of PG and Tx in ZS on the level of beta-oxidation. These data strongly support the hypothesis that prostanoids are exclusively beta-oxidized by the peroxisomal pathway in vivo.