Impaired Degradation of Prostaglandins and Thromboxane in Zellweger Syndrome

Abstract

Cyclooxygenase products are metabolized by o-oxidation as well as p-oxidation. Children with Zellweger syndrome (ZS) are characterized by peroxisome deficiency. To evaluate the role of peroxisomal p-oxidation on cyclooxygenase metabolites, the degradation of endogenous prostanglandin (PC) E,, prostacyclin, and thromboxane (Tx) A, was assessed in children with ZS (n = 7) and in healthy children (n = 7). PGE,, prostacyclin, TxB,, and their major urinary metabolites 7a-hydroxy-5,ll-dioxotetranor-prosta-1,16-dioic acid, 2,3-dinor-6-0x0-PGF,,, and 2,3-dinor-TxB,, respectively, were measured in urine by gas chromatography-mass spectrometry/mass spectrometry. The median excretion of healthy children was 17.9 ng of 7a-hydroxy-5,ll-dioxo-tetranor-prosta-l,l6-dioic acidlmg creatinine (interquartile range, 6.3 to 19.4 nglmg), 0.38 ng of 2,3-dinor-6-0xo-PGF,~/rng creatinine (interquartile range, 0.34 to 0.70 nglmg), and 0.36 ng of 2,3-dinor-TxB2/mg creatinine (interquartile range, 0.14 to 0.54 nglmg). 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, 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,ll-dihydroxy-150x0-prost-5-en-1,20-dioic acid the main urinary metabolite of PGF, in ZS. Importantly, these two metabolites were only detectable in urine of children with ZS. Furthermore, we found highly elevated amounts of PGE,, 6-0x0-PGF,,, and TxB, 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 P-oxidation. These data strongly support the hypothesis that prostanoids are exclusively P-oxidized by the peroxisomal pathway in vivo. (Pediatr Res 36: 449-455, 1994) Abbreviations PC, prostaglandin Tx, thromboxane LT, leukotriene PGE-MUM, prostaglandin E major urinary metabolite (7a-hydroxy-5,11-dioxo-tetranor-prosta-l,l6-dioic acid) PGF-MUM, prostaglandin F major urinary metabolite (5a,7a-dihydroxy-ll-oxo-tetranor-prosta-1,16-dioic acid) RP-HPLC, reversed-phase high-performance liquid chromatography GC-MS, gas chromatography-mass spectrometry CC-MSIMS, gas chromatography-mass spectrometry/mass spectrometry PFB, pentafluorobenzyl CAD, collisionally activated dissociation NICI, negative-ion chemical ionization

Severe hyperprostaglandin E syndrome with hyperthyroidism — studies of pathogenetic mechanisms

“…The significantly increased urinary PGE-M concentration, which was greater than measured in previous patients (Leonhardt et al 1992), also indicates the presence of ]3-and co-oxidation. In children with Zellweger syndrome, a disorder characterized by peroxisome deficiency, impaired degradation of prostaglandins with no excretion of PGE-M has been reported (Fauler et al 1994). The clinical symptoms of our patient --increased heat production, failure to gain weight, irritability --resembled those found in Luft disease, a mitochondrial disorder with loose coupling of oxidative phosphorylation (Luft et al 1962).…”

Simultaneous Solid Phase Extraction, Derivatization, and Gas Chromatographic Mass Spectrometric Quantification of Thromboxane and Prostacyclin Metabolites, Prostaglandins, and Isoprostanes in Urine

“…GC/MS methods are best suited and have been described for the index metabolites of prostacyclin − and thromboxane − formation, classical prostaglandins, and isoprostanes. − These methods usually require a separate, extensive sample workup for a single prostaglandin metabolite. A few methods have been tried to accomplish the analysis of more than one prostanoid or their metabolites, − but these usually include time-consuming chromatographic steps requiring the splitting of the sample or the use of tandem mass spectrometry (GC/MS/MS). The aim of this study was to speed up and unify in one vial the sample purification and derivatization for the index metabolites from different arachidonic acid pathways and quantify them in a single GC/MS run.…”