Metabolism of prostaglandin F2 alpha in Zellweger syndrome. Peroxisomal beta-oxidation is a major importance for in vivo degradation of prostaglandins in humans.

Abstract

We have recently shown in vitro that the peroxisomal fraction of a rat liver homogenate has the highest capacity to (-oxidize prostaglandins. In order to evaluate the relative importance of peroxisomes for this conversion also in vivo, we administered [Hjprostaglandin F2. to an infant suffering from Zellweger syndrome, a congenital disorder characterized by the absence of intact peroxisomes. As a control, labeled compound was administered to two healthy volunteers. Urine was collected, fractionated on a SEP-PAK Cl3 cartridge, and subjected to reversed-phase high-performance liquid chromatography. The Zellweger patient was found to excrete prostaglandin metabolites considerably less polar than those of the control subjects. The major urinary metabolite in the control subjects was practically absent in the urine from the Zellweger patient. The major urinary prostaglandin F2. metabolite from the Zellweger patient was identified as an w-oxidized C"0-prostaglandin, 9,11-dihydroxy-15-oxoprost-5-ene-1,20-dioic acid. The major urinary prostaglandin Fu, metabolite from the control subjects had chromatographic properties of a tetranor (C16) prostaglandin, in accordance with earlier published data. The present results, in combination with our previous in vitro data, indicate that peroxisomal (i-oxidation is of major importance for in vivo chain shortening of prostaglandins. (J. Clin. Invest. 1991. 88:978-984.)

Impaired Degradation of Prostaglandins and Thromboxane in Zellweger Syndrome

“…In contrast to healthy children, none of these p-oxidized major urinary metabolites could be detected by GC-MSMS in urine of children with ZS. The complete absence of PGF-MUM and 2,3-dinor-TxB, in the urine from children with ZS is in line with other reports (18,19). Importantly, we found a new metabolite of the E PG in urine.…”

“…All these signals are increased by 54 D [CH=CH-(CH,),] with respect to the signals of the PFB-MO-TMS derivative of PGF-MUM. On the basis of the present data, we suggest that this metabolite is identical with 9,ll-dihydroxy-15-0x0-prost-5-ene-1,20-dioic acid, which is identical with that described by Diczfalusy et al (18).…”

“…In the present study, we also identified by GC-MS and GC-MSMS (Fig. 6) the new urinary metabolite of PGF,, which was recently discovered in urine of children with ZS (18). In the NICI mass spectrum of this metabolite, the most intense signal was observed at m/z 736 ([M-PFBI-).…”

“…In addition, using the same methodology, we identified a second metabolite as 9,ll-dihydroxy-15-0x0-prost-5-en-1,20-dioic acid in urine from children with ZS. This metabolite is probably identical with a new major metabolite of PGF, in urine of children with ZS described by Diczfalusy et al (18). Because no suitable internal standard is available, quantification of these novel metabolites by GC-MSMS was not possible.…”

Molecular Cloning and Characterization of Two Mouse Peroxisome Proliferator-activated Receptor α (PPARα)-regulated Peroxisomal Acyl-CoA Thioesterases

“…Peroxisomal ␤-oxidation of very long-and longchain CoA esters results in chain shortening of fatty acids, which may then be transported to the mitochondria as carnitine esters for further oxidation. ␤-Oxidation of other types of lipids such as prostanoids leads to chain shortening in the peroxisome for excretion as free carboxylic acids in the urine (3). Almost 30 years ago a group of compounds was identified that were shown to cause peroxisome proliferation in rodents; hence they were named peroxisome proliferators.…”