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We have shown that rat liver peroxisomes can chain-shorten prostaglandins to dinor- and tetranor-metabolites. In a recent in vivo study we could demonstrate that peroxisomes are of major importance for chain-shortening of prostaglandin F2 alpha in humans (1991, Diczfalusy et al. J. Clin. Invest. 88:978-984). This was shown by identifying the major urinary metabolites of radiolabeled prostaglandin F2 alpha given intravenously to a patient lacking functional peroxisomes (Zellweger syndrome). In the present investigation we have studied the peroxisomal chain-shortening of thromboxane B2, a compound structurally related to prostaglandins. Isolated rat liver peroxisomes oxidized thromboxane B2 to a chain-shortened metabolite in an NAD(+)-dependent reaction. The metabolite was identified as 9,11,15-trihydroxy-2,3,4,5-tetranor-thromb-13-enoic acid (tetranor-thromboxane B1). The urinary excretion of the major beta-oxidized metabolites of thromboxane B2 and prostacyclin was determined in three Zellweger patients and six age-matched controls. The controls excreted on an average 1.7 and 1.1 ng/mg creatinine of 2,3-dinorthromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha, respectively. In none of the three Zellweger patients could these dinor-metabolites be detected, i.e., the urinary excretion was less than 0.2 ng/mg creatinine. This shows that peroxisomes play an important role in the degradation of the carboxyl side chain of thromboxane B2 in vivo.

We have recently shown in vitro that the peroxisomal fraction of a rat liver homogenate has the highest capacity to beta-oxidize prostaglandins. In order to evaluate the relative importance of peroxisomes for this conversion also in vivo, we administered [3H]prostaglandin F2 alpha 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 C18 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 alpha metabolite from the Zellweger patient was identified as an omega-oxidized C20-prostaglandin, 9,11-dihydroxy-15-oxoprost-5-ene-1,20-dioic acid. The major urinary prostaglandin F2 alpha 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 beta-oxidation is of major importance for in vivo chain shortening of prostaglandins.

Infantile Zellweger syndrome belongs to the group of peroxisomal disorders that lack peroxisomes. Both trihydroxycoprostanic acid (THCA), the precursor to cholic acid, and dihydroxycoprostanic acid (DHCA), the precursor to chenodeoxycholic acid, accumulate in this disease. In previous studies, we have shown that liver peroxisomes are required for the conversion of THCA into cholic acid both in vitro and in vivo by measuring a defective conversion in infants with Zellweger syndrome. In our present study, the conversion of DHCA into chenodeoxycholic acid has been measured in an infant with Zellweger syndrome to evaluate the importance of liver peroxisomes for the formation of chenodeoxycholic acid. Coprostanic acidemia was present from the second day of life with high levels of THCA and only trace amounts of DHCA. The conversion of i.v. administered [3H]DHCA into chenodeoxycholic acid was only 7% compared with the 80% conversion in an analogous study in an adult. There was, however, a rapid incorporation of 3H into biliary THCA and, after a lag phase, the 3H was incorporated into biliary cholic acid. After 72 h, 15% of [3H]DHCA was converted to cholic acid. The pool size of DHCA was 1.2 mg/m2 and the pool size of both cholic acid and chenodeoxycholic acid was markedly reduced. The renal excretion of cholic acid was more efficient than that of the less polar chenodeoxycholic acid. More polar metabolites of DHCA and THCA are formed in alternative metabolic pathways facilitating renal excretion of these toxic intermediates. We conclude that liver peroxisomes are essential for a normal conversion of DHCA into chenodeoxycholic acid.

Bile acids are the end products of cholesterol metabolism, and represent the principal form in which cholesterol is eliminated from the body. Salts of bile acids are the major driving force to bile flow and are important to maintain insoluble constituents of bile in solution. The detergent properties of bile salts permit dispersion and absorption of lipophilic substances in the gut. This overview is intended to summarize the knowledge of the role of liver peroxisomes in bile acid formation.