PEROXISOMAL CHAIN-SHORTENING OF THROMBOXANE-B(2) - EVIDENCE FOR IMPAIRED DEGRADATION OF THROMBOXANE-B(2) IN ZELLWEGER-SYNDROME

We have shown that rat liver peroxisomes can chain-shorten prostagland ins to dinor- and tetranor-metabolites. In a recent in vivo study we c ould demonstrate that peroxisomes are of major importance for chain-sh ortening of prostaglandin F2alpha in humans (1991. Diczfalusy et al. J . Clin. Invest. 88: 978-984). This was shown by identifying the major urinary metabolites of radiolabeled prostaglandin F2alpha given intrav enously to a patient lacking functional peroxisomes (Zellweger syndrom e). In the present investigation we have studied the peroxisomal chain -shortening of thromboxane B2, a compound structurally related to pros taglandins. Isolated rat liver peroxisomes oxidized thromboxane B2 to a chain-shortened metabolite in an NAD+-dependent reaction. The metabo lite was identified as ,11,15-trihydroxy-2,3,4,5-tetranor-thromb-13-en oic acid (tetranor-thromboxane B1). The urinary excretion of the major beta-oxidized metabolites of thromboxane B2 and prostacyclin was dete rmined in three Zellweger patients and six age-matched controls. The c ontrols excreted on an average 1.7 and 1.1 ng/mg creatinine of 2,3-din orthromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1alpha, respectiv ely. In none of the three Zellweger patients could these dinor-metabol ites 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.