Journal of Lipid Research, Vol 34, 1107-1113, Copyright © 1993 by Lipid Research, Inc.
Peroxisomal chain-shortening of thromboxane B2: evidence for impaired degradation of thromboxane B2 in Zellweger syndrome
U Diczfalusy, O Vesterqvist, BF Kase, E Lund and SE Alexson
Department of Clinical Chemistry, Huddinge University Hospital, Sweden.
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.
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