Peroxisomal chain-shortening of thromboxane B2: evidence for impaired degradation of thromboxane B2 in Zellweger syndrome.
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.
Diczfalusy
U
U
Department of Clinical Chemistry, Huddinge University Hospital, Sweden.
Vesterqvist
O
O
Kase
B F
BF
Lund
E
E
Alexson
S E
SE
D000818:Animals; D011464:Epoprostenol / Q000652:urine; D066298:In Vitro Techniques; D008830:Microbodies / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D012016:Reference Values; D013929:Thromboxane B2 / Q000378:metabolism* / Q000652:urine; D015211:Zellweger Syndrome / Q000378:metabolism* / Q000652:urine
D013929:Thromboxane B2; D011464:Epoprostenol