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.