Abnormal mitochondrial structure and function have been documented in patients with Zellweger's syndrome (cerebrohepatorenal syndrome). In vitro studies have suggested that the formation of C24 bile acids (chenodeoxycholic acid and cholic acid) from C27 cholesterol requires mitochondrial oxidative clevage of the terminal three carbons of the side chain. Therefore, three patients with Zellweger's syndrome were examined for the presence of mitochondrial defects in bile acid synthesis. All three excreted excessive amounts of 3 alpha, 7 alpha-dihydroxy-5 beta-cholestan-26-oicacid, 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-oic acid, and 3 alpha, 7 alpha, 12 alpha, 24 xi-tetrahydroxy-5 beta-cholestan-26-oic acid (varanic acid), precursors of chenodeoxycholic acid and cholic acid that have undergone only partial side chain oxidation. These findings give added support to the role of mitochondrial oxidative side chain cleavage in the overall scheme of bile acid synthesis.

The purpose of this study was to determine

A B S T R A C T Studies were carried out in a family in which two children with cholestasis due to intrahepatic bile duct anomalies were shown to have increased amounts of the cholic acid precursor, 3a,7a, 12a-trihydroxy-5P-cholestan-26-oic acid (THCA). The metabolism of THCA was studied in one of these patients after an intravenous injection of [8H]THCA, and the cause of the increased amounts of THCA in this condition was found to be due to a metabolic defect in the conversion of this compound into cholic acid. A small amount of ['H]cholic acid was also identified after [3H]THCA administration, confirming that this metabolic defect was incomplete. Varanic acid (3a,7a,12a, 24t-tetrahydroxy-5fi-cholestan-26-oic acid), a metabolite of THCA, could not be identified in either of these patients. By assuming that this compound would be conjugated and excreted if the metabolic block occurred after the formation of varanic acid, the defect in these patients appears to be due to a deficiency of a 24-hydroxylating enzyme system required to convert THCA into varanic acid.This condition appears to be transmitted in an autosomal recessive fashion, because the two affected patients were of opposite sex, and neither a normal Presented in abstract form at the annual meeting of the American

No abstract

Lithocholic acid was present in the serum of three patients with, jaundice and, in smaller amounts, in two healthy adults. This bile acid occurs naturally in human feces but induces cirrhosis of the liver when fed to a wide variety of experimental animals. The finding of lithocholic acid in blood is of interest because of its possible role in injuring human liver.