NEONATAL CHOLESTASIS: IDENTIFICATION OF A METABOLIC ERROR IN BILE ACID SYNTHESIS

The metabolism of 3β-hydroxy-chol-5-en-24-oic acid, (3β-chol) a naturally occurring monohydroxy bile acid known to induce cholestasis, was studied in a 6 yr old female with cholestasis since birth. Initial evaluation revealed a total serum bile acid of 229 μmole/1 of which 10% was 3β-chol. Administration of 1.1μCi of (16, 17, 22, 23)-3H-3β-chol intravenously was followed by recovery of 50% in the urine within 72 hrs. Urinary bile acids were fractionated as their methyl esters by glycophase column chromatography following solvolysis and alkaline and enzymatic (β-glucuronidase) hydrolysis. In contrast to previous findings in the hamster and normal humans, less than 3% metabolism to chenodeoxycholic acid could be detected. The results indicate absence of a P-450 microsomal 7α-hydroxylase that normally produces 3β, 7α-dihydroxy-chol-5-en-24-oic acid, an intermediate in the "Yamasaki" pathway for chenodeoxycholic acid synthesis (Kulkharni & Javitt, Steroids, 40:581, 1982). We postulate that accumulation of 3β-chol and ita monohydroxy derivatives is pathogenetic in inducing cholestasis.