MECHANISMS FOR FETAL EXCRETION OF HEPATOTOXIC MONO- HYDROXY BILE ACIDS

Abstract

Non-polar monohydroxy bile acids (MBA) either synthesized by the fetus as 3β Δ5 cholenoic acid (3β-OL) or transplacentally acquired as lithocholic acid(LC)are potentially hepatotoxic to the fetus. In order to establish whether MBA conjugates are secreted into bile by the fetus, bile acids in meconium from 15 fullterm infants were identified(before and after solvolysis)by thin layer chromatography and then by gas liquid chromatography-mass spectroscopy. 80-90% of the LC and all of the fetally synthesized 3β-OL were present as sulfated conjugates, suggesting that the fetus may detoxify MBA by sulfation and then concentrate the excreted bile acids in the intestine. Studies of sheep meconium demonstrated the presence of MBA including 3β-OL as the sulfate. Accordingly, the metabolism and biotransformation of 14C-LC or Taurolitho-cholic acid(TLC)was studied in 10 fetal sheep near term.Both bile acids were cleared rapidly by the fetus(t ½=11.0±5.4 min, AVG±SD); 23±4.6% of the dose was excreted transplacentally and recovered in maternal bile. The remainder was taken up by the fetal liver and secreted into the fetal bile. LC was conjugated 78.5±9.4% as TLC and 9.0±3.6%. as glycolithocholate(GLC); 10% of the TLC and 40% of the GLC were sulfated without further metabolism. No hydroxylation of LC sulfate occurred. Conclusion: 1)the fetal liver can take up, conjugate and secrete LC into the fetal intestine, 2) GLC is preferentially sulfated, and 3) two major mechanisms for MBA detoxification exist in the fetus: transplacental excretion and sulfation of conjugated derivatives.