Fifty years with bile acids and steroids in health and disease

Abstract

Cholesterol and its metabolites, e.g., steroid hormones and bile acids, constitute a class of compounds of great biological importance. Their chemistry, biochemistry, and regulation in the body have been intensely studied for more than two centuries. The author has studied aspects of the biochemistry and clinical chemistry of steroids and bile acids for more than 50 years, and this paper, which is an extended version of the Schroepfer Medal Award lecture, reviews and discusses part of this work. Development and application of analytical methods based on chromatography and mass spectrometry (MS) have been a central part of many projects, aiming at detailed characterization and quantification of metabolic profiles of steroids and bile acids under different conditions. In present terminology, much of the work may be termed steroidomics and cholanoidomics. Topics discussed are bile acids in human bile and feces, bile acid production, bacterial dehydroxylation of bile acids and steroids during the enterohepatic circulation, profiles of steroid sulfates in plasma of humans and other primates, development of neutral and ion-exchanging lipophilic derivatives of Sephadex for sample preparation and group separation of steroid and bile acid conjugates, profiles of steroids and bile acids in human urine under different conditions, hydroxylation of bile acids in liver disease, effects of alcohol-induced redox changes on steroid synthesis and metabolism, alcohol-induced changes of bile acid biosynthesis, compartmentation of bile acid synthesis studied with 3H-labeled ethanol, formation and metabolism of sulfated metabolites of progesterone in human pregnancy, abnormal patterns of these in patients with intrahepatic cholestasis of pregnancy corrected by ursodeoxycholic acid, inherited and acquired defects of bile acid biosynthesis and their treatment, conjugation of bile acids and steroids with N-acetylglucosamine, sulfate-glucuronide double conjugates of hydroxycholesterols, extrahepatic 7alpha-hydroxylation and 3-dehydrogenation of hydroxycholesterols, and extrahepatic formation of C27 bile acids. The final part discusses analysis of free and sulfated steroids in brain tissue by capillary liquid chromatography-electrospray MS and suggests a need for reevaluation of the function of steroid sulfates in rat brain.

Bile salts of vertebrates: structural variation and possible evolutionary significance

“…We note the synthetic efforts of the laboratory of G. Salen ( 34 ) and T. Iida ( 35,36 ) who has developed new methods for synthesizing natural bile acids. We also acknowledge the extensive work on bile acid metabolism by Swedish workers in the school of bile acids launched by the late Sune Bergstrom ( 37 ) and continued by his pupils such as Sjövall ( 38 ) ( 22 ). Data in that review also give structural information for bile alcohols with chain lengths other than C 24 and C 27 .…”

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

“…The rewards of discovery are great for the patient, as bile acid replacement may be life-saving. Some of the early history is given in J. Sjövall's retrospective review ( 10 ).…”

Chemical Synthesis of Uncommon Natural Bile Acids: The 9α-Hydroxy Derivatives of Chenodeoxycholic and Lithocholic Acids

“…Attempted reductive cleavage of 8a and b with lithiumethylamine or with LiAlH 4 alone was unsuccessful; both the reactions did not proceed at all. However, when 8a and b were subjected to AlH 2 Cl, generated in situ from LiAlH 4 and AlCl 3 , 22) to afford the expected 3α,9α,24-triol (9a) and 3α,7α,9α,24-tetrol (9b) with good selectivity in fairly low isolated yields of 18 and 36%, respectively, after preparative high-performance liquid chromatography with a refractive index detector (HPLC-RI) chromatographic purification of the reaction products; the remaining compound recovered was the unreacted one (69% for 8a and 51% for 8b). AlH 2 Cl was therefore found to be effective for the regio-and stereoselec- tive hydroxylation of the sterically crowded epoxides.…”

“…Since some of the uncommon bile acids are present in the biliary and/or urinary bile salts of specific vertebrates or patients with hepatobiliary diseases, the bile acid profile can be used as a biomarker for clinical purposes, as well as for suggesting phylogenetic relationships. 4) Nuclear hydroxylation of bile acids in the liver of vertebrates is the result of CYP-mediated hydroxylation. If one accepts the concept of a default steroid nucleus with hydroxyl groups at C-3 and C-7, then further modifications can be considered as additions to the default structure.…”