Bile Acid Synthesis: From Nature to the Chemical Modification and Synthesis and Their Applications as Drugs and Nutrients

Abstract

Bile acids (BAs) are amphiphilic molecules with 24 carbon atoms and consist of a hydrophobic and a rigid steroid nucleus, to which are attached a hydrophilic hydroxyl group and a flexible acidic aliphatic side chain. The steroidal core of BAs constitutes a saturated cyclopentanoperhydrophenanthrene skeleton, consisting of three six-membered (A, B, and C) and one five-membered ring (D). Primary BAs are produced in the hepatocytes, while secondary BAs are formed by modifying the primary BAs in the intestinal lumen, i.e., by the reactions of 7α-dehydroxylation and deconjugation of cholic acid (CA) and chenodeoxycholic acid (CDCA). The most important secondary BAs are deoxycholic acid (DCA) and lithocholic acid (LCA). The BAs realize their effects through nuclear farnesoid X receptors (FXRs) and membrane TGR5 receptors. It has been found that BAs are also associated with other receptors such as the vitamin D receptor (VDR), from which the most significant ligand is calcitriol, as well as with pregnane X receptor (PXR) and potentially with the constitutive androstane receptor (CAR), whose ligands are numerous, structurally different xenobiotics that show greater affinity to BAs. The BAs as therapeutic agents (drugs) have the potential to produce beneficial effects in cases of sexually transmitted diseases, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, gallstones, digestive tract diseases, cystic fibrosis, and cancer. Ursodeoxycholic acid (UDCA) was the only drug approved by the US Food and Drug Administration (FDA) for the treatment of PBC. In this paper, the different pathways of bile acid biosynthesis are explained as well as chemical modifications and the synthesis of different keto derivatives of BAs. Also, the effects of BAs on digestion of nutrients, their role as drugs, and, in particular, the emphasis on the hypoglycemic properties of 7α, 12α-dihydroxy−12–keto−5β-cholanic acid in the treatment of diabetes mellitus are examined in detail.

Isoxanthohumol, a hop-derived flavonoid, alters the metabolomics profile of mouse feces

“…We have also confirmed the changes in the fecal contents of bile acids. Bile acids are derivatives of steroids and are ubiquitously contained in the bile of vertebrates [42]. After being endogenously synthesized from cytochrome P450-mediated cholesterol metabolism in the liver and excreted into the duodenum, bile acids are mixed with phospholipids such as phosphatidylcholine and cholesterols to form micelles.…”

Was der (Viszeral-)Chirurg als neue Erkenntnisse über die Gallensäuren und deren Zusammenspiel mit dem Darmmikrobiom wissen sollte

“…In einem vielstufigen, von Enzymen der Zytochrom-P450-Familie katalysierten Prozess wird das Sterangerüst des Cholesterins hydroxyliert, hydriert und die Seitenkette am D-Ring oxidativ zu einem Fettsäurerest verkürzt (▶ Abb. 1, [5]). Das geschwindigkeitsbestimmende Schlüsselenzym der Gallensäurebildung ist die mikrosomale Cholesterin-7α-Hydroxylase (CYP7A1).…”

“…Mit der Identifizierung der Gallensäuren als Liganden des FXR ergaben sich neue medikamentöse Behandlungen mit modifizierten Gallensäuren. Ein Beispiel dafür ist die Obeticholsäure (Ocaliva ® ), ein CDCA-Derivat, zur Behandlung der primären biliären Cholangitis [5].…”

“…So wird die in der menschlichen Galle nur zu 3 % vorkommende Ursodesoxycholsäure (lat. ursus = Bär) zur Auflösung kleiner Gallensteine und als Apoptosehemmer zur Behandlung der primären biliären Cholangitis eingesetzt [5,60].…”

Pathways and Inborn Errors of Bile Acid Synthesis

“…The primary bile acids are synthesized from cholesterol with a complex series of reactions involving 17 different enzymes found in endoplasmic reticulum, mitochondria, cytoplasm and peroxisomes [17]. Recent studies have identified four major biosynthetic pathways of bile acids, named the Classic / Neutral pathway, the Alternative / Acidic pathway, the Yamasaki pathway and the 25-hydroxylation pathway [18,19] (Figure 1). Cholesterol is a C27-sterol and has a double bond at position C5 (cholest-5-en-3β-ol).…”