Ursodeoxycholic acid in cholestasis: linking action mechanisms to therapeutic applications

Abstract

UDCA (ursodeoxycholic acid) is the therapeutic agent most widely used for the treatment of cholestatic hepatopathies. Its use has expanded to other kinds of hepatic diseases, and even to extrahepatic ones. Such versatility is the result of its multiple mechanisms of action. UDCA stabilizes plasma membranes against cytolysis by tensioactive bile acids accumulated in cholestasis. UDCA also halts apoptosis by preventing the formation of mitochondrial pores, membrane recruitment of death receptors and endoplasmic-reticulum stress. In addition, UDCA induces changes in the expression of metabolizing enzymes and transporters that reduce bile acid cytotoxicity and improve renal excretion. Its capability to positively modulate ductular bile flow helps to preserve the integrity of bile ducts. UDCA also prevents the endocytic internalization of canalicular transporters, a common feature in cholestasis. Finally, UDCA has immunomodulatory properties that limit the exacerbated immunological response occurring in autoimmune cholestatic diseases by counteracting the overexpression of MHC antigens and perhaps by limiting the production of cytokines by immunocompetent cells. Owing to this multi-functionality, it is difficult to envisage a substitute for UDCA that combines as many hepatoprotective effects with such efficacy. We predict a long-lasting use of UDCA as the therapeutic agent of choice in cholestasis.

Ursodeoxycholic Acid and Its Taurine- or Glycine-Conjugated Species Reduce Colitogenic Dysbiosis and Equally Suppress Experimental Colitis in Mice

“…As we demonstrated no advantage of using either the taurine or glycine conjugate of UDCA, we suggest that UDCA could be a safe and readily available treatment option for IBD. This conclusion is further supported by the current therapeutic use of UDCA in cholestatic patients (65) and by its preventive effects on IBD-associated colorectal carcinogenesis (66)(67)(68).…”

Therapeutic and Chemopreventive Effects of Ursodeoxycholic Acid (UDCA): Potential Role in Patients with Barrett’s Esophagus

“…3 One way in which UDCA has been shown to protect cholangiocytes against bile acid toxicity in cholestasis is to positively modulate ductular bile flow by regulating hepatocellular transporters that are involved in bile formation. 4 A common feature in cholestasis is the endocytosis of canalicular export pumps that normally are involved in generating the flow of bile. The internalization of these export pumps therefore decreases bile flow and impairs biliary output of choleretic causing compounds.…”

“…The internalization of these export pumps therefore decreases bile flow and impairs biliary output of choleretic causing compounds. 4 UDCA has been shown to prevent the endocytic internalization of these canalicular transporters thus enhancing bile flow and preserving the integrity of cholangiocytes. 4 More recently studies suggest that stabilization of the "biliary HCO 3 − umbrella" may be a crucial mechanism of action of UDCA in cholestatic liver diseases.…”

“…4 UDCA has been shown to prevent the endocytic internalization of these canalicular transporters thus enhancing bile flow and preserving the integrity of cholangiocytes. 4 More recently studies suggest that stabilization of the "biliary HCO 3 − umbrella" may be a crucial mechanism of action of UDCA in cholestatic liver diseases. 2 The "biliary HCO 3 − umbrella" allows for the maintenance of an alkaline pH near the apical surface of the hepatocytes and cholangiocytes which prevents toxic, protonated, glycine-conjugated bile acids from penetrating the cell membrane.…”

Ursodeoxycholic acid in liver diseases

“…Do tych głównych fizjologicznych funkcji dochodzi wiele szczegółowych. Jak wynika z danych zamieszczonych w ostatnio opublikowanej pracy poglądowej [4], ze zbiorczej charakterystyki leku [5] oraz z innych źródeł, są trzy grupy aktywności UDCA: ochronna dla komórek układu wątrobowo-żółciowego, związana z przepływem żółci i immunomodulacyjna. Z jednej strony stabilizacja błon komórkowych uodpornia je na toksyczny wpływ KŻ zalegających w przebiegu cholestazy (dlatego UDCA bywa nazywany pompą detoksykacyjną), a z drugiejhamuje sygnały proapoptotyczne.…”