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.
- bile acid
- cell death
- hepatocellular transporter
- ursodeoxycholic acid (UCDA)
Abbreviations: ABC, ATP-binding cassette; AE2/Ae2, anion exchanger 2; ASBT/Asbt, apical sodium-dependent bile salt transporter; BSEP/Bsep, bile salt export pump; CDCA, chenodeoxycholic acid; CLT, cytotoxic T-lymphocyte; cPKC, Ca2+-dependent protein kinase C; CYP3A4, cytochrome P450 family 3 subfamily A polypeptide 4; DISC, death-inducing signalling complex; E217G, oestradiol 17β-glucuronide; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; ERK, extracellular-signal regulated-kinase; FADD, Fas-associated death domain; FAK, focal adhesion kinase; FasL, Fas ligand; FXR, farnesoid X receptor; HTL, helper T-lymphocyte; ICAM-1, intercellular adhesion molecule-1; IFN-γ, interferon-γ; IL, interleukin; LDH, lactate dehydrogenase; LFA-1, lymphocyte function-associated antigen-1; MAPK, mitogen-activated protein kinase; MDR/Mdr, multidrug-resistance protein; MPT, mitochondria permeability transition; MPTP, MPT pore; MRP/Mrp, multidrug resistance-associated protein; NASH, non-alcoholic steatohepatitis; NF-κB, nuclear factor κB; NTCP/Ntcp, Na+/taurocholic acid co-transporting polypeptide; OATP1/Oatp1, organic anion-transporting polypeptide 1; PBC, primary biliary cirrhosis; PFIC, progressive familial intrahepatic cholestasis; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PSC, primary sclerosing cholangitis; PXR, pregnane X receptor; ROS, reactive oxygen species; SRF, serum-response factor; tBid, truncated Bid; TCF, T-cell factor; TGF-β1, transforming growth factor-β1; TLCA, taurolithocholic acid; TNF, tumour necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; TRAILR-2, TRAIL receptor-2; TUDCA, tauroursodeoxycholic acid; UDCA, ursodeoxycholic acid; UGT1A1, UDP glucuronosyltransferase 1 family polypeptide A1
- © The Authors Journal compilation © 2011 Biochemical Society