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Int. J. Mol. Sci. 2012, 13(7), 8882-8914; doi:10.3390/ijms13078882
Review

Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode

Received: 1 June 2012 / Revised: 3 July 2012 / Accepted: 6 July 2012 / Published: 17 July 2012
(This article belongs to the Special Issue Molecular Mechanisms of Organ-Specific Toxicity)
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Abstract

Ursodeoxycholic acid (UDCA) is a steroid bile acid approved for primary biliary cirrhosis (PBC). UDCA is reported to have “hepato-protective properties”. Yet, UDCA has “unanticipated” toxicity, pronounced by more than double number of deaths, and eligibility for liver transplantation compared to the control group in 28 mg/kg/day in primary sclerosing cholangitis, necessitating trial halt in North America. UDCA is associated with increase in hepatocellular carcinoma in PBC especially when it fails to achieve biochemical response (10 and 15 years incidence of 9% and 20% respectively). “Unanticipated” UDCA toxicity includes hepatitis, pruritus, cholangitis, ascites, vanishing bile duct syndrome, liver cell failure, death, severe watery diarrhea, pneumonia, dysuria, immune-suppression, mutagenic effects and withdrawal syndrome upon sudden halt. UDCA inhibits DNA repair, co-enzyme A, cyclic AMP, p53, phagocytosis, and inhibits induction of nitric oxide synthatase. It is genotoxic, exerts aneugenic activity, and arrests apoptosis even after cellular phosphatidylserine externalization. UDCA toxicity is related to its interference with drug detoxification, being hydrophilic and anti-apoptotic, has a long half-life, has transcriptional mutational abilities, down-regulates cellular functions, has a very narrow difference between the recommended (13 mg/kg/day) and toxic dose (28 mg/kg/day), and it typically transforms into lithocholic acid that induces DNA strand breakage, it is uniquely co-mutagenic, and promotes cell transformation. UDCA beyond PBC is unjustified.
Keywords: ursodeoxycholic acid; primary biliary cirrhosis; neonatal cholestasis; vanishing bile duct syndrome; toxicity; side effects; primary sclerosing cholangitis; PSC; extrahepatic biliary atresia; neonatal hepatitis ursodeoxycholic acid; primary biliary cirrhosis; neonatal cholestasis; vanishing bile duct syndrome; toxicity; side effects; primary sclerosing cholangitis; PSC; extrahepatic biliary atresia; neonatal hepatitis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Kotb, M.A. Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode. Int. J. Mol. Sci. 2012, 13, 8882-8914.

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