Molecular mechanisms of ursodeoxycholic acid toxicity & side effects: ursodeoxycholic acid freezes regeneration & induces hibernation mode.
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.
['Kotb|Magd A|MA|']
D000818:Animals D006528:Carcinoma, Hepatocellular D002756:Cholagogues and Choleretics D003065:Coenzyme A D000242:Cyclic AMP D004260:DNA Repair D006801:Humans D008105:Liver Cirrhosis, Biliary D008113:Liver Neoplasms D008115:Liver Regeneration D016159:Tumor Suppressor Protein p53 D014580:Ursodeoxycholic Acid
ursodeoxycholic acid toxicity side effects primary biliary cirrhosis primary sclerosing cholangitis vanishing bile duct syndrome PSC extrahepatic biliary atresia neonatal cholestasis neonatal hepatitis