Differential effects of norUDCA and UDCA in obstructive cholestasis in mice

Abstract

Background & AimsThe quest for effective drugs to treat cholangiopathies led to the development of norUDCA previously shown to have potent choleretic effects and to heal cholangiopathy in Abcb4 knockout (Abcb4−/−) mice. Its mother compound UDCA had detrimental effects in common bile duct ligated (CBDL) mice, presumably related to its choleretic effects. norUDCA choleretic effects may therefore raise safety concerns when used in cholangiopathies with biliary obstruction. We therefore aimed at comparing the effects of UDCA and norUDCA in clear-cut obstructive cholestasis.Methods0.5% UDCA- or norUDCA-fed wild type and Abcb4−/− mice were subjected to CBDL or selective bile duct ligation (SBDL) and compared to controls with regard to liver injury. Bile flow, bile composition, and biliary manometry were compared in UDCA-fed, norUDCA-fed and control mice. Toxicity of UDCA and norUDCA was compared in vitro.ResultsCompared to UDCA, liver injury in CBDL mice was significantly lower in almost all norUDCA groups. In SBDL mice, only UDCA induced bile infarcts in the ligated lobes, whereas norUDCA even ameliorated liver injury. In vitro, UDCA induced cellular ATP depletion and was significantly more toxic than norUDCA in HepG2 cells, mouse bile duct epithelial cells, and primary human hepatocytes.ConclusionsCompared to norUDCA, UDCA is significantly more toxic in CBDL mice. norUDCA, in contrast to UDCA, significantly ameliorates liver injury in SBDL mice. Our findings uncover profound differences in metabolism and therapeutic mechanisms of both bile acids with important clinical consequences.

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

“…norUDCA, the C 23 homolog of UDCA, is also in clinical trials for the treatment of primary sclerosing cholangitis. In the bile duct ligated mouse, its feeding causes less damage than UDCA feeding ( 469 ).…”

Sweroside ameliorates α-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses

“…Ursodeoxycholic acid is the only drug approved by the Food and Drug Administration for cholestasis treatment [20,21] . INT-747 has been investigated in a phase II trial for the treatment of PBC, liver fibrosis, and diet-induced atherosclerosis [22] .…”

Current research on the treatment of primary sclerosing cholangitis

“…Recently, Zenouzi et al (73) reported the longterm follow up on three cases originally described in 1996. All three patients were alive (22,27, and 25 years after initial presentation) and have shown disease progression, two of whom are on the liver transplantation list (both developed esophageal varices and one developed weight loss). The third patient underwent liver transplantation 22 years after initial presentation.…”

“…In a rodent model of cholestasis, the administration of norUDCA to Mdr2 knockout mice improved sclerosing cholangitis, possibly by altering the composition of the bile acid pool through displacing the toxic bile acids and increasing the hydrophilicity of the bile acids (21). In a more recent animal model of cholestasis, norUDCA significantly improved indices of liver injury in common bile ductligated (CBDL) mice when compared to UDCA (22). Taken together, these results suggest that norUDCA could be of potential benefit in patients with PSC.…”