S-adenosyl-L-methionine (SAMe) halts the autoimmune response in patients with primary biliary cholangitis (PBC) via antioxidant and S-glutathionylation processes in cholangiocytes

Biochim Biophys Acta Mol Basis Dis. 2020 Nov 1;1866(11):165895. doi: 10.1016/j.bbadis.2020.165895. Epub 2020 Jul 16.


S-adenosyl-L-methionine is an endogenous molecule with hepato-protective properties linked to redox regulation and methylation. Here, the potential therapeutic value of SAMe was tested in 17 patients with PBC, a cholestatic disease with autoimmune phenomena targeting small bile ducts. Nine patients responded to SAMe (SAMe responders) with increased serum protein S-glutathionylation. That posttranslational protein modification was associated with reduction of serum anti-mitochondrial autoantibodies (AMA-M2) titers and improvement of liver biochemistry. Clinically, SAMe responders were younger at diagnosis, had longer duration of the disease and lower level of serum S-glutathionylated proteins at entry. SAMe treatment was associated with negative correlation between protein S-glutathionylation and TNFα. Furthermore, AMA-M2 titers correlated positively with INFγ and FGF-19 while negatively with TGFβ. Additionally, cirrhotic PBC livers showed reduced levels of glutathionylated proteins, glutaredoxine-1 (Grx-1) and GSH synthase (GS). The effect of SAMe was also analyzed in vitro. In human cholangiocytes overexpressing miR-506, which induces PBC-like features, SAMe increased total protein S-glutathionylation and the level of γ-glutamylcysteine ligase (GCLC), whereas reduced Grx-1 level. Moreover, SAMe protected primary human cholangiocytes against mitochondrial oxidative stress induced by tBHQ (tert-Butylhydroquinone) via raising the level of Nrf2 and HO-1. Finally, SAMe reduced apoptosis (cleaved-caspase3) and PDC-E2 (antigen responsible of the AMA-M2) induced experimentally by glycochenodeoxycholic acid (GCDC). These data suggest that SAMe may inhibit autoimmune events in patients with PBC via its antioxidant and S-glutathionylation properties. These findings provide new insights into the molecular events promoting progression of PBC and suggest potential therapeutic application of SAMe in PBC.

Keywords: Cholestasis; Hepatoprotection; Primary biliary cholangitis; S-adenosyl-L-methionine; S-glutathionylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / metabolism
  • Autoimmunity / drug effects*
  • Cells, Cultured
  • Cholangitis / drug therapy*
  • Cholangitis / immunology
  • Cholangitis / physiopathology*
  • Cholestasis / drug therapy
  • Cholestasis / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Glutathione / analogs & derivatives
  • Glutathione / metabolism
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Male
  • Middle Aged
  • S-Adenosylmethionine / pharmacology*
  • S-Adenosylmethionine / therapeutic use*


  • Antioxidants
  • S-glyceroylglutathione
  • S-Adenosylmethionine
  • Glutathione