Nicotinamide N-methyltransferase (NNMT) and 1-methylnicotinamide (MNA) in experimental hepatitis induced by concanavalin A in the mouse

Abstract

Nicotinamide N-methyltransferase (NNMT), which converts nicotinamide (NA) to 1-methylnicotinamide (MNA), is up-regulated in the cirrhotic liver. Because MNA displays PGI(2)-dependent anti-inflammatory effects, the up-regulation of NNMT may play a regulatory role in liver inflammation. In the present work, we analyzed changes in NNMT activity in the liver and concomitant changes in the concentration of endogenous MNA in plasma in T-cell dependent hepatitis induced by concanavalin A (ConA) in BALB/c mice. Furthermore, we tested whether exogenous MNA possessed a protective effect against ConA-induced hepatitis. Development of liver injury induced by ConA (10 mg/kg, iv) was characterized by measurements of plasma concentration of alanine aminotransaminase (ALT), inflammatory cytokines (INF gamma and TNFalpha) and by histopathological examination. ConA-induced hepatitis was characterized by an early activation of inflammatory cytokines (IFN gamma; from below 0.05 ng/ml to 23.72 +/- 8.80 ng/ml; TNFalpha;from 0.07 +/- 0.01 ng/ml to 0.71 +/- 0.12 ng/ml, 2 h after ConA), an elevation of ALT (from 40.65 +/- 3.2 U/l to 5,092.20 +/- 1,129.05 U/l, 8 h after ConA) and by morphological signs of severe liver inflammation and injury (24 h after ConA). In mice injected with ConA, NNMT activity in the liver was up-regulated approximately 2-fold to 3-fold, 8-24 h after ConA injection. The concentration of MNA and its metabolites (Met-2PY and Met-4PY) in plasma were elevated approximately 2-fold 8 h after ConA injection. Exogenous MNA (100 mg/kg, iv) diminished ConA-induced liver injury, and this effect was reversed by an antagonist of the prostacyclin receptor, RO 3244794 (10 mg/kg, po). In conclusion, the present study demonstrated that hepatic NNMT activity and MNA concentration in plasma significantly increased during the progression of ConA-induced hepatitis in mice. This response may play a hepatoprotective role compatible with the PGI(2)-releasing properties of MNA.

The expression of nicotinamideN-methyltransferase increases ATP synthesis and protects SH-SY5Y neuroblastoma cells against the toxicity of Complex I inhibitors

“…Such a cytoprotective effect for NNMT is not without precedent. A recent study has shown that NNMT expression is induced in both the cirrhotic liver and experimental hepatitis as a hepatoprotective mechanism in response to the underlying pathogenic process, and that this is mediated by elevated MeN production [41]. Our results also suggest that the overexpression of NNMT in a variety of cancers may be a contributory factor to their accelerated growth, raising the possibility of using NNMT inhibitors for the treatment of cancer.…”

Differential involvement of IL-6 in the early and late phase of 1-methylnicotinamide (MNA) release in Concanavalin A-induced hepatitis

“…Accordingly, increase in the concentration of MNA in ConA-induced hepatitis may reflect an endogenous defensive mechanism limiting the inflammatory processes along the progression of liver injury by a PGI 2 -dependent pathway. In fact, hepatoprotective action of exogenous MNA in ConA-induced hepatitis was reversed by a prostacyclin receptor antagonist [35]. We also demonstrated that carboprostacyclin (cPGI 2 ) reduced the production of IFNS, IL-4, TNFα in spleen cells (data not published).…”

Role of nicotinamide N-methyltransferase in non-small cell lung cancer: in vitro effect of shRNA-mediated gene silencing on tumourigenicity

“…This compound was found to have anti-thrombotic ( Chlopicki et al, 2007 ), vasoprotective ( Bartu ś et al, 2008 ), gastroprotective ( Brzozowski et al, 2008 ), antiinflammatory ( Sternak et al, 2010 ), and neuroprotective ( Milani et al, 2013 ) properties. It could be interesting to speculate whether N1-methylnicotinamide exerts a cytoprotective effect against antineoplastic compounds in cancer cells.…”