Nicotinamide n-methyltransferase (nnmt) and 1-methylnicotinamide (mna) in experimental hepatitis induced by concanavalin a in the mouse

Nicotinamide n-methyltransferase (nnmt),which converts nicotinamide (na) to 1-methylnicotinamide (mna),is up-regulated in the cirrhotic liver. because mna displays pgi2-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 (infγ and tnfα) and by histopathological examination. cona-induced hepati- tis was characterized by an early activation of inflammatory cytokines (ifnγ from below 0.05 ng/ml to 23.72 ± 8.80 ng/ml; tnfα 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 pgi2-releasing properties of mna. © by institute of pharmacy polish acadamy of sciences.