title: 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.
authors.affiliation: Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, PL 31-531 Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sternak
authors.forename: Tamara I
authors.initials: TI
authors.lastname: Khomich
authors.forename: Andrzej
authors.initials: A
authors.lastname: Jakubowski
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Szafarz
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szczepański
authors.forename: Magdalena
authors.initials: M
authors.lastname: Białas
authors.forename: Marta
authors.initials: M
authors.lastname: Stojak
authors.forename: Joanna
authors.initials: J
authors.lastname: Szymura-Oleksiak
authors.forename: Stefan
authors.initials: S
authors.lastname: Chłopicki
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D003208:Concanavalin A / Q000008:administration & dosage; D005260:Female; D006520:Hepatitis, Animal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D050903:Nicotinamide N-Methyltransferase / Q000097:blood / Q000378:metabolism*; D011994:Recombinant Proteins; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D009536:Niacinamide; D007371:Interferon-gamma; D050903:Nicotinamide N-Methyltransferase; D000410:Alanine Transaminase; C024058:N(1)-methylnicotinamide