Nicotinamide N-methyltransferase (NNMT) and 1-methylnicotinamide (MNA) in experimental hepatitis induced by concanavalin A in the mouse |
| |
Authors: | Magdalena Sternak Tamara I. Khomich Andrzej Jakubowski Małgorzata Szafarz Wojciech Szczepański Magdalena Białas Marta Stojak Joanna Szymura-Oleksiak Stefan Chłopicki |
| |
Affiliation: | 1. Department of ExperimentalPharmacology, Chair of Pharmacology, Jagiellonian University MedicalCollege, Grzegórzecka 16, PL 31–531 Kraków, Poland;2. Institute of Pharmacology and Biochemistry, NAS of Bielarus, BLK-50, 230017, Grodno, Belarus;3. Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, Medyczna 9, PL 30–688 Kraków, Poland;4. Chair of Pathomorphology, Jagiellonian University Medical College, Grzegórzecka 16, PL 31–531 Kraków, Poland |
| |
Abstract: | 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 (IFNγ and TNFα) and by histopathological examination. ConA-induced hepatitis 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 ConAinjection. 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. |
| |
Keywords: | nicotinamide N-methyltransferase 1-methylnicotinamide concanavalin A hepatits BALB/c mice |
本文献已被 ScienceDirect 等数据库收录! |
|