Nicotinamide N-methyltransferase (NNMT) and 1-methylnicotinamide (MNA) in experimental hepatitis induced by concanavalin A in the mouse.
Journal Title: Pharmacological Reports - Year 2010, Vol 62, Issue 3
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 (INFgamma and TNFalpha) and by histopathological examination. ConA-induced hepatitis was characterized by an early activation of inflammatory cytokines (IFNgamma; 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 and Affiliations
Magdalena Sternak, Tamara Khomich, Andrzej Jakubowski, Małgorzata Szafarz, Wojciech Szczepański, Marta Stojak, Joanna Szymura-Oleksiak, Stefan Chłopicki
Keywords
Related Articles
- EP ID EP149998
- DOI -
- Views 73
- Downloads 0
Effect of quercetin on experimental hyperlipidemia and atherosclerosis in rabbits.
Cardiovascular disease is currently the leading cause of death in the West, and a search for factors limiting its occurrence is ongoing. Accumulated data indicate that quercetin, the major flavonol in the plant kingdom,...
Sildenafil increases the force of right atrial contractions in vitro via the NO-guanylyl cyclase pathway involving beta-adrenoceptor linked mechanisms.
Sildenafil, a drug used in the treatment of erectile dysfunction, is a phosphodiesterase 5A inhibitor that increases cyclic guanosine monophosphate (cGMP) levels. In addition to its vascular actions, sildenafil is also k...
Guanidine-reactive agent phenylglyoxal induces DNA damage and cancer cell death.
DNA-damaging compounds (e.g., alkylating agents, cytotoxic antibiotics and DNA topoisomerase poisons) are themost widely used anticancer drugs. The inability of tumor cells to properly repair some types of DNA damage may...
Versatile effects of sildenafil: recent pharmacological applications.
Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor and is predominantly used in the treatment of erectile dysfunction. While maintaining an excellent safety and tolerability profile in the management of erectile dysfun...
Effects of the noradrenergic neurotoxin DSP-4 on the expression of α(1)-adrenoceptor subtypes after antidepressant treatment.
We have previously reported that chronic imipramine and electroconvulsive treatments increase the α(1A)-adrenoceptor (but not the α(1B) subtype) mRNA level and the receptor density in the rat cerebral cortex. Furthermore...