Nicotinamide Late Protective Effects against Carbon Tetrachloride-Induced Liver Necrosis

Abstract

Nicotinamide (NIC) is known to increase the synthesis of pyridine nucleotides and also to inhibit the hydrolysis of them to ADP-ribose, which in turn is involved in Ca 2+ release from mitochondria via the ADP ribosylation of crucial mitochondrial proteins. In this work, we test the potential ability of NIC to be a late protective agent against CCl 4-induced liver necrosis. We observed that 1 g/kg po NIC, 30 min before or 6 or 10 hr after CCl 4 (1 ml/kg), given ip as a 20% (v/v) solution in olive oil, was able to significantly prevent the necrogenic effect of the hepatotoxin at 24 hr as evidenced by determination of isocitric dehydrogenase activity in plasma or by histological observation. NIC administration 6 hr after CCl 4 prevented fatty liver induced by hepatotoxin at 24 hr. NIC did not modify CCl 4-induced lipid peroxidation process at 1 hr after CCl 4 and decreased the covalent binding of 14CCl 4 to lipids. NIC decreased the levels of 14 CCl 4 reaching the liver when given 30 min before hepatotoxin but not when given 6 hr after it. NIC lowered body temperature of rats at 1, 3, and 6 hr and augmented it at 24 hr after CCl 4. NIC concentrations in liver as determined by GC/MS/SIM analysis were 21 μg/g liver 1 hr after administration and 53 μg/g at 3 hr. Late preventive effects of NIC against CCl 4 induced liver necrosis when given at 6 or 10 hr after CCl 4 are compatible with the hypothesis that NIC restores mitochondrial ability for Ca 2+ uptake. This hypothesis remains to be proved and is being further challenged in our laboratory.