NICOTINAMIDE LATE PROTECTIVE EFFECTS AGAINST CARBON TETRACHLORIDE-INDUCED LIVER NECROSIS

Nicotinamide (NIC) is known to increase the synthesis of pyridine nucl eotides and also to inhibit the hydrolysis of them to ADP-ribose, whic h in turn is involved in Ca2+ release from mitochondria via the ADP ri bosylation of crucial mitochondrial proteins. In this work, we test th e potential ability of NIC to be a late protective agent against CCl4- induced liver necrosis. We observed that 1 g/kg po NIC, 30 min before or 6 or 10 hr after CCl4 (1 ml/kg), given ip as a 20% (v/v) solution i n olive oil, was able to significantly prevent the necrogenic effect o f the hepatotoxin at 24 hr as evidenced by determination of isocitric dehydrogenase activity in plasma or by histological observation. NIC a dministration 6 hr after CCl4 prevented fatty Liver induced by hepatot oxin at 24 hr. NIC did not modify CCl4-induced lipid peroxidation proc ess at 1 hr after CCl4 and decreased the covalent binding of (CCl4)-C- 14 to lipids. NIC decreased the levels of (CCl4)-C-14 reaching the liv er 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 augment ed it at 24 hr after CCl4. NIC concentrations in liver as determined b y GC/MS/SIM analysis were 21 mu g/g liver 1 hr after administration an d 53 mu g/g at 3 hr. Late preventive effects of NIC against CCl4 induc ed liver necrosis when given at 6 or 10 hr after CCl4 are compatible w ith the hypothesis that NIC restores mitochondrial ability for Ca2+ up take. This hypothesis remains to be proved and is being further challe nged in our laboratory. (C) 1994 Academic Press, Inc.