Heterogeneous Liver Lobe Responses of Carbon Tetrachloride-Induced Hepatotoxicity in Male Rats Pretreated with Hepatic Enzyme-Inducing Agents

Abstract

The present study was designed to compare the susceptibility to carbon tetrachloride (CCl4)-induced hepatotoxicities of the different liver lobes of rats which had been subjected to pretreatment with phenobarbital sodium (PB) or β-naphthoflavone (BNF). A detailed investigation was done to determine whether the susceptibility to CCl4 hepatotoxicities was correlated with hepatic cytochrome P450 (CYP) activities in the different liver lobes. Male Wistar rats were given a single oral administration of CCl4 (0.1 mL/kg, dissolved in liquid paraffin) or vehicle alone following three daily intraperitoneal injections of PB (40 mg/kg, dissolved in sterile saline) or BNF (40 mg/kg, suspended in sesame oil). One day after the CCl4 administration, all animals were necropsied, and liver samples were obtained from the left and median lobes. Each sample was used for histopathological examination and 7-alkoxycoumarin O-dealkylase activity assay to evaluate the CYP activity. All the CCl4-treated animals revealed typical liver damage, such as the presence of ballooning degeneration and necrosis in centrilobular hepatocytes. PB pretreatment remarkably enhanced the extent of the liver damage, which was greater in the median lobe than the left lobe. BNF pretreatment only slightly enhanced the extent of the liver damage, which was also greater in the median lobe. These results indicate the different susceptibilities of rat liver lobes to CCl4-induced hepatotoxicities enhanced by pretreatment with PB or BNF. Moreover, the heterogeneity of the CYP activities enhanced by PB pretreatment was closely correlated with the susceptibility to CCl4-induced hepatotoxicities in the different liver lobes, although that by BNF pretreatment was not.