PROTECTION OF ACETAMINOPHEN-INDUCED HEPATOCELLULAR APOPTOSIS AND NECROSIS BY CHOLESTERYL HEMISUCCINATE PRETREATMENT

This study of acetaminophen (AAP) hepatotoxicity examined whether some aspects of the highly integrated process of drug-induced toxicity inv olves apoptosis, in addition to necrosis in vivo; and if so, whether c holesteryl hemisuccinate (CS) pretreatment would selectively interfere with apoptotic or necrotic liver cell death. We have previously demon strated that CS preexposure in vivo, protects hepatocellular necrosis and necrosis-related events induced by carbon tetrachloride (CCl4) adm inistration. Our study demonstrates that administration of hepatotoxic doses of AAP (350-500 mg/kg, i.p.) to ICR mice (CD-1) results in seve re liver injury leading to cell death both by necrosis and apoptosis. AAP-induced cell death was preceded by massive elevation in serum alan ine aminotransferase coupled with rapid loss of large genomic DNA (2-2 4 hr), fragmentation of DNA in the form of a ladder (2-24 hr), apoptot ic nuclear condensation at early hours (2-6 hr) followed by massive fr agmentation and margination of heterochromatin at later (6-24) hours a nd a near total loss of glycogen in pericentral areas. Although CS (10 0 mg/kg, i.p.) alone had no noticeable biochemical or morphological ef fects, its administration before AAP (350-500 mg/kg, i.p.) abrogated h istological and biochemical diagnostics of both apoptosis and necrosis . These include near total absence of loss of large genomic DNA and gl ycogen, and dramatic protection from escalating levels of liver injury . CS pretreatment also arrested AAP-induced ultrastructural changes ty pical of both apoptosis and necrosis. Histopathological examination of periodic acid-Schiff stained liver sections mirrored the biochemical and ultrastructural findings. In conclusion, this study for the first time establishes that apoptosis, in addition to necrosis, significantl y contributes to AAP hepatotoxicity in vivo, and preexposure of mice t o CS prevents AAP-induced hepatic apoptosis and necrosis.