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Dose-Dependent Modulation of Cell Death: Apoptosis Versus Necrosis in Thioacetamide Hepatotoxicity

Division of Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe, Louisiana, USA

Prathibha S. Rao

Division of Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe, Louisiana, USA

Annette Andrews

Pathology Associates, Inc., National Center for Toxicology Research, Jefferson, Arkansas, USA

Thomas J. Bucci

Pathology Associates, Inc., National Center for Toxicology Research, Jefferson, Arkansas, USA

Frank A. Witzmann

Division of Molecular Anatomy, Indiana University—Purdue University at Indianapolis, Columbus, Indiana, USA

Harihara M. Mehendale

Division of Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe, Louisiana, USA

Apoptosis is programmed cell death, morphologically and biochemically distinct from necrosis. The objective of the present study was to examine thioacetamide-induced apoptosis over an early time course of 0 to 8 h after administration of a 12-fold dose range (50, 150, 300, and 600 mg/kg, ip) of thioacetamide (TA). Male Sprague-Daw ley rats (200-225 g) were used for the study. The incidence of apoptosis was determined by in situ end labeling, transmission electron microscopy, and charge modification of heat shock protein 70 (Hsp 70). Light microscopic examination of liver sections revealed apoptotic bodies (ABs)as early as 2 h after TA administration. A dose-dependent increase in the incidence of ABs was seen with all doses until 4 h. Thereafter, the incidence of ABs continued to increase in a temporal manner with 50 and 150 mg/kg, while it decreased in the rats treated with 300 and 600 mg/kg. Between 4 and 8 h, while necrosis as assessed by serum alanine aminotransferase (ALT) and histopathology declined in the sixfold dose range (50, 150, and 300 mg TA/kg), it increased in a temporal manner with 600 mg TA/kg. Preliminary studies indicate an inverse relation between Hsp 70 abundance and the incidence of apoptosis. Hsp 70 expression was significantly higher in the 600 mg TA/kg group compared to the lower doses. Lowest abundance was recorded in the groups receiving 50 and 150 mg TA/kg, where maximum apoptosis was noted. These findings collectively suggest that although the processes of apoptosis and necrosis are initiated simultaneously, the proportion of cells dying via either mechanism seems to be regulated by the dose of TA. Lower doses seem to favor cell death via apoptosis, while higher doses favor cell death via necrosis. Additionally, the inverse relation between Hsp 70 and apoptosis at lower doses suggests a regulatory role for Hsp 70.

Key Words: apoptosis • dose response • heat shock protein 70 • in situ end labeling • necrosis • thioacetamide • transmission electron microscopy

International Journal of Toxicology, Vol. 17, No. 2, 193-211 (1998)
DOI: 10.1080/109158198226701


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