ABSTRACT
The purpose of this chapter will be to provide a brief overview of the subject of cell death and
then to focus on what is known about the role of apoptosis and necrosis in drug hepatotoxicity.
OVERVIEW OF CELL DEATH
It is currently recognized that the demise of cells reflects the triggering of the activation of a
death program either by death receptor signaling or from a source of intracellular stress leading
to apoptosis versus the massive loss of cell integrity from overwhelming stress leading to
necrosis (1,2). The former involves shrinkage and nuclear disassembly (apoptosis) and the
latter involves swelling and lysis (necrosis). The type of cell death and the susceptibility to
death-inducing stimuli vary greatly from cell type to cell type and from transformed cells
to normal cells. In the liver, death of hepatocytes is the major event leading to organ failure but
in special circumstances the sinusoidal endothelial cells (e.g., veno-occlusive disease) (3) or bile
duct epithelium (vanishing duct syndrome) (4) may be a key target. Hepatocyte death accounts
for the key findings in drug-induced hepatitis, namely elevated serum aspartate aminotrans-
ferase, alanine aminotransferase, and functional disorders due to parenchymal extinction, such
as jaundice and coagulopathy.
