Hepatic enzyme induction is generally an adaptive response associated with increases in liver weight, induction of gene expression, and morphological changes in hepatocytes. The additive growth and functional demands that initiated the response to hepatic enzyme induction cover a wide range of stimuli including pregnancy and lactation, hormonal fluctuations, dietary constituents,
infections associated with
acute-phase proteins, as well as responses to exposure to
xenobiotics. Common
xenobiotic enzyme inducers trigger pathways involving the
constitutive androstane receptor (CAR), the
peroxisome proliferator-activated receptor (
PPAR), the
aryl hydrocarbon receptor (AhR), and the
pregnane-X-receptor (PXR). Liver enlargement in response to hepatic enzyme induction is typically associated with hepatocellular
hypertrophy and often, transient hepatocyte
hyperplasia. The
hypertrophy may show a lobular distribution, with the pattern of lobular zonation and severity reflecting species, strain, and sex differences in addition to effects from specific
xenobiotics. Toxicity and hepatocarcinogenicity may occur when liver responses exceed adaptive changes or induced
enzymes generate toxic metabolites. These undesirable consequences are influenced by the type and dose of
xenobiotic and show considerable species differences in susceptibility and severity that need to be understood for assessing the potential effects on human health from similar exposures to specific
xenobiotics.