Alteration of Liver Cell Function and Proliferation: Differentiation Between Adaptation and Toxicity

Exposure of experimental animals to biologically effective levels of chemicals, either endogenous or exogenous, the latter of either synthetic or natural origin, elicits a response(s) that reflects the diverse ways in which the various units of organization of an organism deal with chemical perturbation. For some chemicals, an initial response constitutes an adaptive effect that maintains homeostasis. Disruption of this equilibrium at any level of organization leads to an adverse effect, or toxicity. The livers of laboratory animals and humans, like other organs, undergo programmed phases of growth and development, characterized by proliferation followed by differentiation. With organ maturity, the process of differentiation leads to the commitment of differentiated cells to constitutive functions that maintain homeostasis and to specialized functions that serve organismal needs. In the mature livers of all species, proliferation of all cell types subsides to a low level. Thus, the mature liver consists of 2 types of cells: intermediate cells, the hepatocytes, which replicate infrequently, but can respond to signals for replication, and replicating cells, the stem cells, endothelial, Kupffer, and stellate cells (Ito or pericytes), bile duct epithelium, and granular lymphocytes (pit cells). Quantifiable alterations or effects at the molecular level underlie alterations at the organelle level, which in turn lead to alterations at the cellular level, which can ultimately be manifested as a change in the whole organism. Alterations can be quantal (binary), either all or none, as with cell replication, cell necrosis or apoptosis, and cell differentiation, which take place at the cellular level. They can also be graded or continuous (nonbinary), as with enzyme induction, organelle hypertrophy, and extracellular matrix elaboration, occurring either at the intra- or extra (supra) cellular level. Any quantifiable change induced in the function or structure of a cell or tissue constitutes a response or effect. Each of the several types of cell in the liver responds to a given stimulus according to its localization and function. Generally, renewing cells are more vulnerable to chemical injury than intermediate cells, which are largely quiescent. Hepatic adaptive responses usually involve actions of the chemical on cellular regulatory pathways, often receptor mediated, leading to changes in gene expression and ultimately alteration of the metabolome. The response is d