The perturbation of apoptosis and mitosis by drugs and xenobiotics.

Drugs such as the barbiturate phenobarbitone and fibrate hypolipidaemic agents, in addition to a range of chemicals of environmental and industrial significance, are able to perturb rodent tissue homeostasis, leading to tissue enlargement. Many of these xenobiotics are rodent nongenotoxic carcinogens since they do not damage DNA, yet cause tumours in the rat and mouse. These nongenotoxic carcinogens display both species and tissue specificity; for example, rat and mouse hepatocytes display S-phase induction and a suppression of apoptosis in response to drugs such as phenobarbitone or the hypolipidaemic peroxisome proliferators (PPs). In contrast, human hepatocytes or other types of rodent cells are refractory to these effects. However, in the absence of a discrete mechanism of action, the clear species differences preclude extrapolation of rodent data to provide an accurate human risk assessment. Recent data have demonstrated that PPs activate the PP-activated receptor alpha in rodent liver, leading to enzyme induction, stimulation of S-phase, and a suppression of apoptosis. How these acute effects may lead to hepatocarcinogenesis and the relevance of this for humans will be discussed.