The perturbation of apoptosis and mitosis by drugs and xenobiotics

Drugs such as the barbiturate phenobarbitone and fibrate hypolipidaemic age nts, in addition to a range of chemicals of environmental and industrial si gnificance, are able to perturb rodent tissue homeostasis, leading to tissu e enlargement. Many of these xenobiotics are rodent nongenotoxic carcinogen s since they do not damage DNA, yet cause tumours in the rat and mouse. The se nongenotoxic carcinogens display both species and tissue specificity; fo r example, rat and mouse hepatocytes display S-phase induction and a suppre ssion of apoptosis in response to drugs such as phenobarbitone or the hypol ipidaemic peroxisome proliferators (PPs). In contrast, human hepatocytes or other types of rodent cells are refractory to these effects. However, in t he absence of a discrete mechanism of action, the clear species differences preclude extrapolation of rodent data to provide an accurate human risk as sessment. 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 discus sed. (C) 1999 Elsevier Science Inc. All rights reserved.