毒理学相关资料,第七章内容参考文献18.pdfVIP

Pharmacol. Ther. Vol. 82, No. 1, pp. 63–70, 1999 ISSN 0163-7258/99 $–see front matter Copyright © 1999 Elsevier Science Inc. PII S0163-7258(98)00058-8 Associate Editor: S. S. Hickman The Perturbation of Apoptosis and Mitosis by Drugs and Xenobiotics Susan C. Hasmall and Ruth A. Roberts* ZENECA CENTRAL TOXICOLOGY LABORATORY, ALDERLEY PARK, MACCLESFIELD, CHESHIRE, SK10 4TJ, UK ABSTRACT. 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 in rodent liver, leading to enzyme induction, stimulation of S-phase, and a suppression of apoptosis. How these acute effec