title: Evidence that the capacity of nongenotoxic carcinogens to induce oxidative stress is subject to marked variability.
abstract: Many drugs and environmental chemicals which are not directly mutagenic have the capacity to increase the incidence of tumors in the liver and other tissues. For this reason, such compounds are known as nongenotoxic carcinogens. The mechanisms underlying their effects remain unclear; however, their capacity to induce oxidative stress is considered to be a critical step in the carcinogenic process, although the evidence that this is actually the case remains equivocal and sparse. We have exploited a novel heme oxygenase-1 reporter mouse to evaluate the capacity of nongenotoxic carcinogens with different mechanisms of action to induce oxidative stress in the liver in vivo. When these compounds were administered at doses reported to cause liver tumors, marked differences in activation of the reporter were observed. 1,4-Dichlorobenzene and nafenopin were strong inducers of oxidative stress, whereas phenobarbital, piperonyl butoxide, cyproterone acetate, and WY14,643 were, at best, only very weak inducers. In the case of phenobarbital and thioacetamide, the number of LacZ-positive hepatocytes increased with time, and for the latter also with dose. The data obtained demonstrate that although some nongenotoxic carcinogens can induce oxidative stress, it is not a dominant feature of the response to these compounds. Therefore in contrast to the current models, these data suggest that oxidative stress is not a key determinant in the mechanism of nongenotoxic carcinogenesis but may contribute to the effects in a compound-specific manner.
authors.affiliation: Division of Cancer Research, Medical Research Institute, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Henderson
authors.affiliation: Division of Cancer Research, Medical Research Institute, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Cameron
authors.affiliation: Division of Cancer Research, Medical Research Institute, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Chatham
authors.affiliation: Division of Cancer Research, Medical Research Institute, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Stanley
authors.affiliation: Division of Cancer Research, Medical Research Institute, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK c.r.wolf@dundee.ac.uk.
authors.forename: Charles Roland
authors.initials: CR
authors.lastname: Wolf
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D051547:Heme Oxygenase-1 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D011401:Promoter Regions, Genetic
chemical_list: D002273:Carcinogens; D051547:Heme Oxygenase-1
keywords: heme oxygenase-1; nongenotoxic carcinogens; oxidative stress; transgenic mice