Evidence that the capacity of nongenotoxic carcinogens to induce oxidative stress is subject to marked variability

Colin J. Henderson, Amy R. Cameron, Lynsey Chatham, Lesley A. Stanley, Charles Roland Wolf (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    4 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)138-148
    Number of pages11
    JournalToxicological Sciences
    Volume145
    Issue number1
    DOIs
    Publication statusPublished - May 2015

    Fingerprint

    Oxidative stress
    Carcinogens
    Oxidative Stress
    Liver
    Phenobarbital
    Tumors
    Nafenopin
    Piperonyl Butoxide
    Thioacetamide
    Cyproterone Acetate
    Heme Oxygenase-1
    Hepatocytes
    Neoplasms
    Carcinogenesis
    Chemical activation
    Tissue
    Incidence
    Pharmaceutical Preparations

    Cite this

    @article{cf99f9e7e39043fab8b38acfc06e21da,
    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.",
    author = "Henderson, {Colin J.} and Cameron, {Amy R.} and Lynsey Chatham and Stanley, {Lesley A.} and Wolf, {Charles Roland}",
    note = "{\circledC} The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.",
    year = "2015",
    month = "5",
    doi = "10.1093/toxsci/kfv039",
    language = "English",
    volume = "145",
    pages = "138--148",
    journal = "Toxicological Sciences",
    issn = "1096-6080",
    publisher = "Oxford University Press",
    number = "1",

    }

    Evidence that the capacity of nongenotoxic carcinogens to induce oxidative stress is subject to marked variability. / Henderson, Colin J.; Cameron, Amy R.; Chatham, Lynsey; Stanley, Lesley A.; Wolf, Charles Roland (Lead / Corresponding author).

    In: Toxicological Sciences, Vol. 145, No. 1, 05.2015, p. 138-148.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Evidence that the capacity of nongenotoxic carcinogens to induce oxidative stress is subject to marked variability

    AU - Henderson, Colin J.

    AU - Cameron, Amy R.

    AU - Chatham, Lynsey

    AU - Stanley, Lesley A.

    AU - Wolf, Charles Roland

    N1 - © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.

    PY - 2015/5

    Y1 - 2015/5

    N2 - 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.

    AB - 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.

    U2 - 10.1093/toxsci/kfv039

    DO - 10.1093/toxsci/kfv039

    M3 - Article

    C2 - 25690736

    VL - 145

    SP - 138

    EP - 148

    JO - Toxicological Sciences

    JF - Toxicological Sciences

    SN - 1096-6080

    IS - 1

    ER -