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Oxidative stress and its relationship to carcinogen activation

  • Conference paper
Oxidative Stress and Aging

Part of the book series: Molecular and Cell Biology Updates ((MCBU))

Summary

Understanding the mechanism of activation of xenobiotics to biologically reactive derivatives as well as the resultant critical biological modifications provides a basis for both predicting toxicological risk and developing protective strategies. The ability of xenobiotics to undergo metabolic activation to genotoxic derivatives is a fundamental concept in chemical carcinogenesis. There are a number of enzymatic and non-enzymatic processes which can convert chemicals to biologically reactive intermediates. These processes include enzymes, such as cytochrome P-450 and prostaglandin H synthase, lipid peroxidation and the interaction of chemicals with oxidants derived from cells and metals.

Inflammatory cells, such as polymorphonuclear leukocytes (PMNs), are particularly adept at generating and releasing a spectrum of oxidative species. Of particular importance to PMN-mediated xenobiotic activation processes is myeloperoxidase (MPO). For example, MPO can activate benzo(a)pyrene-7,8-dihydrodiol (BP-7,8-diol), the proximate carcinogenic metabolite of benzo(a)pyrene, to a (+)anti-diolepoxide resulting in covalent binding to DNA and the induction of mutagenesis in bacteria and sister chromatid exchanges in V-79 cells. Human PMNs are particularly effective because of their high MPO content relative to PMNs from mice and rats. PMNs elicited to the skin by phorbol ester treatment have been implicated in the activation of BP-7,8-diol in vivo. Such observations are important with regard to organs where PMNs are normally found, such as the bone marrow.

Metal-mediated oxidative processes can also result in the activation of xenobiotics, particular those with phenolic groups. Recent studies have demonstrated that copper(II) can oxidize 1,4-hydroquinone (HQ), a metabolite of benzene, resulting in the generation of benzoquinone (BQ) and 11202. BQ is an electrophile which is reactive toward sulfhydryl groups and DNA bases. The subsequent interaction of the H2O2 with copper(I) results in the generation of ESR detectable species which can elicit DNA strand breaks. Thus it appears that through metalredox cycle reactions the localized activation of some xenobiotics can result in genotoxic and DNA damaging oxidants. In addition to copper, the copper-containing enzyme, Cu,Zn-superoxide dismutase is capable of accelerating the oxidation of HQ, resulting in the generation of BQ and reactive oxygen species which cause DNA strand breaks in øX-174 plasmid DNA.

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  1. Division of Toxicological Sciences, Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, 615 North Wolfe Street, Baltimore, Maryland, USA

    Y. Li & M. A. Trush

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  1. Y. Li
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Editors and Affiliations

  1. Gerontology Research Center, National Institute on Aging, NIH, 21224, Baltimore, MD, USA

    R. G. Cutler

  2. Dept. Molecular and Cell Biology, 251 Life Science Addition, Membrane Bioenergetics Group, 94720, Berkeley, CA, USA

    L. Packer

  3. Cancer Research Center of Hawaii, Molecular Oncology, University of Hawaii at Manoa, 1236 Lauhala Street, 96813, Honolulu, HI, USA

    J. Bertram

  4. Dept. of Neuroscience, Institute of Cellular and Molecular Medicine, Okayama University, 2-5-1 Shikatacho, Okayama 700, Japan

    A. Mori

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© 1995 Birkhäuser Verlag Basel/Switzerland

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Li, Y., Trush, M.A. (1995). Oxidative stress and its relationship to carcinogen activation. In: Cutler, R.G., Packer, L., Bertram, J., Mori, A. (eds) Oxidative Stress and Aging. Molecular and Cell Biology Updates. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-7337-6_21

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  • DOI: https://doi.org/10.1007/978-3-0348-7337-6_21

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