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Increased resistance of GPx‐1 transgenic mice to tumor promoter–induced loss of glutathione peroxidase activity in skin
Author(s) -
Bilodeau JeanFrançois,
Mirault MarcEdouard
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990315)80:6<863::aid-ijc11>3.0.co;2-9
Subject(s) - glutathione peroxidase , genetically modified mouse , tumor promotion , transgene , gpx1 , carcinogenesis , chemistry , glutathione , biology , endocrinology , medicine , microbiology and biotechnology , biochemistry , enzyme , gene
Reactive oxygen species formation is strongly suspected to play a role in multistep carcinogenesis, notably in tumor promotion. The tumor promoter 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA) induces peroxide production, oxidative damage to DNA and inflammation in mouse skin. TPA is also known to cause a decrease in the activity of several anti‐oxidant enzymes including glutathione peroxidases (GPx). The observation that several anti‐oxidants can inhibit TPA‐mediated tumor promotion suggests that a decline in GPx activity could contribute to tumor promotion. We report here the effects of TPA on GPx activity in the skin of transgenic GPx mice that contain human GPx‐1 transgenes under the regulation of a metallothionein II A promoter. As expected, no significant difference in basal level of skin GPx activity was detected in the 3 lines of tg‐MT‐GPx mice investigated compared with non‐transgenic controls. A single topical application of TPA induced gradually, over 20 hr, a small but detectable increase in GPx mRNA and protein levels in skin of non‐transgenic mice and a contrasting decrease in both selenium‐dependent and selenium‐independent GPx activity. The extent of GPx induction was more pronounced in transgenic mice, and in contrast with non‐transgenic mice, no significant loss of GPx activity was observed in the TPA‐treated skin of these mice. Transgenic mice may, therefore, offer a novel model suitable to assess the role of GPx‐1 in skin carcinogenesis, without the potential disadvantage of abnormally high levels of GPx activity produced constitutively in other transgenic models. Int. J. Cancer 80:863–867, 1999. © 1999 Wiley‐Liss, Inc.