2,3,7,8-Tetrachlorodibenzo-p-dioxin: Potent anticarcinogenic activity in CD-1 mice

doi:10.1016/0006-291X(79)91752-2

Biochemical and Biophysical Research Communications

Volume 86, Issue 3, 14 February 1979, Pages 577-584

https://doi.org/10.1016/0006-291X(79)91752-2 Get rights and content

Abstract

Topical pretreatment with non-toxic doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a contaminant formed in the commercial synthesis of the herbicide 2,4,5-trichlorophen-oxyacetic acid, strongly inhibited the initiation of skin tumors by 7,12-dimethylbenz(a)-anthracene and benzo(a)pyrene in female CD-1 mice. 2,3,7,8-tetrachlorodibenzo-p-dioxin also produced marked induction of epidermal monooxygenase enzymes functional in the conversion of 7,12-dimethylbenz(a)anthracene to a variety of hydroxylated products. The time course of anticarcinogenic effects resulting from pretreatment with the dioxin correlated with the magnitude of induction as well as with a singnificant reduction in the quantity of 7,12-dimethylbenz(a)anthracene metabolites covalently bound $in vivo$ to epidermal DNA and RNA but not protein.

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Primary hepatocyte cultures prepared from adult male Sprague-Dawley rats were extremely sensitive to induction of benzo[a]pyrene (BaP) metabolism by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), added to the cells in culture. A 48-hr exposure to 1 pmol TCDD/10⁶ cells resulted in a 4-fold induction of BaP metabolism. Significant induction was produced by a 48-hr exposure to a dose as low as 0.01 pmol (3 pg) TCDD/10⁶ cells. Cells exposed to TCDD from 7 to 55 hr in culture and then assayed for BaP metabolism responded to much lower doses of TCDD than did cells assayed at 36 hr in culture after being exposed to TCDD from 7 to 36 hr in culture. The doses of TCDD required for half-maximal induction of BaP metabolism were 24.8 and 164 fmol TCDD/10⁶ cells for cells assayed at 55 and 36 hr, respectively. Hepatocytes treated with TCDD starting at later times in culture showed a much more rapid time course of induction than did cells treated at earlier times in culture. A 2.6-fold induction occurred in cells treated from 49 to 55 hr in culture, compared to a 1.2-fold induction from 31 to 37 hr in culture. In contrast to cells exposed to TCDD from 7 to 55 hr in culture, cells exposed from 49 to 55 hr in culture were nearly as sensitive to inhibition of BaP metabolism by SKF 525-A as were uninduced control cells. An apparent derepression of the induction of BaP metabolism is occurring in primary hepatocyte cultures, resulting in an increase in the intitial rate of induction by TCDD and a decrease in the dose of TCDD required to obtain the half-maximum response.
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^☆: Supported by grants HD-04839 from the National Institute of Child Health and Human Development, U.S.P.H.S., National Institutes of Health, U.S.P.H.S. Training Grant GM-00109, by Grant CA-20076 from the National Cancer Institute, U.S.P.H.S. and by the U.S. Department of Energy under contract W-7405-eng-26 with the Union Carbide Corporation.

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2,3,7,8-Tetrachlorodibenzo-p-dioxin: Potent anticarcinogenic activity in CD-1 mice☆

Abstract

Lif Sci

J. Invest. Dermatol

J. Biol. Chem

Cancer Res

Cancer Res

Cancer Res

Cancer Res

Cancer Res

Int. J. Clin. Pharmacol