Metabolism and DNA binding of the environmental pollutant 6-nitrochrysene in primary culture of human breast cells and in cultured MCF-10A, MCF-7 and MDA-MB-435s cell lines
✍ Scribed by Telih Boyiri; Joanna Leszczynska; Dhimant Desai; Shantu Amin; Daniel W. Nixon; Karam El-Bayoumy
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- French
- Weight
- 134 KB
- Volume
- 100
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Abstract
The environmental pollutant 6‐nitrochrysene (6‐NC) is a potent mammary carcinogen in the rat. To determine if the results obtained in 6‐NC‐treated rodents can be applicable to humans, we examined its metabolic activation in primary cultures of human breast cells prepared from tissues obtained from reduction mammoplasty from 3 women and in a cultured, immortalized human mammary epithelial cell line (MCF‐10A), as well as estrogen‐dependent (MCF‐7) and estrogen‐independent (MDA‐MB‐435s) human breast cancer cell lines. Metabolites identified following 24 hr incubations of [^3^H]6‐NC (2.5, 5.0 and 10 μM) with human breast cells were derived from ring‐oxidation (trans‐1,2‐dihydroxy‐1,2‐dihydro‐6‐nitrochrysene [1,2‐DHD‐6‐NC]) and nitro‐reduction (6‐aminochrysene [6‐AC]); chrysene‐5,6‐quinone (C‐5,6‐Q) was also detected. Levels of metabolites (pmol/mg protein) varied greatly depending on the concentration of 6‐NC and the individual breast tissue used; 1,2‐DHD‐6‐NC, ranged from not detected to 15.6 ± 1.0; 6‐AC, from 11.5 ± 4.0 to 155 ± 10.2; C‐5,6‐Q, from 18.3 ± 10.8 to 196.7 ± 15.4. Qualitatively similar metabolic profiles were obtained upon incubation of [^3^H]6‐NC with MCF‐10A, MCF‐7 and MDA‐MB‐435s. We also detected 1,2‐dihydroxy‐6‐aminochrysene (1,2‐DH‐6‐AC; ranged from not detected to 50.4 ± 9.8). Some of the metabolites identified in our study are known to be proximate carcinogenic forms of 6‐NC in rodents. MCF‐7 was the most efficient cell line in catalyzing 6‐NC to genotoxic metabolites, and we demonstrated that the major DNA adduct is chromatographically identical to that found in the mammary gland of rats treated by gavage with 6‐NC and that obtained from the incubation of [^3^H]1,2‐DHD‐6‐NC with MCF7 cells or from nitro‐reduction of 1,2‐DHD‐6‐NC in the presence of 2′‐deoxyguanosine 5′‐monophosphate in vitro. This is the first report to demonstrate the ability of human breast cells, MCF‐10A, and breast cancer cell lines to activate 6‐NC to metabolites that can damage DNA. © 2002 Wiley‐Liss, Inc.