Abstract
We examined the effects of (+/-)-indenestrol A (IA), an antioxidative and superoxide-producing metabolite of diethylstilbestrol (DES), on the activation of murine macrophages (RAW 264.7 cells) in vitro, particularly with regard to interferon (IFN)-gamma-induced nitric oxide (NO) production. (+/-)-IA inhibited NO production more strongly than DES as assessed by a nitrite assay. The inhibitory effect of (+/-)-IA on IFN-gamma-induced intracellular NO production was confirmed by direct staining of intracellular NO with diaminofluorescein-2 diacetyl. Inhibition of NO production was confirmed by Western blot analysis of IFN-gamma-induced NO synthase. Under IFN-gamma-stimulated conditions, the IFN-gamma activation site (GAS), which was the most important transcription factor, was significantly inhibited by (+/-)-IA. (+/-)-IA also promoted the activation of NF-kappaB. (+/-)-IA at 1 and 3 microM delayed the onset of apoptosis. Our results suggest that (+/-)-IA inhibited the activation of macrophages, resulting in the suppression of NO-mediated apoptosis. These results suggest a novel mechanism for the carcinogenic promoting activity of DES via its metabolite, (+/-)-IA.
| Original language | English |
|---|---|
| Pages (from-to) | 187-195 |
| Number of pages | 9 |
| Journal | Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis |
| Volume | 534 |
| Issue number | 1-2 |
| Publication status | Published - 2003 Jan 10 |
ASJC Scopus subject areas
- Health, Toxicology and Mutagenesis
- Molecular Biology