Oxathiolene oxides: a novel family of compounds that induce ferritin, glutathione S-transferase, and other proteins of the phase II response
| Autor: | E. Christine Pietsch, Suzy V. Torti, Alan J. Townsend, Sandra Leone-Kabler, Allison L. Hurley, Elizabeth E. Scott, Mark E. Welker, Benjamin P. Duckworth, Frank M. Torti |
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| Rok vydání: | 2003 |
| Předmět: |
Transcription
Genetic Biochemistry Cell Line Heterocyclic Compounds 1-Ring Structure-Activity Relationship chemistry.chemical_compound Western blot medicine Humans RNA Messenger Northern blot Enzyme inducer Glutathione Transferase Pharmacology biology medicine.diagnostic_test Cytochrome P450 Glutathione Enzyme assay Cyclic S-Oxides Isoenzymes Ferritin Glutathione S-transferase Gene Expression Regulation chemistry Ferritins biology.protein |
| Zdroj: | Biochemical Pharmacology. 65:1261-1269 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/s0006-2952(03)00081-9 |
| Popis: | Compounds that induce the synthesis of cytoprotective phase II enzymes have shown promise as cancer chemopreventive agents. Although chemically diverse, phase II enzyme inducers are capable of participating in Michael reaction chemistry. We have synthesized a novel class of organosulfur compounds, termed oxathiolene oxides (OTEOs). Based on their chemical properties, we hypothesized that these compounds could function as phase II enzyme inducers. Northern blot analysis showed that oxathiolene oxides induce the phase II enzymes glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), and ferritin H and L mRNA in a concentration-dependent fashion in a normal embryonic mouse liver cell line, BNLCL.2. OTEO-562 (3-cyclohexenyl-4-methyl-1,2-oxathiol-3-ene-2-oxide) was the strongest inducer. Western blot analysis demonstrated that GST-α and ferritin H protein levels were also induced in cells treated with OTEO-562, as was total GST and NQO1 enzyme activity. Further, induction of NQO1 activity by OTEO-562 was equivalent in aromatic hydrocarbon (Ah) receptor wild-type and Ah receptor mutant cell lines, suggesting that oxathiolene oxides activate phase II enzymes by an Ah receptor-independent mechanism. Consistent with this observation, OTEO-562 failed to induce cytochrome P450 1A1 mRNA. These results suggest that oxathiolene oxides may merit further investigation as candidate chemopreventive agents. |
| Databáze: | OpenAIRE |
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