Chemoprotective and toxic potentials of synthetic and natural chalcones and dihydrochalcones in vitro
Language English Country Ireland Media print
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
15664435
DOI
10.1016/j.tox.2004.11.011
PII: S0300-483X(04)00611-0
Knihovny.cz E-resources
- MeSH
- Cell Line MeSH
- Chalcones pharmacology toxicity MeSH
- Epithelial Cells drug effects metabolism MeSH
- Cytochrome P-450 Enzyme Inhibitors MeSH
- Microsomes, Liver drug effects enzymology MeSH
- Liver drug effects ultrastructure MeSH
- Carcinogens metabolism toxicity MeSH
- Rats MeSH
- Gap Junctions drug effects metabolism physiology MeSH
- Cell Communication drug effects physiology MeSH
- Lipid Peroxidation drug effects MeSH
- Rats, Wistar MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- In Vitro Techniques MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- Chalcones MeSH
- Cytochrome P-450 Enzyme Inhibitors MeSH
- Carcinogens MeSH
- Cytochrome P-450 Enzyme System MeSH
Cytochrome P4501A activity, oxidative stress and inhibition of gap junctional intercellular communication (GJIC) are involved in metabolic activation of promutagens and tumor-promoting activity of various xenobiotics, and their prevention is considered to be an important characteristic of chemoprotective compounds. In this study, a series of 31 chalcones and their corresponding dihydroderivatives, substituted in 2,2'-, 3,3'-, 4- or 4'-position by hydroxyl or methoxy group, were tested for their ability to inhibit Fe(II)/NADPH-enhanced lipid peroxidation and cytochrome P4501A-dependent 7-cethoxyresorufin-O-deethylase (EROD) activity in rat hepatic microsomes. Effects of the compounds on GJIC were determined in rat liver epithelial WB-F344 cells. Most of the chalcones and dihydrochalcones inhibited EROD activity in a dose-dependent manner at the range 0.25-25 microM, which was comparable to model flavonoid inhibitors alpha-naphthoflavone and quercetin. The chalcones exhibited higher inhibition activity than the corresponding dihydroderivatives. Mono and dihydroxylated chalcones, and dihydrochalcones showed none or only a weak antioxidant activity; trihydroxyderivatives inhibited in vitro lipid peroxidation significantly only at 50 microM concentration. Potential adverse effects, namely inhibition of GJIC and/or cytotoxicity were detected after treatment of WB-F344 cells with a number of chalcone and dihydrochalcone derivatives, suggesting that they should be excluded from additional screening as chemoprotective compounds. Chalcones and dihydrochalcones substituted at 4- and/or 4'-position, which elicited no inhibition of GJIC, were further tested for the potential enhancing effects on GJIC. The present data seem to suggest that 4-hydroxy, 2',4'-dihydroxy-3-methoxy, 2,4,4'-trihydroxy, and 2',4,4'-trihydroxychalcone, 2',4-dihydroxy and 2'-hydroxy-3,4-dimethoxydihydrochalcone might be promising chemoprotective compounds against CYP1A activity, and partly also against oxidative damage without inducing adverse effects, such as GJIC inhibition. In general, determination of potencies of tested compounds to inhibit GJIC should be involved in any set of methods for the in vitro screening of chemoprotective characteristics of potential drugs, in order to reveal their potential adverse effects associated with tumor promotion.
References provided by Crossref.org
Applicability of Scrape Loading-Dye Transfer Assay for Non-Genotoxic Carcinogen Testing