title: Chemoprotective and toxic potentials of synthetic and natural chalcones and dihydrochalcones in vitro.
abstract: 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.
authors.affiliation: Department of Natural Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Forejtníková
authors.forename: Kamila
authors.initials: K
authors.lastname: Lunerová
authors.forename: Renata
authors.initials: R
authors.lastname: Kubínová
authors.forename: Dagmar
authors.initials: D
authors.lastname: Jankovská
authors.forename: Radek
authors.initials: R
authors.lastname: Marek
authors.forename: Radovan
authors.initials: R
authors.lastname: Kares
authors.forename: Václav
authors.initials: V
authors.lastname: Suchý
authors.forename: Jan
authors.initials: J
authors.lastname: Vondrácek
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D047188:Chalcones / Q000494:pharmacology* / Q000633:toxicity*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D002273:Carcinogens; D047188:Chalcones; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System