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PubMed1986

cis- and trans-1,2-diphenylaziridines: induction of xenobiotic-metabolizing enzymes in rat liver and mutagenicity in Salmonella typhimurium.

trans-Stilbene imine (trans-1,2-diphenylaziridine) is the nitrogen analog of trans-stilbene oxide, a potent inducer of several microsomal and cytosolic xenobiotic-metabolizing enzymes. Although the acute toxicity of cis- and trans-stilbene imines prevents their application at the usual dose for trans-stilbene oxide (400 mg/kg/day), it is apparent that the imines nevertheless potently induce several xenobiotic-metabolizing enzymes in rat liver. The IP administration of trans-stilbene imine resulted in statistically significant increases in the activities of aminopyrine N-demethylase, microsomal epoxide hydrolase, glutathione transferase (toward 1-chloro-2,4-dinitrobenzene, 1,2-dichloro-4-nitrobenzene and delta 5-androstene-3,17-dione) and UDP-glucuronosyltransferase (toward testosterone). cis-Stilbene imine was less potent in inducing these activities. Although trans-stilbene imine (total dose = 400 mg/kg) was more potent than trans-stilbene oxide (total dose = 1200 mg/kg) in inducing the activities of glutathione transferase (toward 1-chloro-2,4-dinitrobenzene) and UDP-glucuronosyltransferase (toward testosterone), both compounds belong to the class of substances which are more potent inducers of conjugating (phase II) enzymes. Because of their structural similarity with K-region arene imines which are potent mutagens, cis-stilbene imine and trans-stilbene imine were investigated for mutagenicity (reversion of his- strains of Salmonella typhimurium). cis-Stilbene imine and trans-stilbene imine were direct mutagens in the strain TA100. This result, and the finding that acenaphthene 1,2-imine efficiently reverts various strains of Salmonella typhimurium, demonstrates that not only K-region arene imines, but also other aziridines substituted at the two carbons with aromatic moieties, are mutagenic.

Animals↗
PubMed1985

Effect of dietary clofibrate on epoxide hydrolase activity in tissues of mice.

The effects of dietary clofibrate on the epoxide-metabolizing enzymes of mouse liver, kidney, lung and testis were evaluated using trans-stilbene oxide as a selective substrate for the cytosolic epoxide hydrolase, cis-stilbene oxide and benzo[a]pyrene 4,5-oxide as substrates for the microsomal form, and cis-stilbene oxide as a substrate for glutathione S-transferase activity. The hydration of trans-stilbene oxide was greatest in liver followed by kidney greater than lung greater than testis. Its hydrolysis was increased significantly in the cytosolic fraction of liver and kidney of clofibrate-treated mice and in the microsomes from the liver. Isoelectric focusing indicates that the same enzyme is responsible for hydrolysis of trans-stilbene oxide in normal and induced liver and kidney. Clofibrate induced glutathione S-transferase activity on cis-stilbene oxide only in the liver. Hydrolysis of both cis-stilbene oxide and benzo[a]pyrene 4,5-oxide was highest in testis followed by liver greater than lung greater than kidney. Hydration of cis-stilbene oxide was induced significantly in both liver and kidney by clofibrate but that of benzo[a]pyrene 4,5-oxide was induced only in the liver. These and other data based on ratios of hydration of benzo[a]pyrene 4,5-oxide to cis-stilbene oxide in tissues of normal and induced animals indicate that there are one or more novel epoxide hydrolase activities which cannot be accounted for by either the classical cytosolic or microsomal hydrolases. These effects are notable in the microsomes of kidney and especially in the cytosol of testis.

Animals↗
PubMed2006

Structure-activity relationship studies of resveratrol and its analogues by the reaction kinetics of low density lipoprotein peroxidation.

Resveratrol (3,5,4'-trans-trihydroxystibene) is a natural phytoalexin present in grapes and red wine, which possesses a variety of biological activities including antioxidative activity. To find more active antioxidants, with resveratrol as the lead compound, we synthesized resveratrol analogues, i.e., 3,4,3',4'-tetrahydroxy-trans-stilbene (3,4,3',4'-THS), 3,4,4'-trihydroxy-trans-stilbene (3,4,4'-THS), 2,4,4'-trihydroxy-trans-stilbene (2,4,4'-THS), 3,3'-dimethoxy-4,4'-dihydroxy-trans-stilbene (3,3'-DM-4,4'-DHS), 3,4-dihydroxy-trans-stilbene (3,4-DHS), 4,4'-dihydroxy-trans-stilbene (4,4'-DHS), 3,5-dihydroxy-trans-stilbene (3,5-DHS) and 2,4-dihydroxy-trans-stilbene (2,4-DHS). Antioxidative effects of resveratrol and its analogues against free-radical-induced peroxidation of human low density lipoprotein (LDL) were studied. The peroxidation was initiated either by a water-soluble initiator 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH), or by cupric ion (Cu(2+)). The reaction kinetics were monitored either by the uptake of oxygen and the depletion of alpha-tocopherol (TOH) presented in the native LDL, or by the formation of thiobarbituric acid reactive substances (TBARS). Kinetic analysis of the antioxidation process demonstrates that these trans-stilbene derivatives are effective antioxidants against both AAPH- and Cu(2+)-induced LDL peroxidation with the activity sequence of 3,4,3',4'-THS approximately 3,3'-DM-4,4'-DHS>3,4-DHS approximately 3,4,4'-THS>2,4,4'-THS>resveratrol approximately 3,5-DHS>4,4'-DHS approximately 2,4-HS, and 3,4,3',4'-THS approximately 3,4-DHS approximately 3,4,4'-THS>3,3'-DM-4,4'-DHS>4,4'-DHS>resveratrol approximately 2,4-HS>2,4,4'-THS approximately 3,5-DHS, respectively. Molecules bearing ortho-dihydroxyl or 4-hydroxy-3-methoxyl groups possess significantly higher antioxidant activity than those bearing no such functionalities.

Antioxidants↗
PubMed1991

Effects of environmentally encountered epoxides on mouse liver epoxide-metabolizing enzymes.

Male mice were treated (i.p.) for 3 days with 15 different environmentally encountered epoxides, and the effects of these compounds on liver microsomal and cytosolic epoxide hydrolase (mEH and cEH), glutathione S-transferase (mGST and cGST) and carboxylesterase (mCE) activities were determined. The epoxides included the pesticides: heptachlor epoxide, dieldrin, tridiphane, and juvenoid R-20458; the natural products: disparlure, limonin, nomilin, and epoxymethyloleate; the endogenous steroids: lanosterol epoxide, cholesterol-alpha-epoxide, and progesterone epoxide; and the industrial or synthetic epoxides: epichlorohydrin, araldite, trans-stilbene oxide, and 4'-phenylchalcone oxide. The pesticide epoxides were the most effective inducers of liver weight, microsomal protein, and the enzyme activities measured, with mEH and cEH activities towards cis-stilbene oxide (mEHcso and cEHcso), cGST activities towards four of five substrates, and mCE towards clofibrate (mCEclof) and p-nitrophenylacetate (mCEpna) increased following treatment with most of the pesticides. The synthetic epoxides increased some of the same activities, while the natural products, except for increases in cGST activities, and endogenous steroid epoxides were generally not inductive. cEH activity towards trans-stilbene oxide (cEHtso) was increased only following treatment with the peroxisome proliferator, tridiphane, but decreased following treatment with several of the epoxides, while microsomal cholesterol epoxide hydrolase (mEHchol) was increased only moderately by disparlure. Microsomes could effectively conjugate glutathione to chlorodinitrobenzene (mGSTcdnb) and cis-stilbene oxide (mGSTcso). These two activities were differentially induced by a few of the epoxides, suggesting that they may be selective substrates for different isozymes of mGST. Correlation coefficients were determined for the relative response of liver weight, subfraction protein, and enzyme activities. A relatively high correlation was found between the response of liver weight and cytosolic hydrolysis of trans-stilbene oxide (r = 0.73) and cis-stilbene oxide (r = 0.62), and cytosolic glutathione conjugation of dichloronitrobenzene (r = 0.66) and trans-stilbene oxide (r = 0.75). In addition, relatively high correlations were found between the different cGST activities, in particular for dichloronitrobenzene with trans-stilbene oxide (r = 0.89). These studies show that there exists a wide variation in the response of xenobiotic-metabolizing enzymes to environmentally encountered epoxides and that a fairly strong correlation exists between the increases in liver size and increases in certain cytosolic enzyme activities; they also suggest further studies concerning the possibility of an additional isozyme of mGST.

Animals↗
PubMed2002

Antioxidant effects of resveratrol and its analogues against the free-radical-induced peroxidation of linoleic acid in micelles.

The antioxidant effect of resveratrol (3,4',5-trihydroxy-trans-stilbene) and its analogues, that is, 4-hydroxy-trans-stilbene (4-HS), 3,5-dihydroxy-trans-stilbene (3,5-DHS), 4,4'-dihydroxy-trans-stilbene (4,4'-DHS), 3,4-dihydroxy-trans-stilbene (3,4-DHS), 3,4,5-trihydroxy-trans-stilbene (3,4,5-THS) and 3,4,4'-trihydroxy-trans-stilbene (3,4,4'-THS), against the peroxidation of linoleic acid has been studied in sodium dodecyl sulfate (SDS) and cetyltrimethyl ammonium bromide (CTAB) micelles. The peroxidation was initiated thermally by a water-soluble azo initiator 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH), and the reaction kinetics were studied by monitoring the formation of linoleic acid hydroperoxides. The synergistic antioxidant effect of these compounds with alpha-tocopherol (vitamin E) was also studied by following the decay kinetics of alpha-tocopherol and the reaction intermediate, the alpha-tocopheroxyl radical. Kinetic analysis of the antioxidant process demonstrates that these compounds are effective antioxidants in micelles used either alone or in combination with alpha-tocopherol. The antioxidative action involves trapping the propagating lipid peroxyl radical and reducing the alpha-tocopheroxyl radical to regenerate alpha-tocopherol. It was found that the antioxidant activity of resveratrol analogues depends significantly on the position of the hydroxyl groups, the oxidation potential of the molecule and the reaction medium. Molecules with ortho-dihydroxyl and/or para-hydroxyl functionalities possess high activity.

Antioxidants↗
PubMed1986

Selective inhibition and selective induction of multiple microsomal epoxide hydrolases.

The inhibition in vitro and induction in vivo of microsomal trans-stilbene oxide hydrolase have been studied. This microsomal epoxide hydrolase activity is distinguishable from the previously well-defined microsomal arene oxide hydrolase by a number of catalytic criteria. Two substituted chalcone oxides, 4-phenylchalcone oxide and 4'-phenylchalcone oxide, are potent inhibitors of microsomal trans-stilbene oxide hydrolase, but have no apparent activity against benzo[a]pyrene 4,5-oxide hydrolase. Conversely, compounds that are potent inhibitors of benzo[a]pyrene 4,5-oxide hydrolase, including styrene oxide, cyclohexene oxide, and trichloropropene oxide, inhibit microsomal trans-stilbene oxide hydrolase only at very high (millimolar) concentrations. The chalcone oxides inhibit microsomal trans-stilbene oxide hydrolase noncompetitively, and have micromolar or nanomolar affinity constants for the enzyme. Attempts were made to induce microsomal trans-stilbene oxide hydrolase in vivo. Compounds that induced microsomal benzo[a]pyrene 4,5-oxide hydrolase levels in mice did not simultaneously induce trans-stilbene oxide hydrolase levels. Clofibrate was an exception; it induced levels of both enzymes to a small but statistically significant degree. The two microsomal hydrolase activities have, therefore, very different catalytic sites and appear to be under separate genetic control. 4-Phenylchalcone oxide and 4'-phenylchalcone oxide are selective inhibitors of microsomal trans-stilbene oxide hydrolase and may prove to be very useful in assessing the involvement of this enzyme in the metabolism of endogenous or xenobiotic epoxides.

Animals↗
PubMed1994

Substituent effects on the in vitro and in vivo genotoxicity of 4-aminobiphenyl and 4-aminostilbene derivatives.

4-Amino-4'-substituted biphenyls and 4-aminostilbenes substituted in the 3' or 4' position were studied for their in vitro and in vivo genotoxicity. The in vitro mutagenicity of the biphenyls with and without S9 activation was established with Salmonella strains TA98 and TA100 and that of the stilbenes with the same strains plus TA98/1,8-DNP6. The in vivo genotoxicity assay with both series of compounds was for chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of the chemicals. Hammett values of substituents, partition coefficients and frontier orbital energies (ELUMO and EHOMO) of the compounds were used for correlations with mutagenicity. The Salmonella mutagenicity in TA98 and TA98/1,8-DNP6 with S9 was correlated to Hammett sigma + values for the 4-aminostilbene substituents, showing a strong trend of increasing mutagenicity with an increase in the electron-withdrawing capability of the substituent. Hydrophobicity of the stilbenes, however, had little effect on their relative mutagenicity. The 4-aminobiphenyls showed a correlation between their mutagenicity and Hammett sigma + values of their 4'-substituents in stain TA98 with S9, although the trend was not as strong as for the stilbenes. But unlike the stilbenes, TA98 mutagenicity of the biphenyls could also be correlated to hydrophobicity, and structure-activity correlations for the biphenyls was substantially improved when both sigma + and hydrophobicity data were included. For strain TA100 with S9, little correlation was found between mutagenicity of the stilbenes and any of the parameters. However, a limited correlation did exist between the mutagenicity of the biphenyls and their hydrophobicity. There was also limited correlations of the mutagenicity for the stilbenes in TA98 and TA98/1,8-DNP6 with S9 to ELUMO or EHOMO. The in vivo genotoxicity results for the biphenyls and stilbenes could not be correlated to electronic effects as for the in vitro results, nor could they be explained by hydrophobicity. However, it is interesting to note that 3'-substituted 4-aminostilbenes were all substantially more genotoxic in vivo than their corresponding 4'-substituted counterparts. The most genotoxic compound in vivo in either series was 4-aminostilbene which would not have been predicted from the in vitro results.

Aminobiphenyl Compounds↗
PubMed2002

Synthesis of trithiolanes and tetrathianes from thiiranes catalyzed by ruthenium salen nitrosyl complexes.

The compound [Ru(salen)(NO)(H(2)O)](SbF(6)) (1) (salen = N,N'-ethylene-bis-salicylidene aminate) reacts catalytically with thiiranes and converts them to olefins and 1,2,3,4-tetrathianes or 1,2,3-trithiolanes. The monosubstituted thiiranes styrene sulfide and propylene sulfide reacted to form the corresponding olefin and the 4-substituted 1,2,3-trithiolane in a 2:1 ratio in isolated yields in excess of 90%. The disubstituted thiirane cis-stilbene sulfide was converted to cis-stilbene and 5,6-trans-1,2,3,4-diphenyltetrathiane in a 3:1 ratio in the presence of a catalytic amount of 1 in CD(3)NO(2). Coordination of cis-stilbene sulfide to the salen complex in a ligand substitution reaction was established by isolation of [Ru(salen)(NO)(cis-stilbene sulfide)](SbF(6)) (6). (1)H NMR studies performed on 6 indicated that the salen macrocycle had rearranged upon thiirane coordination. A similar rearrangement was found to be stabilized by other ligands including tetramethylethylene sulfide, tetrahydrothiophene, and d(3)-acetonitrile. The alpha-deuterio-cis-stilbene sulfide catalyst adduct (d-6) reacted with unlabeled cis-stilbene sulfide to form deuterium-labeled trans-diphenyl-tetrathiane and unlabeled cis-stilbene as shown by GCMS and (1)H NMR. Thus, the solution thiirane behaves as a sulfur donor and forms olefin, whereas the coordinated thiirane becomes the cyclic polysulfide. beta-cis-Deuteriostyrene sulfide was used to show that ring closure to form cyclic polysulfide incorporated inversion of stereochemistry versus starting thiirane. A mechanism for catalysis consistent with experimental data is presented that requires coordination of thiirane to the metal complex followed by bimolecular attack of free thiirane on the coordinated thiirane.

Journal Article↗
PubMed1993

Disease resistance results from foreign phytoalexin expression in a novel plant.

Although phytoalexins have long been inferred to be important in the defence of plants against fungal infection, there are few reports showing that they provide resistance to infection. Several plants, including grapevine, synthesize the stilbene-type phytoalexin resveratrol when attacked by pathogens. Stilbenes with fungicidal potential are formed in several unrelated plant species, such as peanut (Arachis hypogaea), grapevine (Vitis vinifera) and pine (Pinus sylvestris). Stilbene biosynthesis only specifically requires the presence of stilbene synthase. Furthermore, the precursor molecules for the formation of hydroxy-stilbenes are malonyl-CoA and p-coumaroyl-CoA, both present in plants. To investigate the potential of stilbene biosynthetic genes in a strategy of engineering pathogen resistance, we isolated stilbene synthase genes from grapevine, where they are expressed at a high level, and transferred them into tobacco. We report here that regenerated tobacco plants containing these genes are more resistant to infection by Botrytis cinerea. This is, to our knowledge, the first report of increased disease resistance in transgenic plants based on an additional foreign phytoalexin.

Acyltransferases↗
PubMed2003

Temperature-dependent behavior of protein-chromophore interactions: a theoretical study of a blue fluorescent antibody.

The unusual temperature-dependent excited-state dynamics of a stilbene-antibody complex reported by Simeonov et al. are explored using theoretical methods. The anomalous temperature-dependent fluorescence emission and lifetime are shown to be the result of interplay among temperature-modulated protein flexibility, the excited-state potential surface for the stilbene central twist, and changes in the stilbene charge distribution upon excitation. Stilbene is found to possess a similar geometry and orientation within the antibody binding pocket at all temperatures in the ground state and at low temperatures (approximately 240 K) in the excited state. At higher temperatures (approximately 260 K), the excited-state conformation twists around the central double bond and adopts an alternate orientation within the binding pocket. These changes result from protein side chain and loop motions that are frozen out at lower temperatures and account for the observed red shift of the fluorescence emission spectrum (a calculated shift of 3.8 kcal mol-1 compares favorably with the approximately 5 kcal.mol-1 observed experimentally). Approximately 3.0 kcal mol-1 of this stabilization is global in nature and is not attributable to specific local interactions. Local interactions between stilbene and Tyr-B39 contribute approximately 0.8 kcal mol-1 to the fluorescence shift. The primary structural change in simulations of the high temperature excited state involves a decrease in the stilbene-tyrosine distance and a relative change in orientation of the aromatic rings. We identify several nearby charged residues that contribute to the fluorescence emission shift and provide targets for mutagenesis to probe the temperature-dependent dynamics of protein-chromophore interactions.

Light↗
PubMed1985

Induction of epoxide hydrolase in cultured rat hepatocytes and hepatoma cell lines.

The expression of epoxide hydrolases was studied in cultured rat hepatocytes and hepatoma cell lines. Styrene 7,8-oxide and benzo[a]pyrene 4,5-oxide were used as substrates for microsomal epoxide hydrolase and trans-stilbene oxide for the cytosolic form of this enzyme. In freshly isolated hepatocytes from control rats, microsomal epoxide hydrolase activity was 7.7 and 10.8 nmoles/mg cellular protein/min with benzo[a]pyrene 4,5-oxide and styrene 7,8-oxide as substrates respectively. This enzyme activity increased by more than 2-fold in hepatocytes after 24 hr in culture and remained elevated throughout 96 hr using both substrates. In cultured hepatocytes from rats pretreated in vivo with phenobarbital, trans-stilbene oxide, 2-acetylaminofluorene and N-hydroxy-2-acetylaminofluorene, both benzo[a]pyrene 4,5-oxide and styrene 7,8-oxide hydrolase activities were increased greater than 1.8 relative to controls. Hepatocytes from 2-acetylaminofluorene-pretreated animals at 24 hr in culture had approximately 9-fold higher activities than control hepatocytes. In marked contrast to microsomal epoxide hydrolase activity, the cytosolic enzyme showed an initial activity of 191 pmoles/mg cellular protein/min in freshly isolated hepatocytes, decreased by 75% after 24 hr in culture, and was barely detectable at 96 hr. A similar trend was apparent in hepatocytes from the pretreated animals. In vitro treatment of hepatocytes with trans-stilbene oxide and phenobarbital increased microsomal epoxide hydrolase, while this activity was refractory to 2-acetylaminofluorene treatment. Styrene 7,8-oxide hydrolase activity was increased in the McA-RH-7777 rat hepatoma cell line by phenobarbital, trans-stilbene oxide and 2-acetylaminofluorene treatment. Similarly, benzo[a]pyrene 4,5-oxide hydrolase activity was also increased in this cell line by treatment with phenobarbital and trans-stilbene oxide but not by 2-acetylaminofluorene. Microsomal epoxide hydrolase activity in rat H4-II-E hepatoma cells was refractory to induction, except by trans-stilbene oxide treatment, which caused a 70% increase in benzo[a]pyrene 4,5-oxide hydrolase activity.

2-Acetylaminofluorene↗
PubMed1986

Epoxide hydrolysis in the cytosol of rat liver, kidney, and testis. Measurement in the presence of glutathione and the effect of dietary clofibrate.

The hydrolysis of trans- and cis-stilbene oxide and benzo[a]pyrene-4,5-oxide was measured in cytosol and microsomes of liver, kidney, and testis of control and clofibrate-fed rats. Significant levels of nonprotein sulfhydryls were detected in cytosol from liver (4.6 mM) and testis (1.5 mM). Glutathione was moderately stable in these fractions and interfered with the partition assays as conjugates were retained in the aqueous phase along with diols. When the products were separated by thin-layer chromatography, significant amounts of glutathione-conjugates were found to have been formed in the cytosol of liver and testis. Overnight dialysis or preincubation of cytosol with 0.5 mM diethylmaleate eliminated conjugate formation without affecting diol production. In dialyzed cytosol from clofibrate-fed rats (0.5%, 14 days), the rates of hydrolysis of trans-stilbene oxide were 506, 171, and 96% of controls for liver, kidney, and testis, respectively, and 126% of controls in liver microsomes. Rates of hydrolysis of cis-stilbene oxide were 149, 172, and 96% of controls in microsomes and 154, 124, and 91% of controls in cytosols from livers, kidneys, and testis of clofibrate-fed rats respectively. Hydrolysis of benzo[a]pyrene-4,5-oxide was similar to that of cis-stilbene oxide. Conjugation of the cis-stilbene oxide with glutathione was detected in cytosols from all three tissues with lesser amounts in the microsomes from liver and kidneys. After clofibrate treatment, the rates of this activity were 200, 173, and 95% of controls in cytosol from liver, kidneys and testis, and 203 and 202% of controls in microsomes from liver and kidneys respectively. These results indicate that epoxide hydrolysis and conjugation in rat liver and kidney are responsive to clofibrate treatment and support other evidence which suggests that hydrolysis of cis- and trans-stilbene oxides in cytosol is catalyzed, in part, by distinct enzymes.

Animals↗
PubMed2003

Effects of hydroxystilbene derivatives on tyrosinase activity.

Synthesis of melanin starts from the conversion of L-tyrosine to 3,4-dihydroxyphenylalanine (L-dopa) and then the oxidation of L-dopa yields dopaquinone by tyrosinase. Therefore, tyrosinase inhibitors have been established as important constituents of depigmentation agents. Recently, polyhydroxystilbene compounds, which are trans-resveratrol (3,4('),5-trihydroxy-trans-stilbene) analogs, have been demonstrated as potent tyrosinase inhibitors. However, their detailed inhibitory mechanisms are not clearly understood. In the present study, a variety of synthesized hydroxystilbene compounds were tested for their inhibitory effects against murine tyrosinase activity. The inhibitory potencies of the hydroxy-trans-stilbene compounds were remarkably elevated by increasing number of phenolic hydroxy substituents. Methylated hydroxy-trans-stilbene lost the inhibitory activity. Furthermore, hydrogenated hydroxystilbene or hydroxy-cis-stilbene exerted little or no inhibitory effect compared with hydroxy-trans-stilbene on tyrosinase activity. The structure-activity relationships demonstrated in the present study suggest that the phenolic hydroxy groups and trans-olefin structure of the parent stilbene skeleton contribute to the inhibitory potency of hydroxystilbene for tyrosinase activity.

Animals↗
PubMed2003

Grape polyphenol resveratrol and the related molecule 4-hydroxystilbene induce growth inhibition, apoptosis, S-phase arrest, and upregulation of cyclins A, E, and B1 in human SK-Mel-28 melanoma cells.

The effect of the naturally occurring polyphenol resveratrol (3,5,4'-trihydroxy-trans-stilbene; RES) on growth, cell cycle, and cyclins A, E, and B1 expression was investigated in the human SK-Mel-28 melanoma cell line. In addition, the structurally related compounds 4-hydroxy-trans-stilbene (4HST), piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene (PICE), and 4-trans-stilbenemethanol (4STMe) were also assayed in order to investigate the requirements of stilbenes to exert activity against melanoma cells. Both RES and 4HST inhibited cell growth in a dose- and time-dependent manner and upregulated the expression of cyclins A, E, and B1 with subsequent irreversible arrest of melanoma cells in the S-phase, concomitant with a decrease in G0/G1 and G2/M phases. In addition, potent apoptosis-mediated cell death was detected with the annexin V assay whereas no apoptosis was observed by flow cytometry, which encourages the assay of different methodologies to evaluate the effect of polyphenols on cell lines. The effect of PICE was not evaluated because of its instability in the reaction medium. No effect on cell cycle and cyclins expression was observed when 4STMe was assayed, which supported the critical requirement of the 4'-hydroxystyryl moiety to exert the above effects. In addition, this structural requirement also influenced the cellular uptake of stilbenes. The presence of two extra hydroxyl groups in RES increased its cytotoxicity whereas it diminished its efficiency to inhibit cell growth, upregulate cyclins expression, and arrest cell cycle in the S-phase with respect to 4HST. The present study suggests that the antimelanoma properties of dietary stilbenes, such as grape RES, cannot be ruled out, taking into account previous studies concerning the relationship between plasma and tissue concentrations and pharmacological activity of RES in animal models.

Apoptosis↗
PubMed2003

Synthesis and biological evaluation of resveratrol and analogues as apoptosis-inducing agents.

Resveratrol 1 (3,4',5-trihydroxy-trans-stilbene), a phytoalexin present in grapes and other food products, has recently been suggested as a potential cancer chemopreventive agent based on its striking inhibitory effects on cellular events associated with cancer initiation, promotion, and progression. This triphenolic stilbene has also displayed in vitro growth inhibition in a number of human cancer cell lines. In this context, a series of cis- and trans-stilbene-based resveratrols were prepared with the aim of discovering new lead compounds with clinical potential. All the synthesized compounds were tested in vitro for cell growth inhibition and the ability to induce apoptosis in HL60 promyelocytic leukemia cells. The tested trans-stilbene derivatives were less potent than their corresponding cis isomers, except for trans-resveratrol, whose cis isomer was less active. The best results were obtained with compounds 11b and 7b, the cis-3,5-dimethoxy derivatives of rhapontigenin 10a (3,5,3'-trihydroxy-4'methoxy-trans-stilbene) and its 3'-amino derivative 10b, respectively, which showed apoptotic activity at nanomolar concentrations. The corresponding trans isomers 12b and 8b were less active both as antiproliferative and as apoptosis-inducing agents. Of interest, 11b and 7b were active toward resistant HL60R cells and their activity was higher than that of several classic chemotherapeutic agents. The flow cytometry assay showed that at 50 nM compounds 7b or 11b were able to recruit almost all cells in the apoptotic sub-G(0)-G(1) peek, thus suggesting that the main mechanism of cytotoxicity of these compounds could be the activation of apoptosis. These data indicate unambiguously that structural alteration of the stilbene motif of resveratrol can be extremely effective in producing potent apoptosis-inducing agents.

Antineoplastic Agents↗
PubMedDate not supplied

Resveratrol oligomers are potent MRP1 transport inhibitors.

BACKGROUND: Knowledge of the structure-activity relationships of multidrug resistance protein 1 (MRP1, ABCC1) inhibitors may aid in developing potent inhibitors that can be used to circumvent MRP1-mediated multidrug resistance. MATERIALS AND METHODS: Six stilbenes were examined for their ability to inhibit MRP1-mediated transport of 2',7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein (BCPCF) from human erythrocytes and into inside-out erythrocyte membrane vesicles (IOVs). The concentrations of stilbenes decreasing BCPCF transport by 50% during 60 min of incubation at 37 degrees C (IC50) were determined from dose-response curves. RESULTS: Stilbenes inhibited BCPCF transport in cells in the rank order (+)-alpha-viniferin (IC50 = 0.8 microM) > sophorastilbene A (IC50 = 3.1 microM) > (-)-epsilon-viniferin (IC50 = 8.9 microM) > piceatannol (IC50 = 57 microM). Resveratrol and rhaponticin were ineffective. (+)-alpha-Viniferin (IC50 = 0.8 microM), sophorastilbene A (IC50 = 3.7 microM) and (-)-epsilon-viniferin (IC50 = 3.5 microM) were also efficient BCPCF transport inhibitors in IOVs. CONCLUSION: Stilbenes may efficiently inhibit MRP1-mediated organic anion transport. This inhibitory potency of stilbenes increases with oligomerisation. The membrane is not a strong barrier for the inhibitory activity of the trimeric stilbenes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Human glutathione S-transferase deficiency as a marker of susceptibility to epoxide-induced cytogenetic damage.

The identification of genetic traits that predispose individuals to environmentally induced cancers is one of the most important problems in cancer risk assessment. Genetic deficiency in the mu-isozyme of the glutathione (GSH) S-transferases (EC 2.5.1.18) has recently been associated with increased lung cancer risk. To test whether this association could arise from a metabolically mediated sensitivity to mutagenic substrates, cytogenetic damage in lymphocytes from 21 isozyme-deficient and 24 nondeficient individuals was induced. Cells were treated with trans-stilbene oxide, an excellent substrate for GSH S-transferase mu, or cis-stilbene oxide, a poor substrate for the isozyme. Sister chromatid exchange induction was measured as an indicator of cytogenetic damage. A trimodal distribution of trans-stilbene oxide-induced sister chromatid exchanges was observed in the population, including resistant, moderate, and highly sensitive groups. Glutathione S-transferase mu deficiency was associated with both moderate and high sensitivity to trans-stilbene oxide-induced damage but had no effect on cis-stilbene oxide-induced sister chromatid exchange. The results indicate that GSH S-transferase mu, a proposed marker of cancer susceptibility, is also a marker of susceptibility to the induction of cytogenetic damage by a certain class of mutagens. The differential effects of the cis- and trans-isomers of stilbene oxide illustrate that the stereoselectivity of GSH S-transferase mu toward various alkene epoxide substrates can be an important factor affecting individual sensitivity to DNA-damaging epoxides.

Adult↗
PubMed2005

Synthesis, dual fluorescence, and fluoroionophoric behavior of dipyridylaminomethylstilbenes.

The synthesis, dual fluorescence, and fluoroionophoric behavior of two donor-sigma spacer-acceptor (D-s-A) compounds, trans-4-(N,N-bis(2-pyridyl)amino)methylstilbene (1H) and trans-4-(N,N-bis(2-pyridyl)amino)methyl-4'-cyanostilbene (1CN), are reported and compared to that of trans-4-(N,N-bis(2-pyridyl)amino)methyl-4'-(N,N-dimethylamino)stilbene (1DPA). To gain insights into the dual fluorescence properties for 1H and 1CN in polar but not in nonpolar solvents, model compounds resulting from a replacement of the stilbene group by alkyl (2R) or xylyl (2X) groups or from a replacement of the dipyridylamino (dpa) group by dianisoleamino (3AA), diethylamino (3EE), methylanilino (3MP), or diphenylamino (3PP) groups also have been investigated. In addition to 1H and 1CN, all four compounds of 3 display dual fluorescence. The locally excited (LE) fluorescence mainly results from the stilbene group and the ICT fluorescence from the through-bond interactions between the amino donor and the stilbene acceptors. In the presence of transition metal ions such as Zn(II), Ni(II), Cu(II), and Cd(II), the ICT processes are switched from dpa (D) --> stilbene (A) in 1H and 1CN to stilbene (D) --> dpa/metal ion (A) in their complexes. Whereas the ICT states for the complexes are generally nonfluorescent, an exception was found for the case of 1H/Zn(II). As a result, substituent-dependent fluoroionophoric behavior has been demonstrated by 1H, 1CN, and 1DPA in response to Zn(II).

Journal Article↗