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PubMed2002

[Quantitative genetic analysis and multiple trait selection of pharmaceutical composition on Ginkgo biloba L. leaves].

The China possesses more than 70% Ginkgo resources in the world. The purposes of this research are to collect fine seedling and grafting clones in China, to probe genetic law on flavone glycosides and terpenes on Ginkgo leaves, and select leaf-used cultivars of high-pharmaceutical composition. In this research, we have collected 87 clones from 13 provenances and have carried out randomized block experiment at Tancheng, Laizhou and Yaoxiang in Shandong Province. Flavone glycosides and terpenes were determined through HPLC method from an improved Van Beek (1991) techniques and Shimadzu Lc-10 AD (Japan). Data and breeding analyses were carried out through IBMPC and SPQG30 software. The results of variance analyses show that there are significant differences to flavone glycosides, terpenes in clones, and the law of genetic parameters on heritability (h2) and genetic variability coefficient (Gcv), is clone > sex > provenance to flavone glycosides in ginkgo leaves. The sigma g2, h2, Gcv and delta G' in male tree clone leaves are higher than female clone leaves on flavone glycosides. We have found that there is a maximum flavone content clone among males and a maximum terpene clone among females. The results of Q-cluster analyses are consistent with R-factor analyses of twenty higher terpenes clones. The results of index selection show that the ri.Y2, E(I) and CGS' of multiple traits selection including (gamma) trait are higher than single trait and multiple traits selection excluding gamma. The direct or index selection is more suited to leaf-used cultivars of Ginkgo. The genetic stability of each clone was appraised by Wricke's ecovalence method and Nassar & Huhu noparameter method. Flavone glycosides and terpenes are more than 2.09%-2.57% and 0.33%-0.41%, respectively, and we have selected four clones.

Breeding↗
PubMedDate not supplied

Effects of flavonoids on cytochrome P450-dependent acetaminophen metabolism in rats and human liver microsomes.

Flavonoids are widely occurring in our diet. In this study, the effects of nine flavonoids on acetaminophen (APAP) oxidation and related cytochrome P450 (P450) enzyme activities were investigated. With rat liver microsomes, APAP oxidation was stimulated 2- to 4-fold by 50 microM flavone or tangeretin and inhibited 65% by myricetin or quercetin. Only a slight inhibition of APAP oxidation was caused by naringenin. All the effects cited herein were from experiments with 50 microM flavonoids. With human liver microsomal samples that had high P450 3A4 activity, APAP oxidation was stimulated 1.6- to 3.0-fold by tangeretin, nobiletin, and flavone, but inhibited 40-60% by myricetin and quercetin. With human P450 1A2 expressed in Hep G2 cells, APAP oxidation was inhibited completely by flavone or quercetin. With expressed P450 3A4, this reaction was stimulated 4-fold by flavone, but inhibited 60% by quercetin. The expressed human P450 2E1-dependent APAP oxidation was only slightly affected by flavone and quercetin. The mechanisms of the inhibition and stimulation were complex and varied with the different P450 forms and flavonoids used in the system. The O-deethylation of ethoxyresorufin in rat liver microsomes was effectively inhibited by myricetin (IC50, 15 microM) and moderately inhibited by flavone, tangeretin, and quercetin (IC50, 50-80 microM); with P450 1A2 in Hep G2 cell microsomes, the activity was markedly inhibited by flavone (IC50, 2.5 microM). The microsomal P450s 2E1 and 3A activities were inhibited by myricetin (IC50, 85-90 microM), but not effectively inhibited by other flavonoids.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed2006

Protective effect of ethanolic and water extracts of sea buckthorn (Hippophae rhamnoides L.) against the toxic effects of mustard gas.

Ethanolic extract of H. rhamnoides L. leaf (HL-EOH), water and ethanolic extract of H. rhamnoides fruit (HF-W and HF-EOH), and H. rhamnoides flavone from fruit (HR-flavone) were evaluated against percutaneously administered sulphur mustard (SM), a chemical warfare agent. The animals administered with SM (9.7, 19.3 and 38.7 mg/kg) died at various days depending upon the dose and there was a significant reduction in the body weight. The H. rhamnoides extracts (1 g/kg; 3 doses; po) significantly protected the lethality, with a protective index of 2.4, 1.7, 1.7 and 2.2 for HL-EOH, HF-W, HF-EOH and HR-flavone respectively. Reduced glutathione (GSH) and oxidized glutalthione (GSSG) levels were reduced, and malondialdehyde (MDA) was elevated after percutaneous administration of SM. Oral administration of HL-EOH and HR-flavone significantly protected the body weight loss. Recovery in the levels of GSH, GSSG and MDA were also observed following oral administration of HL-EOH and HR-flavone. All the extracts were non-toxic and the LD50 was more than 5 g/kg. The present study shows that percutaneous administration of SM induces oxidative stress and ethanolic extract of leaf of H. rhamnoides and H. rhamnoides flavone from fruit can significantly protect it.

Animals↗
PubMedDate not supplied

Dietary agents in cancer prevention: flavonoids and isoflavonoids.

Flavones and isoflavones may play a prominent role in cancer prevention since these compounds are found in numerous plants that are associated with reduced cancer rates. This article reviews recent epidemiological and animal data on isoflavones and flavones and their role in cancer prevention. It covers aspects of the bioavailability of these dietary constituents and explores their mechanism of action. Human epidemiology data comes primarily from studies in which foods rich in isoflavones or flavones are associated with cancer rates. This approach has been particularly useful with isoflavones because of their abundance in specific foods, including soy foods. The bioavailability of flavones and isoflavones has been shown to be influenced by their chemical form in foods (generally glycoside conjugates), their hydrophobicity, susceptibility to degradation, the microbial flora of the consumer, and the food matrix. Some information is available on how these factors influence isoflavone bioavailability, but the information on flavones is more limited. Many mechanisms of action have been identified for isoflavone/flavone prevention of cancer, including estrogenic/antiestrogenic activity, antiproliferation, induction of cell-cycle arrest and apoptosis, prevention of oxidation, induction of detoxification enzymes, regulation of the host immune system, and changes in cellular signaling. It is expected that some combination of these mechanisms will be found to be responsible for cancer prevention by these compounds. Compelling data suggest that flavones and isoflavones contribute to cancer prevention; however, further investigations will be required to clarify the nature of the impact and interactions between these bioactive constituents and other dietary components.

Animals↗
PubMed1998

Synthesis and structure-activity relationships of carboxyflavones as structurally rigid CysLT1 (LTD4) receptor antagonists.

The synthesis and CysLT1 receptor affinities of a new series of highly rigid 3'- and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinolinyl)ethenyl]-substituted, 6-, 7-, or 8-carboxylated flavones are described. CysLT1 receptor affinities of the flavones (down to 11 nM) were determined by their ability to displace [3H]LTD4 from its receptor in guinea pig lung membranes. Structure-affinity relationship studies showed that the relative positions of the carboxylic acid and the quinoline moiety were critical for CysLT1 affinities. While the carboxyl is optimal in the 8 position but tolerated in the 6 position, only the 6- and not the 8-tetrazole has significant activity. The quinoline moiety may be connected to the flavone skeleton by an ethenyl or a methoxy linker, but the substitution position is important for high affinity, especially in the 6-carboxylated flavones. 4'-Substituted 6-carboxyflavones are essentially inactive, whereas the 3'-substituted analogues have submicromolar CysLT1 affinity. Replacement of the quinoline by other heteroaromates generally leads to decreased affinities, with the phenyl and naphthyl analogues displaying only little or no affinity, while the 7-chloroquinoline analogue is comparable in activity to the quinoline. Flavones having CysLT1 receptor affinities of 10-30 nM were selected for determination of their inhibitory effects on the LTD4-induced contraction of guinea pig ileum in vitro. The IC50 values ranged between 15 and 100 nM. Compound 5d (8-carboxy-6-chloro-3'-(2-quinolinylmethoxy)flavone, VUF 5087) was selected for further research because of its high potency in the functional assay. This series contains the most rigid CysLT1 receptor antagonists known to date, and they are useful in the development of a CysLT1 antagonist model, which is discussed in the companion paper.

Animals↗
PubMed2005

Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: a prospective study and cross-sectional analysis.

OBJECTIVE: Flavonoids, as antioxidants, may prevent the progressive impairment of pancreatic beta-cell function due to oxidative stress and may thus reduce the occurrence of type 2 diabetes. The aim of the present study was to examine the association of dietary flavonol and flavone intake with type 2 diabetes, and biomarkers of insulin resistance and systemic inflammation. METHODS: In 38,018 women aged > or =45 y and free of cardiovascular disease, cancer and diabetes with an average 8.8 y of follow-up, we calculated relative risks (RRs) of incident type 2 diabetes (1,614 events) according to dietary intake of total or individual flavonols and flavones and flavonoid-rich foods. We also measured and examined plasma concentrations of insulin, HbA(1C), CRP, and IL-6 in relation to total flavonol and flavone intake among 344 nondiabetic women. RESULTS: During 332,905 person-years of follow-up, none of total flavonols and flavones, quercetin, kaempferol, myricetin, apigenin, and luteolin was significantly associated with risk of type 2 diabetes. Among flavonoid-rich foods, apple and tea consumption was associated with diabetes risk. Women consuming > or =1 apple/d showed a significant 28% reduced risk of type 2 diabetes compared with those who consumed no apples (the multivariate-adjusted RR = 0.72, 95% CI: 0.56, 0.92; p = 0.006 for trend). Tea consumption was also inversely associated with diabetes risk but with a borderline significant trend (> or =4 cups/d vs. none: RR 0.73, 95% CI: 0.52-1.01; p for trend = 0.06). In 344 nondiabetic women, total intake of flavonols and flavones was not significantly related to plasma concentrations of fasting insulin, HbA(1C), CRP, or IL-6. CONCLUSIONS: These results do not support the hypothesis that high intake of flavonols and flavones reduces the development of type 2 diabetes, although we cannot rule out a modest inverse association with intake of apples and tea.

Biomarkers↗
PubMed2006

Functional diversity of flavonoids in the inhibition of the proinflammatory NF-kappaB, IRF, and Akt signaling pathways in murine intestinal epithelial cells.

The molecular understanding of nutritional factors in the process of host factor-mediated activation of the intestinal epithelium may play an important role in the assessment of adjunct nutritional therapy for chronic intestinal inflammation. We characterized the molecular mechanisms of flavonoids including apigenin, luteolin, genistein, 3'-hydroxy-flavone, and flavone in inhibiting tumor necrosis factor-alpha (TNF)-induced interferon-induced protein (IP)-10 gene expression in the murine intestinal epithelial cell (IEC) line Mode-K. We demonstrated that 3'-hydroxy-flavone but not the chemical core structure flavone blocked TNF-alpha-induced nuclear factor (NF)-kappaB transcriptional activity and IP-10 expression at the level of NF-kappaB/IkappaBalpha phosphorylation/degradation by inhibiting IkappaB kinase activity. Although 3'-hydroxy-flavone effectively triggered p38 mitogen-activated protein kinase signaling and late caspase-3 cleavage, the induction of apoptotic cell death in TNF-activated IEC was not the primary mechanism inhibiting NF-kappaB transcriptional activity and IP-10 expression. In addition to the compound-specific inhibition of TNF-induced NF-kappaB DNA binding and NF-kappaB transcriptional activity, apigenin and luteolin selectively blocked Akt phosphorylation/activity. The ability of these polyphenolic compounds to target various signal transduction pathways was further supported by the observation that luteolin and 3'-hydroxy-flavone selectively induced interferon regulatory factor (IRF)-1 degradation. Finally, we showed that genistein blocked IP-10 but not IL-6 expression through NF-kappaB, IRF, and Akt independent mechanisms, demonstrating the functional diversity of flavonoids in inhibiting proinflammatory processes in IEC. In conclusion, we provide molecular evidence for the presence of characteristic inhibition patterns of these polyphenolic compounds to inhibit proinflammatory gene expression in IEC through the specific modulation of the NF-kappaB, IRF and Akt signaling pathways.

Animals↗
PubMed1998

Inhibition of 17beta-hydroxysteroid oxidoreductase by flavonoids in breast and prostate cancer cells.

Several flavonoids and isoflavonoids were found to inhibit 17beta-oxidoreduction of estrogens by the purified 17beta-HSOR type 1, or in cell lines expressing 17beta-HSOR type 1 enzyme (T-47D breast cancer cells) or type 2 (PC-3 prostate cancer cells). The structural demands for the inhibition of estrone (E1) reduction and estradiol (E2) oxidation catalyzed by 17beta-HSOR types 1 and 2, respectively, were not identical. Flavones, flavanones, and isoflavones hydroxylated at both the double ring (positions 5 and 7) and ring B (position 4') were the most potent inhibitors of E1 reduction in T-47D cells, and by the purified type 1 enzyme whereas flavones hydroxylated at positions 3, 5, and 7 of rings A and C, with or without a hydroxyl group in ring B, were capable of inhibiting E2 oxidation in PC-3 cells. Change to flavanone structure, or hydroxylation at position 3 of ring C of flavones, or methylation of the hydroxyl group at position 4' of ring B of flavones and isoflavones reduced or abolished their inhibitory activity on E1 reduction in T-47D cells. On the contrary, hydroxyl group at position 3 of flavones (flavonol structure) markedly increased the inhibition of E2 oxidation in PC-3 cells. Thus, changes in the number and location of hydroxyl groups may discriminate inhibition of E1 reduction and E2 oxidation. Some of the differences may be due to differences in pharmacokinetics of these compounds in T-47D and PC-3 cells. Inhibition of 17beta-HSORs could lead to an alteration in the availability of the highly active endogenous estrogen, but the effects of these compounds in vivo cannot be predicted on the basis of these results alone. Some of these compounds (isoflavones) are estrogenic per se, and they may replace endogenous estrogens, whereas flavones are only very weakly estrogenic or nonestrogenic. Regarding prevention or treatment of estrogen-related diseases, apigenin, coumestrol, and genistein raise special interest.

17-Hydroxysteroid Dehydrogenases↗
PubMed1998

Effects of selected flavonoids on deformability, osmotic fragility and aggregation of human erythrocytes.

The effects of 8 selected flavonoids of deformability, osmotic fragility and dextran-induced aggregation of human erythrocytes were studied. The following flavonoids were found to protect against loss of filterability (deformability) through 5 microns diameter pores of erythrocytes dehydrated with calcium ionophore A23187 (1.9 mumol/l): apigenin > quercetin > cirsimaritin > rutin > luteolin > chrysoeriol-4'-O-glucoside > 3,5,7-trihydroxy 4'-methoxy flavone 7-rutinoside, whereas beta-naphtho flavone enhanced the loss of filterability. When the potassium ionophore valinomycin (18 mumol/l) was used to induce cell dehydration, the order of potency of the flavonoids in protecting against loss of filterability was apigenin > cirsimaritin = chrysoeriol-4'-O-glucoside > 3,5,7-trihydroxy 4'-methoxy flavone 7-rutinoside > luteolin = rutin > quercetin, whereas beta-naphtho flavone again enhanced the loss of filterability. All flavonoids reduced ESR measured over 1 h except for 3,5,7-trihydroxy 4'-methoxy flavone 7-rutinoside which showed no effect, and for quercetin which significantly enhanced ESR. All flavonoids also improved erythrocyte osmotic fragility except for apigenin which significantly increased osmotic fragility. These effects were explained in terms of the number and location of hydroxyl groups on the basic skeleton of flavone. The results suggest that the presence of an OH and C5 is essential for the described rheological effects of these flavonoids.

Adult↗
PubMed1996

Differential effects of nonhydroxylated flavonoids as inducers of cytochrome P450 1A and 2B isozymes in rat liver.

Flavanone, flavone, and tangeretin differentially affected the activities of cytochrome P540 1A and 2B isozymes in rat liver. Flavone and, to a lesser extent, tangeretin, increased activities of ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, and pentoxyresorufin O-dealkylase (PROD), whereas flavanone mainly enhanced PROD activity. Immunoblot analysis indicated that flavone and tangeretin increased cytochrome P450 1A1, 1A2, and 2B1,2 forms, whereas flavanone only enhanced the cytochrome P450 2B isozymes. Northern blot study showed that flavone and tangeretin increased the level of the cytochrome P450 1A2 mRNAs. The concentration of the other mRNAs were slightly or not affected by flavonoids. These results suggest that the induction of P450 1A2 by flavone and tangeretin might involve a transcriptional and/or post-transcriptional mechanism.

Animals↗
PubMed1992

Inhibition of microsome-mediated binding of benzo[a]pyrene to DNA by flavonoids either in vitro or after dietary administration to rats.

The in vitro and in vivo effects of selected natural flavonoids (flavone, flavanone, tangeretin, quercetin, chrysin) on the microsome-catalysed binding of [3H]benzo[a]pyrene to calf thymus DNA were investigated and compared with those of two synthetic flavonoids, 7,8-benzoflavone and 5,6-benzoflavone. In vitro addition of these flavonoids (0.1 mM) to an incubation system containing hepatic microsomes prepared from Aroclor 1254-pretreated rats strongly inhibited BaP-DNA adduct formation (72-89%). The incubation of BaP with hepatic microsomes prepared from animals fed 0.3% quercetin, tangeretin and 7,8-benzoflavone for 2 weeks also resulted in less effective binding of BaP metabolites to added DNA, than with microsomes from untreated rats. Other tested compounds, chrysin, flavone, flavanone and 5,6-benzoflavone showed no or little effect. The influence of flavonoid pretreatment on hepatic microsomal enzymes involved in BaP metabolism has also been examined. Aryl hydrocarbon hydroxylase activity was moderately increased (1.5-1.8-fold) in microsomes prepared from rats fed flavone, tangeretin, 7,8-benzoflavone and 5,6-benzo-flavone. Epoxide hydrolase activity was enhanced by 7,8-benzoflavone (1,6-fold), and by flavone and flavanone (5-fold). These results confirm that flavonoids, in vitro, are potent inhibitors of carcinogen-DNA binding. Oral administration of 0.3% flavonoids alters the properties of liver microsomes, resulting in the decreased ability of BaP metabolites to bind DNA.

Animals↗
PubMed1997

The estrogenic and antiestrogenic activities of phytochemicals with the human estrogen receptor expressed in yeast.

We have used the expression of the human estrogen receptor (hER) and two estrogen response elements linked to the lacZ gene in yeast (YES) to study the estrogenic and antiestrogenic activities of various phytochemicals. Coumestrol, alpha-zearalenol, or genistein could produce beta-galactosidase activity comparable to estradiol, but these required concentrations 100 to 1000-fold greater than estradiol. These compounds did not possess antiestrogenic activity. Narigenin, kaempferide, phloretin, biochanin A, flavone, or chrysin only partially induced beta-galactosidase activity in the YES at any concentration tested. When narigenin, kaempferide, or phloretin was given concurrently with estradiol, the estradiol-dependent beta-galactosidase activity was not inhibited by more than 50%. However, biochanin A, flavone, or chrysin could inhibit the activity of estradiol in a dose-response manner with IC50 values of 500 nM, 2 microM, and 10 microM, respectively. Combinations of biochanin A, chrysin, and flavone decreased estradiol-dependent beta-galactosidase activity in an additive fashion. Similar to the antiestrogens tamoxifen or ICI 182, 780, the antiestrogenic activity of these compounds with the exception of chrystin involved the disruption of hER dimerization, as demonstrated in the yeast two-hybrid system. Biochanin A, chrysin, or flavone were less effective in inhibiting the activity of an estrogenic polychlorinated biphenyl than they were inhibiting the activity of estradiol. Interestingly, this latter group of antiestrogenic phytocompounds did not inhibit the estrogenic activity of such phytochemicals as coumestrol or genistein. These results suggest that the antiestrogenic activity of biochanin A and flavone occurs by a mechanism similar to tamoxifen or ICI 182,780. Moreover, it seems that phytochemicals functioning as antiestrogens do not inhibit the activity of all estrogenic chemicals to the same extent. This suggests that conformational changes induced by different estrogens bound to the hER may regulate the antiestrogenic activity of a compound.

Anticarcinogenic Agents↗
PubMed1996

Comparative effects of flavonoids and model inducers on drug-metabolizing enzymes in rat liver.

The inducing effects of some flavonoids (flavone, flavanone, tangeretin and quercetin) and model substances have been studied in rats, and the activity and the expression of drug-metabolizing enzymes have been compared in rats. The addition of flavonoids to the diet (0.3% w/w) for 2 weeks did not change the liver cytochrome P450 content nor the activities of the NADPH-cytochrome P450 and NADH-cytochrome b5 reductases, but it affected the activities of phase I and phase II enzymes. Flavone, and to a lesser extent tangeretin, increased the activities mediated by the P450 1A1,2 (EROD) and 2B1,2 (PROD) as well as the activities of p-nitrophenol UDP-glucuronyl transferase (UGT) and glutathione transferase (GST). Flavanone mainly enhanced PROD, UGT and GST, whereas quercetin did not modify any enzyme activities. None of the tested flavonoids modulated the activities catalyzed by P450 2E1, 3A and 4A. Immunoblotting studies showed that flavone and tangeretin increased the expression of cytochrome P450 1A and 2B forms, whereas flavanone only induced cytochrome P450 2B. Flavone and to a lesser extent flavanone, markedly increased the phenol-UGT protein level. Both flavone and flavanone also increased the androsterone- and testosterone-UGTs, whereas tangeretin and quercetin did not increase any UGT isoform. We concluded that the flavonoids tested specifically affected the expression of the drug-metabolizing isozymes in rat liver, their inducing properties were dependent on their chemical structures.

Analysis of Variance↗
PubMed2005

Regio- and stereospecific synthesis of novel 3-enynyl-substituted thioflavones/flavones using a copper-free palladium-catalyzed reaction.

[reaction: see text] A variety of 3-enynyl substituted flavones/thioflavones were synthesized via a sequential one-pot procedure using copper-free palladium-catalyzed cross coupling in a simple synthetic operation. The cross coupling between 3-iodo(thio)flavone and a broad range of terminal alkynes was carried out in the presence of Pd(PPh3)2Cl2 and triethylamine to afford the corresponding 3-enynyl derivatives in a regio- and stereoselective fashion. The best results are obtained by employing 3 equiv of the terminal alkynes. The process worked well irrespective of the substituents present on the (thio)flavone ring as well as in the terminal alkynes except arylalkynes. The reaction is quite regioselective, placing the substituent of the terminal alkyne at the far end of the double bond attached with the (thio)flavone ring. The orientation of the (thio)flavonyl and acetylenic moieties across the double bond was found to be syn in the products isolated. A tandem C-C bond-forming reaction in the presence of palladium catalyst rationalized the formation of coupled product. The catalytic process apparently involves heteroarylpalladium formation, regioselective addition to the C-C triple bond of the terminal alkyne, and subsequent displacement of palladium by another mole of alkyne. The present methodology is useful for the introduction of an enynyl moiety at the C-3 position of flavones and thioflavone rings to afford novel compounds of potential biological interest. In the presence of CuI the process afforded 3-alkynyl (thio)flavones in good yields.

Catalysis↗
PubMed1994

Inhibition of [methyl-3H]diazepam binding to rat brain membranes in vitro by dinatin and skrofulein.

Two flavones, 4',5,7-trihydroxy-6-methoxy flavone (dinatin) and 4',5-dihydroxy-6, 7-dimethoxy flavone (skrofulein), were extracted from Artemisia herba alba L. Dinatin and skrofulein inhibited the binding of [methyl-3H]diazepam to rat brain membranes in vitro with IC50 of 1.3 and 23 mumol.L-1, respectively. The GABA-ratios (the ratio of IC50 values in the absence/presence of GABA in the binding assay) were 1.1 and 1.2 for dinatin and skrofulein, respectively. Both flavones induced a slight increase in [35S] TBPS binding. The data suggest that the flavones are antagonists or partial agonists of benzodiazepine receptors.

Animals↗
PubMed1982

Inhibition of aldose reductases from rat and bovine lenses by flavonoids.

Thirty flavones, four isoflavones and thirteen coumarins were tested as inhibitors of lens aldose reductase, which is believed to participate in the initiation of cataract formation in diabetes. Many were found to be potent inhibitors, and the two most potent ones were axillarin (5,7,3',4'-tetrahydroxy-3,6-dimethoxyflavone) and 6,3',4'-trihydroxy-5,7,8-trimethoxyflavone (LARI 1). These two flavones inhibited aldose reductase purified from rat lens with IC50 values of 2.6 X 10(8) and 3.6 X 10(8) M respectively. They also inhibited aldose reductase purified from bovine lens with IC50 values of 1.8 X 10(7) M. The potencies of the two compounds were superior to those of all the previously reported inhibitors of aldose reductase. Inhibition of rat and bovine lens aldose reductases by the two compounds was of a non-competitive type with DL-glyceraldehyde as the variable substrate. Some flavones including axillarin and LARI 1 were found to be poorly or scarcely inhibitory against several adeninenucleotide-requiring enzymes, which are involved in glycolysis and other metabolic reactions. These results obtained show that the two flavones have some features which may be required in clinically useful drugs for diabetic patients. All the potent inhibitors of the compounds tested had a flavone skeleton, one (or two free) hydroxyl(s) in ring C, and more than three hydroxyls (free or methylated) in ring A. The possible relationships of structures to inhibitory potencies of the compounds tested are discussed.

Aldehyde Reductase↗
PubMed1994

Effects of naturally occurring flavonoids on mitogen-induced lymphocyte proliferation and mixed lymphocyte culture.

In this investigation, 34 structurally different flavonoids including derivatives of chalcone, flavanone, flavan-3-ol, flavone, flavonol, and their glycosides were evaluated for in vitro suppression of mitogen-induced lymphocyte proliferation and mixed lymphocyte culture from mouse spleen. Flavonoids, mainly derivatives of flavone and flavonol, clearly demonstrated the suppressive effects on lymphocyte proliferation at higher than 10(-6) M depending on the structures of flavonoid molecules, although their suppressive activities were less than that of cyclosporin A or prednisolone. Various glycosidic substitutions to A- and/or C-ring of the flavonoid aglycones were found to eliminate the suppressive activities of their aglycones, regardless of sugar compositions and positions of substitutions. In concanavalin A-induced lymphocyte proliferation, derivatives of flavone and flavonol having 2,3-unsaturation and at least 1 hydroxyl group showed the suppressive activity. In lipopolysaccharide-induced lymphocyte proliferation, only myricetin was active among flavonoids tested at the concentrations up to 10(-5) M. In mixed lymphocyte culture, some derivatives of flavone and flavonol with 2,3-unsaturation were active and especially flavone derivatives showed the higher suppressive activities than those of the flavonol derivatives.

Animals↗
PubMed1993

Antimutagenic effects of flavonoids, chalcones and structurally related compounds on the activity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and other heterocyclic amine mutagens from cooked food.

Sixty-four flavonoids were tested for their antimutagenic potencies with respect to IQ in Salmonella typhimurium TA98 and in part also towards MeIQ, MeIQx, Trp-P-2, and Glu-P-1 and in S. typhimurium TA100. Antimutagenic potencies were quantified by the inhibitory dose for 50% reduction of mutagenic activity (ID50). A carbonyl function at C-4 of the flavane nucleus seems to be essential for antimutagenicity: two flavanols and four anthocyanidines were inactive. Again, five isoflavons, except biochanin A, were inactive. Within the other groups of 21 flavones, 16 flavonols and 16 flavanones the parent compounds flavone, flavonol, and flavanone possessed the highest antimutagenic potencies (ID50: 4.1, 2.5, 5.5 nmoles). Increasing polarity by introduction of hydroxyl functions reduced antimutagenic potency. Reducing polarity of hydroxy flavonoids by methyl etherification, however, increased antimutagenic potency again. 6-Hydroxy- and 2'-hydroxy substituted flavonoids were considerably less potent antimutagens. Of 11 flavonoid glycosides tested all compounds except apigenin- and luteolin-7-glucoside (ID50:74, 115 nmoles) were inactive or only weakly antimutagenic. Rings C and A of the nucleus were not essential for antimutagenicity: chalcone and three derivatives were nearly as active as comparable flavones while antimutagenicity of benzylidenacetone was considerably reduced (ID50: 95 nmoles). Cinnamylaldehyde and cinnamoates, however, were inactive. A planar structure in the vicinity of the carbonyl group may also be important for antimutagenicity. Flavanones were less potent antimutagens than the corresponding flavones, but dihydrochalcones and 14 structurally related saturated aromatic carbonyl compounds were inactive. Fisetin and 6-hydroxyflavone were competitive inhibitors, but luteolin was a mixed type inhibitor. The inhibition mechanisms of flavone, kaempferol, morin, flavanone, and 2'-hydroxyflavanone were concentration dependent, being competitive at low concentrations and mixed or non-competitive (2'-hydroxyflavanone) at concentrations about the ID50 value. No fundamental differences between the two tester strains and no clear influence of mutagen structure on antimutagenic potency could be detected.

Animals↗