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PubMed2001

Effect of simple phenolic compounds on azoxymethane-induced aberrant crypt foci in rat colon.

Because complex mixtures of plant polyphenols exert anticancer activity in animal models, we investigated whether low-molecular-weight natural phenolic compounds (2-OH-coumaric acid, 3-OH-coumaric acid, 4-OH-coumaric acid, 3-OH-flavone, 7-OH-flavone, 4-OH-benzoic acid, 3-OH-benzoic acid, and 2,3-OH-benzoic acid) affect azoxymethane (AOM)-induced aberrant crypt foci (ACF), which have been suggested to represent preneoplastic lesions, in the colon of rats. Male Fischer 344 rats were fed diets supplemented with 0.1% (wt/wt) of the different phenolic compounds, and after 2 wk they were treated twice (1 wk apart) with AOM (15 mg/kg s.c.); the dietary treatment continued until sacrifice, 7 wk after the first injection with AOM. The results showed that none of these phenolic compounds exerted chemopreventive activity on the ACF assay. On the contrary, 3-OH-flavone slightly, although significantly, increased (P < 0.05), the number of ACF per colon [157 +/- 7 and 198 +/- 14 (SE) in control and 3-OH-flavone groups, respectively, n = 10]. We also found that the number of "large" ACF was significantly increased in the group treated with 4-OH-benzoic acid. In conclusion, none of the phenolic compounds tested demonstrated a suppressive action on ACF induction by AOM.

Animals↗
PubMed2003

Induction of rat hepatic and intestinal UDP-glucuronosyltransferases by naturally occurring dietary anticarcinogens.

Gastrointestinal tumours are among the most common malignancies in Western society, the majority of which are associated with dietary and lifestyle factors. Many dietary or lifestyle factors have been identified which may have toxic or carcinogenic properties. However, several dietary compounds also able to reduce gastrointestinal cancer rates in both humans and animals have been characterized. Though the exact mechanism leading to the anticarcinogenic action of these compounds is not fully known, it has been demonstrated that this chemopreventive capacity may be due to elevation of the glutathione S-transferase detoxification enzymes. Here we have investigated the effect of several anticarcinogens on the gastrointestinal UDP-glucuronosyltransferase (UGT) enzymes. Diets of male Wistar rats were supplemented with ellagic acid, ferulic acid, Brussels sprouts, quercetin, alpha-angelicalactone, tannic acid, coumarin, fumaric acid, curcumin and flavone, separately, and combinations of alpha-angelicalactone and flavone. Hepatic and intestinal (proximal, mid and distal small intestine and colon) UGT enzyme activities were quantified using 4-nitrophenol and 4-methylumbelliferone as substrates. All anticarcinogens tested increased UGT enzyme activity with both substrates, at one at least of the five different sites investigated. alpha-Angelicalactone, coumarin and curcumin showed enhanced UGT enzyme activities at all five sites. Both small and large intestinal UGT enzyme activities were increased by quercetin, alpha-angelicalactone, coumarin, curcumin and flavone. Except for tannic acid, all agents induced hepatic UGT enzyme activity. Furthermore, dietary administration of alpha-angelicalactone and flavone, given individually or in combination, enhanced the UGT detoxification system in the liver and, to a lesser extent, in intestine. In conclusion, induction of gastrointestinal UGT enzyme activities after consumption of dietary anticarcinogens may contribute to a better detoxification of potentially carcinogenic compounds and subsequently to the prevention of gastrointestinal cancer.

Animals↗
PubMed1998

Genetic mechanisms underlying apimaysin and maysin synthesis and corn earworm antibiosis in maize (Zea mays L.).

C-glycosyl flavones in maize silks confer resistance (i.e., antibiosis) to corn earworm (Helicoverpa zea [Boddie]) larvae and are distinguished by their B-ring substitutions, with maysin and apimaysin being the di- and monohydroxy B-ring forms, respectively. Herein, we examine the genetic mechanisms underlying the synthesis of maysin and apimaysin and the corresponding effects on corn earworm larval growth. Using an F2 population, we found a quantitative trait locus (QTL), rem1, which accounted for 55.3% of the phenotypic variance for maysin, and a QTL, pr1, which explained 64.7% of the phenotypic variance for apimaysin. The maysin QTL did not affect apimaysin synthesis, and the apimaysin QTL did not affect maysin synthesis, suggesting that the synthesis of these closely related compounds occurs independently. The two QTLs, rem1 and pr1, were involved in a significant epistatic interaction for total flavones, suggesting that a ceiling exists governing the total possible amount of C-glycosyl flavone. The maysin and apimaysin QTLs were significant QTLs for corn earworm antibiosis, accounting for 14. 1% (rem1) and 14.7% (pr1) of the phenotypic variation. An additional QTL, represented by umc85 on the short arm of chromosome 6, affected antibiosis (R2 = 15.2%), but did not affect the synthesis of the C-glycosyl flavones.

Alleles↗
PubMed2005

Chronic treatment with flavonoids prevents endothelial dysfunction in spontaneously hypertensive rat aorta.

Flavonoids are known to possess cardioprotective properties. Vascular endothelial function is a surrogate marker for cardiovascular diseases, including hypertension. We have studied the effects of chronic flavonoid treatment on vascular endothelial functions in spontaneously hypertensive rats (SHR). Starting from 6-7 weeks old, SHR were given flavonoids (baicalein, flavone, or quercetin) orally (10 mg/kg, once daily) to the SHRs for 4 weeks. Aortas from all the flavonoid-treated animals showed remarkably higher endothelium-dependent relaxations to acetylcholine, to a similar extent as those pretreated with the angiotensin-converting enzyme inhibitor, captopril. However, in contrast to other experimental groups, flavone pretreatment also enhanced the endothelium-independent relaxations to sodium nitroprusside. In addition, treatment with either flavone or quercetin induced a significant attenuation in systolic blood pressure of the hypertensive animals. The present results suggest that chronic treatment with the flavonoids (baicalein, flavone, and quercetin) preserves vascular endothelial functions in hypertensive animals through several possible actions, including increasing endothelial nitric oxide production and bioavailability and reduction in blood pressure.

Acetylcholine↗
PubMed2003

Species-specific transcriptional activity of synthetic flavonoids in guinea pig and mouse cells as a result of differential activation of the aryl hydrocarbon receptor to interact with dioxin-responsive elements.

To investigate possible species-specificity of aryl hydrocarbon receptor (AhR)-mediated signal transduction pathways, activities of 2,3,7,8-tetrochlorodibenzo-p-dioxin (TCDD) and six synthetic flavonoids were evaluated in mouse hepatoma and guinea pig adenocarcinoma cells transfected with an AhR-responsive luciferase reporter. Rank order potency in these two cell lines was similar for the ability of these flavonoids to antagonize TCDD-induced reporter gene expression. However, in the presence of flavone alone, a species-specific difference in agonist activity was observed. In guinea pig cells, several flavonoids demonstrated agonist activity up to 50% of the maximum TCDD response. In mouse cells, however, no significant agonist activity was observed at the same concentrations based on luciferase enzyme activity, protein expression, and mRNA analysis. Moreover, competitive ligand-binding assays, using [(3)H]TCDD in cytosolic fractions, demonstrated that 3'-methoxy-4'-nitroflavone had a similar IC(50) in both recombinant cell lines, suggesting that the flavone has similar binding affinity to receptors from both species. However, electrophoretic mobility shift assay using the cytosolic fractions demonstrated that this flavone elicited binding to the DRE by guinea pig but not mouse AhR complex. The dependence of the AhR in this differential interaction was further demonstrated using in vitro synthesized guinea pig and mouse Ah receptors and mouse Arnt. Together, these data suggest that the differential agonist/antagonist activity of these flavone derivatives is caused by the efficacy of these flavonoids in eliciting an AhR conformation that recognizes regulatory response elements in a species-specific manner.

Animals↗
PubMed2003

Nitric oxide levels in human preneoplastic colonocytes determine their susceptibility toward antineoplastic agents.

The efficacy of antineoplastic compounds can depend heavily on the genetic background of the cells exposed to the drugs. This becomes evident by the fact that HT-29 human colon cancer cells but not primary murine nontransformed colonocytes are efficiently submitted to apoptosis by the flavonoid flavone. By determining caspase-3 activation, plasma membrane disintegration, and nuclear fragmentation, we show here that flavone also does not promote apoptosis in preneoplastic NCOL-1 colonocytes derived from a nontransformed human biopsy specimen. In clear contrast, the antitumor drug camptothecin potently induces apoptosis in NCOL-1 cells associated with a specific down-regulation of the antiapoptotic factor bcl-XL at the mRNA and protein levels and with the activation of the mitochondrial apoptosis pathway. Confocal microscopy revealed an increased production of superoxide anion radicals in the mitochondria of NCOL-1 cells that preceded the apoptotic events. However, in the case of flavone, the mitochondrial oxygen radicals were effectively scavenged by physiological concentrations of nitric oxide (NO), whereas in the case of camptothecin, the available nitric oxide was rapidly scavenged by the production of large quantities of cytosolic superoxide anions. Increasing the levels of nitric oxide inside NCOL-1 cells by sodium nitroprusside prevented the apoptosis induction by camptothecin. Reducing the levels of nitric oxide by using the NO synthase inhibitor, Nomega-nitro-l-arginine methyl ester in NCOL-1 cells or using HT-29 cells that intrinsically have low NO levels enabled flavone to trigger the apoptosis pathway. In conclusion, our studies demonstrate that the intracellular levels of nitric oxide significantly change the apoptotic response to antineoplastic agents in colonic cells.

Antineoplastic Agents↗
PubMed2002

Pharmaceutical quality of different Ginkgo biloba brands.

Ginkgo biloba-containing brands are one of the top sellers within the growing market for herbal remedies in many European countries as well as in the USA. In the consumers' interest, these brands should feature a certain quality and should be transparent in quality claims. In this investigation, a variety of products on the USA market was studied with respect to pharmaceutical quality, such as quantity of constituents and in-vitro dissolution. In terms of the content of active substances, flavone glycosides ranged from 24% to 36% and terpene lactones from 4% to 11%. With ginkgolic acids, there was a very large range, from < 500 ppm to about 90000 ppm. Comparing the dissolution rates of terpene lactones and flavone glycosides within the single products, most were approximately the same. Thus, terpene lactones and flavone glycosides were released from these products and dissolved at the same rate in most cases. Furthermore, most of the products investigated released more than the required 75% of the content of both components within 30 min. However, several products showed clear and relevant differences in dissolution rates to the rest (e.g. < 75% within 30 min or even less than 25% after 60 min in one case, indicating much poorer pharmaceutical quality). Beside the comparability respectively standardisation of the extracts used, the in-vitro dissolution of the relevant constituents should be similar to other drugs to guarantee comparable in-vivo performance of herbal products. An important step in standardising pharmaceutical quality is the pharmacopoeial monograph for Ginkgo biloba extract in Germany, standardising the content of pharmacologically relevant substances (flavone glycosides 22-27% and terpenlactones 5-7%, 2.8-3.4% ginkgolides A, B, C and 2.6-3.2% bilobalide thereof). Many of the investigated products, which refer to the German Commission E (of the Federal Institute for Drugs and Medicinal Devices) monograph, are not in accordance with this specification. Thus, they can not be considered to be pharmaceutically equivalent.

Chromatography, High Pressure Liquid↗
PubMed2004

Inhibitory effect of flavonoids on sulfo- and glucurono-conjugation of acetaminophen in rat cultured hepatocytes and liver subcellular preparations.

A large group of flavonoids was investigated for inhibitory effects on sulfo- and glucurono-conjugation of acetaminophen when added to rat cultured hepatocytes and liver subcellular preparations. The flavonoids inhibited the production of both sulfate and glucuronide conjugates in the cultured cells, with potencies that depended on the specific flavonoid. Among the flavonols, quercetin, kaempferol and galangin were much more effective than myricetin and morin. Flavones including luteolin, apigenin and chrysin were as effective as the corresponding three flavonols above. The inhibition of conjugation by other simple flavones such as 3-, 5-, 7- and 3',4'-OH flavones, and by catechins such as epicatechin and epigallocatechin, was very weak. These data suggest that the presence of both C5 and 7 hydroxyl substitutions on the A-ring in the flavone structure is required for effective inhibitory activity. The effect of flavonoids on sulfo- and glucurono-conjugation was also examined by incubating acetaminophen with isolated liver cytosolic and microsomal preparations, respectively. The active flavonoids in the cells remarkably inhibited the sulfation, but not glucuronidation, in cell-free enzymatic preparations in vitro. The mechanism of inhibition of conjugation by flavonoids in cultured hepatocytes is not likely to depend on the direct inhibition of sulfo- and glucurono-transferase activity by flavonoids.

Acetaminophen↗
PubMed1993

Studies on the differentiation inducers of myeloid leukemic cells from Citrus species.

An attempt was made to isolate differentiation inducers from Aurantii Nobilis Pericarpium and the fruit peel of Citrus reticulata Blanco (Rutaceae). Twenty-seven kinds of flavones, including five new flavones, were isolated after repeated chromatography from methanol extracts of these plants and their structures were established, from their physicochemical data, to be highly methoxylated flavones. Each compound, except for two flavone glucosides, showed the differentiation inducing activity toward mouse myeloid leukemia cells (M1), and the cells came to have phagocytic activity. Furthermore, differentiation inducing activity was tested using human acute promyelocytic leukemia cell line (HL-60).

Animals↗
PubMed2000

Medicinal foodstuffs. XVIII. Phytoestrogens from the aerial part of Petroselinum crispum MIll. (Parsley) and structures of 6"-acetylapiin and a new monoterpene glycoside, petroside.

In the course of our screening for natural estrogenic compounds from Occidental medicinal herbs, the extracts of several herbs were found to show proliferative activity in MCF-7 (an estrogen-sensitive breast cancer cell line). Among these active herbs, the methanolic extract from the aerial parts of Petroselinum crispum (parsley) showed potent estrogenic activity, which was equal to that of isoflavone glycosides from soybean. Through bioassay-guided separation, we isolated several flavone glycosides and a new flavone glycoside, 6"-acetylapiin, with estrogenic activity together with a new monoterpene glucoside, petroside. The structures of 6"-acetylapiin and petroside were characterized by the chemical and physicochemical evidence. Estrogenic activities of these flavone glycosides were found to be enhanced by removal of their glycoside moieties. The EC50 values (concentration needed to enhance the MCF-7 proliferation 50% compared to non-estrogen treated cell) of their aglycones are as follows, apigenin (1.0 microM), diosmetin (2.9 microM), and kaempferol (0.56 microM). The estrogenic activities of these flavones are nearly equal to those of the isoflavones, daidzein (0.61 microM) and genistein (0.60 microM). The methanolic extract of parsley, apiin, and apigenin restored the uterus weight in ovariectomized mice when orally administered for consecutive 7 days.

Animals↗
PubMed2006

[Effects of active components extracted from Qixue Bingzhi Recipe on proliferation of vascular smooth muscle cells and expressions of platelet-derived growth factor and its receptor genes].

OBJECTIVE: To observe the effects of paeoniflorin and total flavones extracted from Qixue Bingzhi Recipe on proliferation of vascular smooth muscle cells (VSMCs) cultured in endothelial cell conditioned medium (EC-CM) induced by oxidized low-density lipoprotein (ox-LDL) and the expressions of platelet-derived growth factor and its receptor genes. METHODS: The VSMCs were cultured in normal culture medium, EC-CM, simvastatin-medicated EC-CM, paeoniflorin and total flavones (low, medium and high dose) -medicated EC-CM respectively. The growth activity of VSMCs was assessed by thiazolyl blue tetrazolium bromide (MTT) assay. The expressions of platelet-derived growth factor (PDGF)-BB and platelet-derived growth factor receptor-alpha (PDGFR-alpha) mRNAs were detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The growth activity of VSMCs cultured in the EC-CM induced by ox-LDL was significantly higher than that in the normal culture medium (P<0.01), and the expressions of PDGF-BB and PDGFR-alpha mRNAs were obviously increased as compared with those in the normal culture medium. The growth activity of VSMCs cultured in each paeoniflorin and total flavones-medicated EC-CM was significantly lower than that in the EC-CM (P<0.01), and the expressions of PDGF-BB and PDGFR-alpha mRNAs were obviously decreased as compared with those in the EC-CM. CONCLUSION: The paeoniflorin and total flavones extracted from Qixue Bingzhi Recipe may be beneficial to the prevention and treatment of arteriosclerosis, and this efficacy may be correlated with down-regulating the expressions of PDGF-BB and PDGFR-alpha mRNAs which are related to the proliferation of VSMCs cultured in EC-CM induced by ox-LDL.

Animals↗
PubMed1996

Relation between intake of flavonoids and risk for coronary heart disease in male health professionals.

OBJECTIVE: Flavonols and flavones are subgroups of flavonoids and are found in tea, vegetables, fruits, and red wine. Because they have antioxidant properties, we investigated whether intake of these dietary compounds is associated with a lower risk for fatal and nonfatal coronary heart disease. DESIGN: Prospective cohort study. SETTING: United States. PATIENTS: 34,789 male health professionals, 40 to 75 years of age, who responded to a questionnaire in 1986. MEASUREMENTS: In 1986 and 1990, detailed, 131-item questionnaires were used to assess dietary intake of flavonols and flavones. RESULTS: Between 1986 and 1992, 496 patients received a new diagnosis of nonfatal myocardial infarction. The relative risk for nonfatal myocardial infarction was 1.08 (95% Cl, 0.81 to 1.43) for the highest (median, 40.0 mg/d) compared with the lowest (median, 7.1 mg/d) quintiles for intake of flavonols and flavones after adjustment for age, obesity, smoking, intake of vitamin E, intake of alcohol, diabetes, hypertension, hypercholesterolemia, and family history of coronary heart disease. Among the 4814 men who reported that they had previously had coronary heart disease, we found a modest but nonsignificant inverse association between intake of flavonols and flavones and subsequent coronary mortality rates (relative risk, 0.63 [Cl, 0.33 to 1.20] for the highest compared with the lowest quintile for intake of flavonoids). CONCLUSION: The data do not support a strong inverse association between intake of flavonoids and total coronary heart disease, but they do not exclude the possibility that flavonoids have a protective effect in men with established coronary heart disease.

Adult↗
PubMed2004

[Isolation and structural identification of C-glycosylflavones from Corallodiscus flabellata].

AIM: To study the chemical constituents of Corallodiscus flabellata. METHODS: Fresh plant of Corallodiscus flabellata was extracted twice with boiling water, concentrated to small volume under reduced pressure at 55 degrees C. The concentrated material was partitioned with ether, ethyl acetate, and n-butanol. The fraction of ethyl acetate extract was chromatographed over macroporous adsorption resin (Diaion HP-20) eluted with a mixture of H2O and MeOH in increasing MeOH content. Their fractions from resin were repeatedly chromatographed over Sephadex LH-20, silica gel column chromatography. The compounds were identified on the basis of their physiochemical and spectral data. RESULTS: Seven compounds were obtained and identified as 5,3',4'-trihydroxyl-6,7-dimethoxyl-8-C-[beta-D-xylocopyranosyl-(1-->2)]- beta-D-glucopyranosyl flavone (1), 5,4'-dihydroxyl-6,7-dimethoxyl-8-C- [beta-D-xylopyranosyl-(1-->2)]-beta-D-glucopyranosyl flavone (2), 5,4'-dihydroxyl-6,7-dimethoxyl-8-C-beta-D-glucopyranosyl flavone (3), 5,4'-dihydroxyl-6,7-dimethoxyl-8-C-[beta-D-apiofuranosyl- (1-->2)]-beta-D-glucopyranosyl flavone (4), 3,4-dihydroxyl benzoyl acetic acid glycol ester (5), hydroxytyrosol (6), apocynin (7). CONCLUSION: Compound 1 and 2 are new compounds, the others were isolated from Corallodiscus flabellata for the first time.

Acetophenones↗
PubMed1981

Specificity in the activation and inhibition by flavonoids of benzo[a]pyrene hydroxylation by cytochrome P-450 isozymes from rabbit liver microsomes.

The effect of flavone and 7,8-benzoflavone on the metabolism of benzo[a]pyrene to fluorescent phenols by five cytochrome P-450 isozymes obtained from rabbit liver microsomes was determined. Benzo[a]pyrene metabolism was stimulated more than 5-fold by the addition of 600 microM flavone to a reconstituted monooxygenase system consisting of NADPH, cytochrome P-450 reductase, dilauroylphosphatidylcholine, and cytochrome P-450LM3c or cytochrome P-450LM4. In contrast, an inhibitory effect of flavone on benzo[a]pyrene metabolism was observed when cytochrome P-450LM2, cytochrome P-450LM3b, or cytochrome P-450LM6 was used in the reconstituted system. 7,8-Benzoflavone (50-100 microM) stimulated benzo[a]pyrene metabolism by the reconstituted monooxygenase system about 10-fold when cytochrome P-450LM3c was used, but benzo[a]pyrene hydroxylation was strongly inhibited when 7,8-benzoflavone was added to the cytochrome P-450LM6-dependent system. Smaller effects of 7,8-benzoflavone were observed on the metabolism of benzo[a]pyrene by the cytochrome P-450LM2-, cytochrome P-450LM3b-, and cytochrome P-450LM4-dependent monooxygenase systems. These results demonstrate that the activating and inhibiting effects of flavone and 7,8-benzoflavone on benzo[a]pyrene metabolism depend on the type of cytochrome P-450 used in the reconstituted monooxygenase system.

Animals↗
PubMed1997

Silymarin mediated differential modulation of toxicity induced by carbon tetrachloride, paracetamol and D-galactosamine in freshly isolated rat hepatocytes.

Influence of silymarin on the modulation of hepatotoxicity induced by carbon tetrachloride (CCl4), paracetamol (AAP) and D-galactosamine (GalN) was examined in freshly isolated rat hepatocytes in suspension culture. While the three hepatotoxicants produced differential biochemical response, the flavone was able to restore biochemical alterations only in hepatocytes exposed to CCl4 and AAP induced toxicity. Silymarin at 0.4 mM was able to counteract lipid peroxidation and enzyme leakage induced by 3 mM CCl4 The flavone also offered protection by more than 60% in hepatocytes isolated from PB pre-treated rats where CCl4 at 2 mM produced enhanced toxicity over hepatocytes isolated from untreated control rats. Similarly, the flavone protected AAP-induced GSH depletion by more than 75% in hepatocytes isolated from untreated and 3-methylcholanthrene treated rats. However, instead of protecting GalN-induced depletion of UDP-glucuronic acid in hepatocytes, the flavone itself reduced the nucleotide content very rapidly compared to GalN, the later exerted time dependent effect. Silymarin at 0.4 mM reduced UDPGA by more than 60%. The results suggested that freshly isolated hepatocytes in suspension culture offer a simple and convenient method for evaluation of pharmaceutical agents of antihepatotxic potentials against various hepatotoxicants.

Acetaminophen↗
PubMed2004

Identification of biomarkers for the initiation of apoptosis in human preneoplastic colonocytes by proteome analysis.

Development of resistance of cells toward proapoptotic signals is regarded as one of the key processes that allow tumor development. To identify proteins that are crucial for the initiation of apoptosis in NCOL-1 human preneoplastic colonocytes, we analyzed the proteome of cells exposed to the flavonoids flavone and quercetin that differ in their ability to induce apoptosis although they possess similar structures. Both flavonoids inhibited proliferation and induced differentiation of NCOL-1 cells but only quercetin committed the cells to apoptosis. The accessible proteome of NCOL-1 cells was separated by 2D-polyacrylamide-gelelectrophoresis and proteins with changed expression level were identified by peptide mass fingerprints of tryptic digests of the protein spots. A pre-fractionation of soluble and lipophilic proteins was used to enhance the resolution of analysis. After exposure to the test compounds for 24 hr, 73 proteins displayed changed steady state levels in case of quercetin and 32 in case of flavone. Several heat-shock proteins, annexins and cytoskeletal caspase substrates were regulated by quercetin but not by flavone and these protein classes are known to play a role in apoptosis induction and execution. Whereas proteins like lamin A, C and desmoplakin, are indicators that apoptosis has already proceeded, others, such as annexin IV or protein kinase C-beta play a pivotal role in the early phases of apoptosis. In conclusion, proteome analysis allowed the identification of marker proteins that are involved in the initiation of apoptotic cell death in preneoplastic colonocytes and those may help to develop new strategies for cancer prevention.

Apoptosis↗
PubMed2001

Kinetic characterization of the rotenone-insensitive internal NADH: ubiquinone oxidoreductase of mitochondria from Saccharomyces cerevisiae.

Saccharomyces cerevisiae mitochondria contain an NADH:Q6 oxidoreductase (internal NADH dehydrogenase) encoded by NDI1 gene in chromosome XIII. This enzyme catalyzes the transfer of electrons from NADH to ubiquinone without the translocation of protons across the membrane. From a structural point of view, the mature enzyme has a single subunit of 53 kDa with FAD as the only prosthetic group. Due to the fact that S. cerevisiae cells lack complex I, the expression of this protein is essential for cell growth under respiratory conditions. The results reported in this work show that the internal NADH dehydrogenase follows a ping-pong mechanism, with a Km for NADH of 9.4 microM and a Km for oxidized 2,6-dichorophenolindophenol (DCPIP) of 6.2 microM. NAD+, one of the products of the reaction, did not inhibit the enzyme while the other product, reduced DCPIP, inhibited the enzyme with a Ki of 11.5 microM. Two dead-end inhibitors, AMP and flavone, were used to further characterize the kinetic mechanism of the enzyme. AMP was a linear competitive inhibitor of NADH (Ki = 5.5 mM) and a linear uncompetitive inhibitor of oxidized DCPIP (Ki = 11.5 mM), in agreement with the ping-pong mechanism. On the other hand, flavone was a partial inhibitor displaying a hyperbolic uncompetitive inhibition regarding NADH, and a hyperbolic noncompetitive inhibition with respect to oxidized DCPIP. The apparent intercept inhibition constant (Kii = 5.4 microM) and the slope inhibition constant (Kis = 7.1 microM) were obtained by non linear regression analysis. The results indicate that the ternary complex F-DCPIPox-flavone catalyzes the reduction of DCPIP, although with lower efficiency. The effect of pH on Vmax was studied. The Vmax profile shows two groups with pKa values of 5.3 and 7.2 involved in the catalytic process.

2,6-Dichloroindophenol↗
PubMed2004

Flumazenil-independent positive modulation of gamma-aminobutyric acid action by 6-methylflavone at human recombinant alpha1beta2gamma2L and alpha1beta2 GABAA receptors.

In view of the ability of flavones to displace radiolabelled benzodiazepines from brain tissue and the interesting behavioural profile of these compounds, the present study investigated the activity of 6-methylflavone at ionotropic gamma-aminobutyric acid (GABA) receptors expressed in Xenopus laevis oocytes. 6-Methylflavone (1-100 microM) was found to be a positive allosteric modulator at alpha1beta2gamma2L and alpha1beta2 GABAA receptors with no significant difference between the enhancement seen at either receptor subtype. At 100 microM, 6-methylflavone enhanced the response to 5 microM GABA by 183+/-20% at alpha1beta2gamma2L GABAA receptors. The methyl substituent was important since the parent flavone was significantly weaker as a positive modulator (103+/-24% enhancement of 5 microM GABA by 100 microM flavone). This enhancement is not mediated via high-affinity benzodiazepine sites as it was not inhibited by the classical benzodiazepine antagonist flumazenil under conditions where flumazenil inhibits the potentiation of the GABA response to diazepam. 6-Methylflavone (60 microM) did not significantly affect the GABA dose-response curve at rho1 GABAC receptors. 6-Methylflavone acts as a positive modulator of recombinant GABAA receptors at sites independent of flumazenil-sensitive benzodiazepine sites.

Allosteric Regulation↗