Posted by Quintal on August 5, 2007, at 0:09:09
I discovered some interesting information on the plant flavonoid Chrysin while researching the psychoactive effects of chamomile yesterday. Chrysin appears to exert significant anxiolytic properties comparable to diazepam, but lacks the adverse effects of sedation and impairment of learning and memory associated with benzodiazepines. It is postulated that Chrysin is a benzodiazepine partial agonist since some of its anxiolytic effects are reversed by the benzodiazepine antagonist flumazenil.
__________________________________________________1: Fitoterapia. 2000 Aug;71 Suppl 1:S117-23.
Behavioral characterisation of the flavonoids apigenin and chrysin.
Zanoli P, Avallone R, Baraldi M.Department of Pharmaceutical Sciences, Modena and Reggio Emilia University, Modena, Italy. zanoli.paola@unimo.it
The behavioral effects of acute administration of two flavonoids, apigenin and chrysin, contained in Matricaria chamomilla and in Passiflora incarnata, respectively, were studied in rats. The data demonstrate that in our experimental conditions, the two flavonoids were equally able to reduce locomotor activity when injected in rats at a minimal effective dose of 25 mg/kg. However, while chrysin exhibited a clear anxiolytic effect when injected at the dose of 1 mg/kg, apigenin failed to exert this activity. The sedative effect of these flavonoids cannot be ascribed to an interaction with GABA-benzodiazepine receptors, since it was not counteracted by the benzodiazepine antagonist Flumazenil. To the contrary, the anxiolytic effect of chrysin, which was blocked by the injection of Flumazenil, could be linked to an activation of the GABA(A) receptor unit.
PMID: 10930722 [PubMed - indexed for MEDLINE]
--------------------------------------------------2: Pharmacol Biochem Behav. 1997 Dec;58(4):887-91.
Anxiolytic natural and synthetic flavonoid ligands of the central benzodiazepine receptor have no effect on memory tasks in rats.
Salgueiro JB, Ardenghi P, Dias M, Ferreira MB, Izquierdo I, Medina JH.Centro de Memoria, Departamento de Bioquímica, I.C.B.S., Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
The naturally occurring flavonoids, chrysin (5,7-dihydroxyflavone) and apigenin (5,7,4'-trihydroxyflavone), and the synthetic compound, 6,3'-dinitroflavone have been recently reported to selectively bind with high affinity to the central benzodiazepine receptor, and to exert powerful anxiolytic and other benzodiazepine-like effects in rats. Their chemical analog, quercetin, shares none of these effects. In the present article we find that, in contrast to diazepam, chrysin, apigenin, and 6,3'-dinitroflavone have no amnestic effect on acquisition or retention of three different learning tasks (inhibitory avoidance, shuttle avoidance, and habituation to an open field), even when given at doses higher than those previously reported to be anxiolytic. Apigenin had a slight enhancing effect on training session performance and, when given posttraining, on test session retention, of crossing responses in the open field and hindered retention of inhibitory avoidance, and showed no anxiolytic action in an elevated plus maze. Unlike diazepam, none of these drugs had any analgesic effect in the tail-flick test. The data suggest that chrysin, apigenin, and 6,3'-dinitroflavoine, three flavonoids derivatives possessing anxioselective effects acting on central benzodiazepine receptors, may deserve clinical trials as anxiolytic agents.
PMID: 9408191 [PubMed - indexed for MEDLINE]
--------------------------------------------------3: Pharmacol Biochem Behav. 1994 Jan;47(1):1-4.
Possible anxiolytic effects of chrysin, a central benzodiazepine receptor ligand isolated from Passiflora coerulea.
Wolfman C, Viola H, Paladini A, Dajas F, Medina JH.Instituto de Biología Celular, Facultad de Medicina, UBA, Argentina.
The pharmacological effects of 5,7-dihydroxyflavone (chrysin), a naturally occurring monoflavonoid that displaces [3H]flunitrazepam binding to the central benzodiazepine (BDZ) receptors, were examined in mice. In the elevated plus-maze test of anxiety, diazepam (DZ, 0.3-0.6 mg/kg) or chrysin (1 mg/kg) induced increases in the number of entries into the open arms and in the time spent on the open arms, consistent with an anxiolytic action of both compounds. The effects of chrysin on the elevated plus-maze was abolished by pretreatment with the specific BDZ receptor antagonist Ro 15-1788 (3 mg/kg). In the holeboard, diazepam (1 mg/kg) and chrysin (3 mg/kg) increased the time spent head-dipping. In contrast, high doses of DZ (6 mg/kg) but not of chrysin produced a decrease in the number of head dips and in the time spent head-dipping. In the horizontal wire test, diazepam (6 mg/kg) had a myorelaxant action. In contrast, chrysin (0.6-30 mg/kg) produced no effects in this test. These data suggest that chrysin possesses anxiolytic actions without inducing sedation and muscle relaxation. We postulate that this natural monoflavonoid is a partial agonist of the central BDZ receptors.
PMID: 7906886 [PubMed - indexed for MEDLINE]
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4: Planta Med. 2002 Dec;68(12):1059-62.
Structure-activity relationships of flavonoids, isolated from Scutellaria baicalensis, binding to benzodiazepine site of GABA(A) receptor complex.
Wang H, Hui KM, Chen Y, Xu S, Wong JT, Xue H.
Department of Natural Product Chemistry, Shenyang Pharmaceutical University, P.R.China. syliu@mail.sy.In.cnTwenty-six flavonoids were isolated from Scutellaria baicalensis. Their affinities for the benzodiazepine (BDZ) binding site of GABA A receptor have been studied using [ 3H]flunitrazepam binding to rat cortical membranes in vitro. The structure-activity relationships suggested that 2'-OH flavones exhibited the most potent binding affinity, which could lead to the design and discovery of new BDZ receptor ligands.
PMID: 12494329 [PubMed - indexed for MEDLINE]
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5: Curr Top Med Chem. 2002 Aug;2(8):853-67.
GABA(A)-receptor ligands of flavonoid structure.
Marder M, Paladini AC.
Instituto de Quimica y Fisicoquimica Biologicas, Facultad de Farmacia y Bioquimica, Junin 956, Buenos Aires, 1113, Argentina.This review describes the new research developments that have established the CNS-activity of some natural flavonoids. The properties of flavone, chrysin, apigenin and cirsiliol are described and a survey of the occurrence of ligands for the benzodiazepine binding site in the flavonoid field is attempted. Natural compounds, structurally related to flavonoids and with similar CNS-activities, are also included. A medicinal chemistry approach to improve the biochemical and pharmacological properties of the flavone nucleus is described alongside with the enumeration of the principal achievements obtained to date. Quantitative structure-activity relationships studies leading to the formulation of pharmacophore models presumably describing the characteristics of the flavone-binding site in the GABA(A)-receptor are summarized.
PMID: 12171576 [PubMed - indexed for MEDLINE]
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6: Biochem Pharmacol. 1990 Nov 15;40(10):2227-31.
Chrysin (5,7-di-OH-flavone), a naturally-occurring ligand for benzodiazepine receptors, with anticonvulsant properties.
Medina JH, Paladini AC, Wolfman C, Levi de Stein M, Calvo D, Diaz LE, Peña C.
Instituto de Biología Celular, Facultad de Medicina, Buenos Aires, Argentina.Chrysin (5,7-di-OH-flavone) was identified in Passiflora coerulea L., a plant used as a sedative in folkloric medicine. Chrysin was found to be a ligand for the benzodiazepine receptors, both central (Ki = 3 microM, competitive mechanism) and peripheral (Ki = 13 microM, mixed-type mechanism). Administered to mice by the intracerebroventricular route, chrysin was able to prevent the expression of tonic-clonic seizures induced by pentylenetertrazol. Ro 15-1788, a central benzodiazepine receptor antagonist, abolished this effect. In addition, all of the treated mice lose the normal righting reflex which suggests a myorelaxant action of the flavonoid. The presence in P. coerulea of benzodiazepine-like compounds was also confirmed.
PMID: 2173925 [PubMed - indexed for MEDLINE]
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Unfortunately unmethylated flavonoids like Chrysin have low bioavailability. I'm not sure how effective oral administration of Chrysin will be, or if there are any ways to increase the bioavailability of flavonoids. I'd be very grateful to hear from anyone who has further information or any ideas of how to improve bioavailabilty.__________________________________________________
1: Br J Clin Pharmacol. 2001 Feb;51(2):143-6.
Disposition and metabolism of the flavonoid chrysin in normal volunteers.
Walle T, Otake Y, Brubaker JA, Walle UK, Halushka PV.Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Medical University of South Carolina, Charleston, SC 29425, USA. wallet@musc.edu
AIMS: To describe the oral disposition of the dietary flavonoid chrysin in healthy volunteers. METHODS: Oral 400 mg doses of chrysin were administered to seven subjects. Chrysin and metabolites were assayed in plasma, urine and faeces by h.p.l.c. RESULTS: Peak plasma chrysin concentrations were only 3-16 ng ml(-1) with AUCs of 5-193 ng ml(-1) h. Plasma chrysin sulphate concentrations were 30-fold higher (AUC 450-4220 ng ml(-1) h). In urine, chrysin and chrysin glucuronide accounted for 0.2-3.1 mg and 2-26 mg, respectively. Most of the dose appeared in faeces as chrysin. Parallel experiments in rats showed high bile concentrations of chrysin conjugates. CONCLUSIONS: These findings, together with previous data using Caco-2 cells, suggest that chrysin has low oral bioavailability, mainly due to extensive metabolism and efflux of metabolites back into the intestine for hydrolysis and faecal elimination.
PMID: 11259985 [PubMed - indexed for MEDLINE]
--------------------------------------------------2: Drug Metab Dispos. 2006 Oct;34(10):1786-92. Epub 2006 Jul 25.
Methylated flavonoids have greatly improved intestinal absorption and metabolic stability.
Wen X, Walle T.
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Ave., P.O. Box 250505, Charleston, SC 29425, USA.To better understand the relationship between the chemical structure and biological fate of dietary polyphenols, the hepatic metabolic stability and intestinal absorption of methylated polyphenols, in comparison with unmethylated polyphenols, were investigated in pooled human liver S9 fraction and human colon adenocarcinoma (Caco-2) cells. Consistent with previous in vivo studies, the two well known unmethylated polyphenols resveratrol (3,5,4'-trihydroxystilbene) and quercetin (3,5,7,3',4'-pentahydroxyflavone) were rapidly eliminated by the S9 fraction in the presence of the appropriate cofactors for conjugation and oxidation. In contrast, the methylated flavones, i.e., 7-methoxyflavone, 7,4'-dimethoxyflavone, 5,7-dimethoxyflavone, and 5,7,4'-trimethoxyflavone, were relatively stable, indicating high resistance to hepatic metabolism. The corresponding unmethylated flavones, i.e., 7-hydroxyflavone, 7,4'-dihydroxyflavone, chrysin (5,7-dihydroxyflavone), and apigenin (5,7,4'-trihydroxyflavone), were rapidly eliminated because of extensive glucuronidation and/or sulfation just as resveratrol and quercetin were. The rate of intestinal absorption was evaluated using Caco-2 cells grown in porous inserts. The methylated flavones showed approximately 5- to 8-fold higher apparent permeability (P(app), 22.6-27.6 x 10(-6) cm s(-1)) of apical to basolateral flux than the unmethylated flavones (P(app), 3.0-7.8 x 10(-6) cm s(-1)). The lower P(app) values for the unmethylated flavones correlated with their extensive metabolism in the Caco-2 cells. Thus, combined use of the hepatic S9 fraction and Caco-2 cells will be useful for predicting the oral bioavailability of dietary polyphenols. The higher hepatic metabolic stability and intestinal absorption of the methylated polyphenols make them more favorable than the unmethylated polyphenols to be developed as potential cancer chemopreventive agents.
PMID: 16868069 [PubMed - indexed for MEDLINE]
--------------------------------------------------3: Chem Biol Interact. 2006 Dec 1;164(1-2):85-92. Epub 2006 Sep 26.
Accumulation and metabolism of the anticancer flavonoid 5,7-dimethoxyflavone compared to its unmethylated analog chrysin in the Atlantic killifish.
Tsuji PA, Winn RN, Walle T.
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, United States.The use of dietary flavonoids as potential chemopreventive agents is a concept of increasing interest. Recent findings indicate that methylated flavones have the advantage of increased metabolic stability. One such compound, the naturally-occurring 5,7-dimethoxyflavone (5,7-DMF), has been shown to be a potential chemopreventive agent in human cancer originating from the liver, mouth, esophagus and lung. As bioavailability is a key issue for potential in vivo effects, the tissue accumulation and biliary elimination of 5,7-DMF and its non-methylated analog chrysin were examined in a small fish model (Fundulus heteroclitus). The fish were exposed to 5,7-DMF, chrysin or vehicle control (DMSO<0.01%) in seawater for 8h. Toxicity was not observed at the 5microM exposure level. Tissues and bile were harvested and analyzed by HPLC and LC/MS for quantitation and identification of parent compound and metabolites. 5,7-DMF accumulated 20-fold to 100-fold in all tissues examined, with the highest accumulation in liver and brain, whereas chrysin was barely detectable in any tissues except the liver. The bile of chrysin-exposed fish contained very low concentrations of unchanged chrysin but high concentrations of two glucuronic acid conjugates. In the bile of 5,7-DMF-exposed fish, the parent compound was detectable in significant amounts along with glucuronic acid conjugates of O-demethylated 5,7-DMF. In conclusion, our study demonstrated high tissue accumulation and limited metabolism of 5,7-DMF compared to chrysin in vivo, making this flavone a promising chemopreventive molecule.
PMID: 16999945 [PubMed - indexed for MEDLINE]
--------------------------------------------------4: Br J Clin Pharmacol. 2001 Feb;51(2):143-6.
Disposition and metabolism of the flavonoid chrysin in normal volunteers.
Walle T, Otake Y, Brubaker JA, Walle UK, Halushka PV.
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology, Medical University of South Carolina, Charleston, SC 29425, USA. wallet@musc.eduAIMS: To describe the oral disposition of the dietary flavonoid chrysin in healthy volunteers. METHODS: Oral 400 mg doses of chrysin were administered to seven subjects. Chrysin and metabolites were assayed in plasma, urine and faeces by h.p.l.c. RESULTS: Peak plasma chrysin concentrations were only 3-16 ng ml(-1) with AUCs of 5-193 ng ml(-1) h. Plasma chrysin sulphate concentrations were 30-fold higher (AUC 450-4220 ng ml(-1) h). In urine, chrysin and chrysin glucuronide accounted for 0.2-3.1 mg and 2-26 mg, respectively. Most of the dose appeared in faeces as chrysin. Parallel experiments in rats showed high bile concentrations of chrysin conjugates. CONCLUSIONS: These findings, together with previous data using Caco-2 cells, suggest that chrysin has low oral bioavailability, mainly due to extensive metabolism and efflux of metabolites back into the intestine for hydrolysis and faecal elimination.
PMID: 11259985 [PubMed - indexed for MEDLINE]
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Chrysin is an inhibitor of CYP1A2 therefore may interact with these drugs:amitriptyline, caffeine, clomipramine, clozapine, cyclobenzaprine, estradiol, fluvoxamine, haloperidol, imipramine, mexiletine, naproxen, olanzapine, ondansetron, paracetamol, propranolol, riluzole, ropivacaine, tacrine, theophylline, tizanidine, verapamil, warfarin, zileuton, zolmitriptan
http://en.wikipedia.org/wiki/CYP1A2Chrysin also inhibits CYP1B1, and CYP1A1, but I can't find a list of drugs that are substrates to these enzymes right now.
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Arch Pharm Res. 2005 Oct;28(10):1114-21.Links
Effects of hydroxyl group numbers on the B-ring of 5,7-dihydroxyflavones on the differential inhibition of human CYP 1A and CYP1B1 enzymes.
Kim HJ, Lee SB, Park SK, Kim HM, Park YI, Dong MS.
School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.Flavonoids are polyphenols composed of two aromatic rings (A, B) and a heterocyclic ring (C). In order to determine the effects of the number of hydroxyl groups in the B-ring of the flavonoids on human cytochrome P450 (CYP) 1 family enzymes, we evaluated the inhibition of CYP1A-dependent 7-ethoxyresorufin omicron-deethylation activity by chrysin, apigenin and luteolin, using bacterial membranes that co-express human CYP1A1, CYP1A2, or CYP1B1 with human NADPH-cytochrome P450 reductase. Chrysin, which possesses no hydroxyl groups in its B-ring, exhibited the most pronounced inhibitory effects on CYP1A2-dependent EROD activity, followed by apigenin and luteolin. On the contrary, CYP1A1-mediated EROD activity was most potently inhibited by luteolin, which is characterized by two hydroxyl groups in its B-ring, followed by apigenin and chrysin. However, all of the 5,7-dihydroxyflavones were determined to similarly inhibit CYP1B1 activity. Chrysin, apigenin, and luteolin exhibited a mixed-type mode of inhibition with regard to CYP1A2, CYP1B1, and CYP1A1, with apparent Ki values of 2.4, 0.5, and 2.0 microM, respectively. These findings suggested that the number of hydroxyl groups in the B-ring of 5,7-dihydroxyflavone might have some influence on the degree to which CYP1A enzymes were inhibited, but not on the degree to which CYP1B1 enzymes were inhibited.
PMID: 16276964 [PubMed - indexed for MEDLINE]
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Chrysin may effect the metabolism and excretion of acetaminophen:__________________________________________________
1: Biol Pharm Bull. 2004 May;27(5):714-7.
Inhibitory effect of flavonoids on sulfo- and glucurono-conjugation of acetaminophen in rat cultured hepatocytes and liver subcellular preparations.
Morimitsu Y, Sugihara N, Furuno K.
Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Hiroshima, Japan.
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.
PMID: 15133252 [PubMed - indexed for MEDLINE]
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Chrysin therapy may deplete glutathione levels:__________________________________________________
1: Free Radic Biol Med. 2006 Jul 1;41(1):65-76. Epub 2006 Mar 31.
Flavonoid-induced glutathione depletion: potential implications for cancer treatment.
Kachadourian R, Day BJ.
Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA.The ability of a number of flavonoids to induce glutathione (GSH) depletion was measured in lung (A549), myeloid (HL-60), and prostate (PC-3) human tumor cells. The hydroxychalcone (2'-HC) and the dihydroxychalcones (2',2-, 2',3-, 2',4-, and 2',5'-DHC) were the most effective in A549 and HL-60 cells, depleting more than 50% of intracellular GSH within 4 h of exposure at 25 microM. In contrast, the flavones chrysin and apigenin were the most effective in PC-3 cells, depleting 50-70% of intracellular GSH within 24 h of exposure at 25 microM. In general, these flavonoids were more effective than three classical substrates of multidrug resistance protein 1 (MK-571, indomethacin, and verapamil). Prototypic flavonoids (2',5'-DHC and chrysin) were subsequently tested for their abilities to potentiate the toxicities of prooxidants (etoposide, rotenone, 2-methoxyestradiol, and curcumin). In A549 cells, 2',5'-DHC potentiated the cytotoxicities of rotenone, 2-methoxyestradiol, and curcumin, but not etoposide. In HL-60 and PC-3 cells, chrysin potentiated the cytotoxicity of curcumin, cytotoxicity that was attenuated by the catalytic antioxidant manganese(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP). Assessments of mitochondrial GSH levels mitochondrial membrane potential and cytochrome c release showed that the potentiation effects induced by 2',5'-DHC and chrysin involve mitochondrial dysfunction.
PMID: 16781454 [PubMed - indexed for MEDLINE]
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Chrysin is also an effective antioxidant and may confer protection against some cancers. It has also demonstrated efficacy in vitro as a chemotherapeutic agent in the treatment of cancer. It may be particularly effective in treating colon cancer, since large concentrations of Chrysin remain in the intestine due to low oral bioavailability.__________________________________________________
1: Nutr Cancer. 2004;50(1):90-100.
Flavonoids induce apoptosis in human leukemia U937 cells through caspase- and caspase-calpain-dependent pathways.
Monasterio A, Urdaci MC, Pinchuk IV, López-Moratalla N, Martínez-Irujo JJ.
Departamento di Bioquímica y Biología Molecular, Universidad de Navarra, Pamplona, Spain.Flavonoids are polyphenolic phytochemicals that are ubiquitous in plants and present in the common human diet. They may exert diverse beneficial effects, including antioxidant and anticarcinogenic activities. In this study we tested the apoptotic activity of 22 flavonoids and related compounds in leukemic U937 cells. Several flavones but none of the isoflavones or flavanones tested induced apoptotic cell death under these conditions, as determined by reduction in cell viability, flow cytometry, and oligonucleosomal DNA fragmentation. Structure-activity relationship showed that at least two hydroxylations in positions 3, 5, and 7 of the A ring were needed to induce apoptosis, whereas hydroxylation in 3' and/or 4' of the B ring enhanced proapoptotic activity. At lower concentrations, these compounds were also able to sensitize these cells to apoptosis induced by tumor necrosis factor-alpha. Regarding the mechanisms, galangin, luteolin, chrysin, and quercetin induced apoptosis in a way that required the activation of caspases 3 and 8, but not caspase 9. In contrast, an active role of calpains in addition to caspases was demonstrated in apoptosis induced by fisetin, apigenin, and 3,7-dihydroxyflavone. Our data show evidence of the proapoptotic properties of some flavonoids that could support their rational use as chemopreventive and therapeutic agents against carcinogenic disease.
PMID: 15572302 [PubMed - indexed for MEDLINE]
--------------------------------------------------2: Cancer Chemother Pharmacol. 2006 Feb;57(3):309-16. Epub 2005 Jul 8.
A pilot study on the safety of combining chrysin, a non-absorbable inducer of UGT1A1, and irinotecan (CPT-11) to treat metastatic colorectal cancer.
Tobin PJ, Beale P, Noney L, Liddell S, Rivory LP, Clarke S.
Department of Pharmacology, University of Sydney, NSW, Australia.PURPOSE: Recently, it was shown that chrysin causes upregulation of UGT1A1 in Caco-2 intestinal cells. Therefore, we proposed that oral chrysin may reduce irinotecan (CPT-11) induced diarrhoea by shifting the SN-38G/SN-38 equilibrium towards the inactive SN-38G in the gastrointestinal mucosa. The purpose of this study was to examine the safety of combining single agent CPT-11 with chrysin. PATIENTS AND METHODS: Twenty patients with previously treated advanced colorectal cancer were administered chrysin twice daily for 1 week preceding and succeeding treatment with single agent CPT-11 (350 mg/m(2) over 90 min every 3 weeks). Loperamide usage and bowel frequency/consistency were recorded by patients into a study diary and blood samples were collected for CPT-11 pharmacokinetic analysis. RESULTS: There were no observable toxicities that could be attributed to chrysin use. The grades and frequency of delayed diarrhoea were mild, with only 10% of patients experiencing grade 3 toxicity. Loperamide usage was also modest with a median of 1-5 tablets per cycle (range: 0-22). Pharmacokinetic results revealed a mass ratio of plasma SN-38G/SN-38, which was very similar to historical controls (7.15 +/- 5.67, n = 18). CONCLUSIONS: These findings, combined with the observation of clinical activity and grade 3/4 neutropenia in 25% of patients, suggest that combining chrysin with CPT-11 may be a safe and potentially useful means of preventing diarrhoea, although this needs to be further investigated in the setting of a randomised trial.
PMID: 16003560 [PubMed - indexed for MEDLINE]
--------------------------------------------------3: World J Gastroenterol. 2007 Jul 28;13(28):3824-8.
Induction of apoptosis of human gastric carcinoma SGC-7901 cell line by 5, 7-dihydroxy-8-nitrochrysin in vitro.
Ai XH, Zheng X, Tang XQ, Sun L, Zhang YQ, Qin Y, Liu HQ, Xia H, Cao JG.
Institute of Pharmacology, Nahua University, Hengyang 421001, Hunan Province, China. caojianguo2005@yahoo.com.cn.AIM: To investigate the effect of 5, 7-dihydroxy-8-nitrochrysin (NOChR) on apoptosis of human gastric carcinoma SGC-7901 cell line. METHODS: SGC-7901 cells were cultured in vitro and the inhibitory effect of NOChR on proliferation of SGC-7901 cells was measured by using an MTT assay. NOChR-induced apoptosis rate of SGC-7901 cells was detected using flow cytometry (FCM) with PI staining. DNA ladder bands were observed by DNA agarose gel electrophoresis. The influence of NOChR on the proxisome proliferator-activated receptor-gamma (PPARgamma), Bcl-2 and Bax protein expression of SGC-7901 cells was analyzed by Western blot. RESULTS: MTT assay showed that NOChR markedly inhibited proliferation of SGC-7901 cells in a dose-dependent manner, and when IC(50) was 4.14 mumol/L, the potency of NOChR was 10 times than that of lead compound, chrysin (ChR, IC(50) was 40.56 mumol/L), and was similar to 5-fluorouracil (5-FU, IC(50) was 4.51 mumol/L). FCM with propidium iodide (PI) staining demonstrated that the apoptosis rates of SGC-7901 cells treated with 1.25, 5.00 and 20.00 mumol/L NOChR for 48 h were 9.8% +/- 0.2%, 36.8% +/- 1.9% and 45.5% +/- 3.5%, respectively, and were significantly higher when treated with 5.00 and 20.00 mumol/L NOChR than that with 20.00 mumol/L ChR (12.9% +/- 1.5%). DNA agarose gel electrophoresis showed that treatment of SGC-7901 cells with 20.00 mumol/L NOChR for 48 h resulted in typical DNA ladder bands of DNA of SGC-7901 cells, which could be eliminated by treating with 10.00 mumol/L GW9662, a blocker of PPARgamma. Western blot analysis revealed that after 24 h of treatment with 20.00 mumol/L NOChR, PPARgamma and Bax protein expression of SGC-7901 cells increased but Bcl-2 expression decreased; however, pre-incubation with 10.00 mumol/L GW9662 could efficiently antagonize and weaken the regulatory effect of 20.00 mumol/L NOChR on Bax and Bcl-2 protein expression of SGC-7901 cells.
PMID: 17657836 [PubMed - in process]
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Chrysin is an effective vasodilator, promoting relaxation of arterial vessles via release of nitric oxide:__________________________________________________
1: Planta Med. 2005 Sep;71(9):829-34.
Endothelial nitric oxide production stimulated by the bioflavonoid chrysin in rat isolated aorta.
Villar IC, Vera R, Galisteo M, O'Valle F, Romero M, Zarzuelo A, Duarte J.
Departamento de Farmacología, Facultad de Farmacia, Universidad de Granada, Granada, Spain.In the present study, the effects of the bioflavonoid chrysin (5,7-dihydroxyflavone) were analysed on nitric oxide (NO) production from vascular endothelium. In aortic rings, incubation with chrysin or acetylcholine (both at 10 microM) increased L-NAME-sensitive endothelial NO release as measured using the fluorescent probe 4,5-diaminofluorescein diacetate (DAF-2 DA). Moreover, chrysin increased cGMP accumulation only in aortic rings with endothelium. However, at this concentration, chrysin had no effect either on basal or on NADPH-stimulated vascular superoxide production. Moreover, at this low concentration, chrysin, similar to acetylcholine, induced aortic relaxation, which was abolished by both endothelial deprivation and NO synthase inhibition. Endothelium-dependent relaxation induced by chrysin was unaltered by removal of extracellular calcium and incubation with the intracellular calcium chelator BAPTA, while the phosphatidylinositol (PI)-3 kinase inhibitor wortmannin suppressed the endothelial dependence. In conclusion, chrysin stimulated NO release from endothelial cells leading to vascular cGMP accumulation and subsequent endothelium dependent aortic relaxation. Chrysin-stimulated NO release is calcium independent and possibly mediated via PI3-kinase.
PMID: 16206037 [PubMed - indexed for MEDLINE]
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2: Naunyn Schmiedebergs Arch Pharmacol. 2004 Oct;370(4):290-8. Epub 2004 Sep 17.Vasorelaxing effects of flavonoids: investigation on the possible involvement of potassium channels.
Calderone V, Chericoni S, Martinelli C, Testai L, Nardi A, Morelli I, Breschi MC, Martinotti E.
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. calderone@farm.unipi.itA flavonoid-rich diet has been associated with a lower incidence of cardiovascular diseases, probably because of the antioxidant and vasoactive properties of flavonoids. Indeed, many flavonoids show vasorelaxing properties, due to different and often not yet completely clarified mechanisms of action. Among them, the activation of vascular potassium channels has been indicated as a possible pathway, accounting, at least in part, for the vasodilatory action of some flavonoid derivatives, such as apigenin and dioclein. Therefore, this work aims at evaluating, on in vitro isolated rat aortic rings, the endothelium-independent vasorelaxing effects of a number of flavonoid derivatives, to identify a possible activation of calcium-activated and/or ATP-sensitive potassium channels and to indicate some possible structure-activity relationships. Among the several flavonoids submitted to the pharmacological assay, only baicalein and quercetagetin were almost completely ineffective, while quercetin, hesperidin, quercitrin and rhoifolin exhibited only a partial vasorelaxing effect. On the contrary, acacetin, apigenin, chrysin, hesperetin, luteolin, pinocembrin, 4'-hydroxyflavanone, 5-hydroxyflavone, 5-methoxyflavone, 6-hydroxyflavanone and 7-hydroxyflavone, belonging to the chemical classes of flavones and flavanones, showed full vasorelaxing effects. The vasodilatory activity of hesperetin, luteolin, 5-hydroxyflavone and 7-hydroxyflavone were antagonised by tetraethylammonium chloride, indicating the possible involvement of calcium-activated potassium channels. Moreover, iberiotoxin clearly antagonised the effects of 5-hydroxyflavone, indicating the probable importance of a structural requirement (the hydroxy group in position 5) for a possible interaction with large-conductance, calcium-activated potassium channels. Finally, glibenclamide inhibited the vasorelaxing action of luteolin and 5-hydroxyflavone, suggesting that ATP-sensitive potassium channels may also be involved in their mechanism of action.
PMID: 15378228 [PubMed - indexed for MEDLINE]
--------------------------------------------------3: Planta Med. 2002 Sep;68(9):847-50.
Effects of chronic chrysin treatment in spontaneously hypertensive rats.
Villar IC, Jiménez R, Galisteo M, Garcia-Saura MF, Zarzuelo A, Duarte J.
Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spain.The effects of an oral daily dose (20 mg kg(-1)) of the flavonoid chrysin for 6 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. Chrysin reduces SHR elevated blood pressure, cardiac hypertrophy and functional vascular changes, but is without effect in WKY. These protective effects were associated with a reduced oxidative status due to the antioxidant properties of the drug.
PMID: 12357404 [PubMed - indexed for MEDLINE]
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Chrysin may be an effective anti-inflammitory agent by inhibiting prostoglandin-E2 formation:__________________________________________________
1: J Nutr. 2006 Jun;136(6):1517-21.
Luteolin and chrysin differentially inhibit cyclooxygenase-2 expression and scavenge reactive oxygen species but similarly inhibit prostaglandin-E2 formation in RAW 264.7 cells.
Harris GK, Qian Y, Leonard SS, Sbarra DC, Shi X.
United States Department of Agriculture, Diet and Human Performance Laboratory, MD 20705, USA. harrisk@ba.ars.usda.govInflammation and oxidative stress are associated with cancer, atherosclerosis, and other chronic diseases. Dietary flavonoids have been reported to possess antiinflammatory and antioxidant properties, but their mechanisms of action and structure-activity relations have not been fully investigated. We hypothesized that differences in antioxidant activity between the structurally similar flavones, luteolin and chrysin (differing only in B-ring hydroxylation patterns), would differentially affect inflammation-associated Cox-2 expression and PGE2 formation. Pretreatment of RAW 264.7 macrophage-like cells with 25, 50, or 100 micromol/L concentrations of luteolin inhibited lipopolysaccharide (LPS)-induced Cox-2 protein expression (P < 0.0001). Chrysin pretreatment did not reduce LPS-induced Cox-2 protein expression at any level tested. Conversely, both luteolin and chrysin completely suppressed LPS-induced PGE2 formation (P < 0.001). Luteolin, but not chrysin, inhibited xanthine/xanthine oxidase-generated superoxide formation at 100 micromol/L in a cell-free system (P < 0.001). Although both luteolin and chrysin reduced LPS-induced hydroxyl radical formation relative to the positive control (P < 0.001), luteolin was superior to chrysin (P = 0.003). In summary, luteolin and chrysin suppressed PGE2 formation equally well, despite differential effects on Cox-2 protein expression and on superoxide and hydroxyl radical scavenging. These data indicate that flavones may display similar antiinflammatory activity via different mechanisms.
PMID: 16702314 [PubMed - indexed for MEDLINE]
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Chrysin may protect against Parkinson's disease by preventing oxidative damage to the mesencephalic dopamine neurones:___________________________________________________
1:Biochem Pharmacol. 2005 Jan 15;69(2):339-45. Epub 2004 Nov 23.
Dietary polyphenols protect dopamine neurons from oxidative insults and apoptosis: investigations in primary rat mesencephalic cultures.
Mercer LD, Kelly BL, Horne MK, Beart PM.
Department of Pharmacology, Monash University, Clayton, Vic. 3800, Australia. l.mercer@hfi.unimel.edu.auNaturally occurring polyphenols have the potential to prevent oxidative damage in various pathophysiological conditions. Various members of the flavonoid family were investigated to determine if they could protect mesencephalic dopamine (DA) neurones from injury and reduce apoptosis produced by oxidative stressors. Primary mesencephalic cultures were sensitive to oxidative insults (hydrogen peroxide, 4-hydroxynonenal, rotenone, 6-hydroxydopamine and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium hydrochloride (MPP+)) which produced concentration-dependent decreases in cellular viability across an apoptotic-necrotic continuum of injury. Flavonoids (catechin, quercetin, chrysin, puerarin, naringenin, genestein) protected mesencephalic cultures from injury by MPP+, which was shown by DNA fragmentation studies and tyrosine hydroxylase (TH) immunocytochemistry of DA neurones to occur by apoptosis. Catechin also reduced injury produced by hydrogen peroxide, 4-hydroxynonenal, rotenone and 6-hydroxydopamine as shown by increases in cellular viability and [3H]DA uptake. When the neuroprotection of catechin against MPP+-induced injury was compared to that produced by the caspase-3 inhibitor, Z-DVED-FMK, both reduced DNA fragmentation and the injury patterns of TH-positive neurones. These data demonstrate the neuroprotective abilities of flavonoids which are able to attenuate the apoptotic injury of mesencephalic DA neurones. Since these DA neurones are under oxidative stress in Parkinsonism, our findings suggest that flavonoids could provide benefits along with other anti-oxidant therapies in Parkinson's disease.
PMID: 15627486 [PubMed - indexed for MEDLINE]
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Chrysin shows hypoglycemic effect in rats, showing potential as a therapy in diabetes mellitus:___________________________________________________
1: Bioorg Med Chem Lett. 1999 Mar 22;9(6):869-74.
Synthesis and hypoglycemic effect of chrysin derivatives.
Shin JS, Kim KS, Kim MB, Jeong JH, Kim BK.
College of Pharmacy, Seoul National University, Korea.A series of 18 chrysin derivatives, prepared by alkylation and condensation, were fully characterized by NMR and other techniques and tested in vivo against the diabetes mellitus. Several modified compounds especially those with propyl, butyl, octyl and tolyl groups were found to have hypoglycemic effect on diabetec mice in spite of the fact that chrysin itself had inhibited insulin release by 40-60%. None of the test animals died at the maximum dose 500mg/kg and did not cause any significant change in general feature, water and food consumption, body weight and organ weight when we examined the acute oral toxicity of those compounds having significant hypoglycemic effect.
PMID: 10206552 [PubMed - indexed for MEDLINE]
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Chrysin has shown efficacy in reducing the signs of morphine withdrawal in guinea pig ileum, whatever that's worth:__________________________________________________
1: J Pharm Pharmacol. 1998 May;50(5):561-4.
Flavonoids reduce morphine withdrawal in-vitro.
Capasso A, Piacente S, Pizza C, Sorrentino L.Department of Pharmaceutical Sciences, University of Salerno, Penta di Fisciano, Italy.
The effects of quercetin, flavone, catechin and chrysin on the naloxone-precipitated withdrawal contracture of the acute morphine-dependent guinea-pig ileum have been investigated in-vitro. After 4 min in-vitro exposure to morphine a strong contracture of guinea-pig isolated ileum was observed after the addition of naloxone. All the flavonoids, injected 10 min before morphine at concentrations between 10(-7) and 10(-5) M, were capable of blocking naloxone-induced contracture after exposure to morphine in a concentration-dependent fashion. IC50 values calculated for quercetin, flavone, catechin and chrysin were 2.7 x 10(-6), 7.3 x 10(-7), 8.5 x 10(-7) and 5.3 x 10(-6) M, respectively. These results suggest that flavonoids might play an important role in the control of morphine withdrawal.
PMID: 9643451 [PubMed - indexed for MEDLINE]
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And Chrysin seems to boost libido and sexual functioning, and protect against the ravages of aging in rats:__________________________________________________
1: J Med Food. 2002 Spring;5(1):43-8.
Beneficial effects of chrysin and benzoflavone on virility in 2-year-old male rats.
Dhawan K, Kumar S, Sharma A.
Pharmacognosy Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India.This work describes the potential usefulness of bioflavonoids for countering the deleterious effects of aging on male sexuality in 2-year-old rats. A flavone chrysin from Passiflora caerulea Linn. and a benzoflavone moiety (BZF) recently isolated from Passiflora incarnata Linn. were administered to 2-year-old male rats for a period of 30 days. After cessation of these treatments, there was a significant improvement in overall sexual functions in the rats given bioflavonoids, compared with control rats. The rats receiving chrysin (1 mg/kg) and BZF (10 mg/kg) exhibited increased libido when they were allowed to interact with nonestrous female rats. Additionally, both treated groups had increased sperm count, greater fertilization potential, and greater litter size when they were allowed to interact with proven proestrous female rats of a similar strain. BZF was more potent than chrysin as an antiaromatase agent and exhibited better effects on the sexual system of the 2-year-old male rats. Plant flavonoids have great potential for clinical and therapeutic applications against the physiological and biochemical effects of aging.
PMID: 12511112 [PubMed - indexed for MEDLINE]
___________________________________________________If you want to try it after reading all that, you can buy it here:
http://www.iherb.com/ProductsList.aspx?c=1&cid=1858&gclid=CLCfjo7E3Y0CFQLklAodNCYSag
http://www.thesupplementsite.co.uk/MRM/chrysin.htm?gclid=COO0rpnE3Y0CFQ1hMAodlFsNYgQ
poster:Quintal
thread:774066
URL: http://www.dr-bob.org/babble/alter/20070601/msgs/774066.html