Diosmetin

300.26

300.26

208-291-8

TWZ37241OT

DTXSID80199966

Yellow powder

2914509090

96.2

1.7

light yellow to yellow

1.512 g/cu cm

253.5 °C

576.7°C at 760 mmHg

220.3±23.6 °C

1.697

DMSO: soluble 1mg/mL, clear, light yellow to yellow

-20°C Freezer

3.8X10-12 mm Hg at 25 deg C (est)

Henry's Law constant = 3.0X10-18 atm-cu m/mol at 25 °C (est)

164.8 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant = 2.3X10-10 cu cm/molecule-sec at 25 °C (est)

NONH for all modes of transport

3

22

24/25

Xi,Xn

Stable under recommended storage conditions.

P264, P270, P301+P312, P330, P501

H302

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). Hand protection: Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. Eye protection: Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). Skin and body protection: Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Wear imperatively an appropriated mask/respirator, tested and approved by standards such as NIOSH (US) or CEN (EU). ... Handle with protective gloves. The selected gloves have to satisfy the specifications of EU Directive 89/686/EEC and the standard EN 374 derived from it. ... Wear safety glasses. ... Wear suitable protective clothing according to the quantity and the level of activity of the substance at the workplace.

Extinguishing media: Carbon dioxide, dry powder.|Wear an autonomous breathing apparatus and suitable protection clothing against chemical agents.

Clean-up without creating dust and place in adapted and sealed containers for elimination. Wash the contaminated area with water and soap. Confine washing water and dispose of it complying with the local regulations. After cleaning, quickly eliminate traces of water with a product absorbing liquids (for example: sand, sawdust, universal binder, Kieselguhr).

Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Avoid formation of dust. Avoid contact with skin and eyes. During handling, wear suitable personal protective equipment.

Diosmetin has been identified in the following plants: Capsella bursa-pastoris (Shepherd's Purse plant), Citrus limon (lemon), Mentha spicata (spearmint plant), Origanum vulgare (oregano), Rosmarinus officinalis (rosemary plant), Salvia officinalis (sage), Salvia tomentosa (sage), Tanacetum vulgare (tansy plant), Thymus vulgaris (thyme plant)(1). Diosmetin is found naturally in citrus fruits and juices, such as orange juice, grapes and grapefruit(2).

Diosmetin's production and use in pharmacological, food and cosmetic research and as an intermediate and ingredient in food supplements and beverages(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2000(SRC), determined from a structure estimation method(2), indicates that diosmetin is expected to have low mobility in soil(SRC). Volatilization of diosmetin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.0X10-18 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Diosmetin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-12 mm Hg at 25 °C(SRC) determined from a fragment constant method(2). Diosmetin does contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis on soil surfaces exposed to sunlight(SRC).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2000(SRC), determined from a structure estimation method(2), indicates that diosmetin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.0X10-18 atm-cu m/mole(SRC) developed using a fragment constant estimation method(2). Phenols can undergo sensitized photo-oxidation in surface waters exposed to sunlight via reaction with hydroxyl and RO2 radicals with half-lives on the order of days to weeks at the water surface(4); therefore, photo-oxidation may be an important fate process for diosmetin in natural water(SRC). Diosmetin is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(3). Biodegradation data in water were not available(SRC, 2012).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), diosmetin, which has an estimated vapor pressure of 3.8X10-12 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase diosmetin may be removed from the air by wet and dry deposition(SRC).

The rate constant for the vapor-phase reaction of diosmetin with photochemically-produced hydroxyl radicals has been estimated as 2.3X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Diosmetin is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Diosmetin does contain chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC). Phenols can undergo sensitized photo-oxidation in surface waters exposed to sunlight via reaction with hydroxyl and RO2 radicals with half-lives on the order of days to weeks at the water surface(3); therefore, photo-oxidation may be an important fate process for diosmetin in natural water(SRC).

An estimated BCF of 13 was calculated in fish for diosmetin(SRC) using a log Kow of 3.10(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of diosmetin can be estimated to be 2000(SRC). According to a classification scheme(2), this estimated Koc value suggests that diosmetin is expected to have low mobility in soil.

The Henry's Law constant for diosmetin is estimated as 3.0X10-18 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that diosmetin is expected to be essentially nonvolatile from water surfaces(2). Diosmetin's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Diosmetin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-12 mm Hg(SRC) determined from a fragment constant method(1).

Diosmetin is found in citrus fruits and juices, such as orange juice, lemons, grapes and grapefruit(1).|Diosmetin has been extracted from the traditional Chinese herb Galium verum L.(1).

Diosmin is hydrolyzed to its aglycone diosmetin by intestinal microflora enzymes before its absorption into the body.

... Diosmetin was metabolised to the structurally similar flavone luteolin in MDA-MB 468 cells, whereas no metabolism was seen in MCF-10A cells...|Various types of tumors are known to overexpress enzymes belonging to the CYP1 family of cytochromes P450. The present study aimed to characterize the metabolism and further antiproliferative activity of the natural flavonoid diosmetin in the CYP1-expressing human hepatoma cell line HepG2. Diosmetin was converted to luteolin in HepG2 cells after 12 and 30 hr of incubation. In the presence of the CYP1A inhibitor alpha-naphthoflavone, the conversion of diosmetin to luteolin was attenuated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed luteolin to be more cytotoxic than diosmetin. The antiproliferative effect of diosmetin in HepG2 cells was attributed to blockage at the G2/M phase as determined by flow cytometry. Induction of G2/M arrest was accompanied by up-regulation of phospho-extracellular-signal-regulated kinase (p-ERK), phospho-c-jun N-terminal kinase, p53 and p21 proteins. More importantly, induction of G2/M arrest and p53 and p-ERK up-regulation were reversed by the application of the CYP1 inhibitor alpha-naphthoflavone. Taken together, the data provide new evidence on the tumor-suppressing role of cytochrome P450 CYP1A enzymes and extend the hypothesis that the anticancer activity of dietary flavonoids is enhanced by P450-activation.|CYP1A1 and CYP1B1 are two extrahepatic enzymes that have been implicated in carcinogenesis and cancer progression. Selective inhibition of CYP1A1 and CYP1B1 by dietary constituents, notably the class of flavonoids, is a widely accepted paradigm that supports the concept of dietary chemoprevention. In parallel, recent studies have documented the ability of CYP1 enzymes to selectively metabolize dietary flavonoids to conversion products that inhibit cancer cell proliferation. In the present study /the authors/ have examined the inhibition of CYP1A1 and CYP1B1-catalyzed EROD activity by 14 different flavonoids containing methoxy- and hydroxyl-group substitutions as well as the metabolism of the monomethoxylated CYP1-flavonoid inhibitor acacetin and the poly-methoxylated flavone eupatorin-5-methyl ether by recombinant CYP1A1 and CYP1B1. The most potent inhibitors of CYP1-EROD activity were the methoxylated flavones acacetin, diosmetin, eupatorin and the di-hydroxylated flavone chrysin, indicating that the 4'-OCH(3) group at the B ring and the 5,7-dihydroxy motif at the A ring play a prominent role in EROD inhibition. Potent inhibition of CYP1B1 EROD activity was also obtained for the poly-hydroxylated flavonols quercetin and myricetin. HPLC metabolism of acacetin by CYP1A1 and CYP1B1 revealed the formation of the structurally similar flavone apigenin by demethylation at the 4'-position of the B ring, whereas the flavone eupatorin-5-methyl ether was metabolized to an as yet unidentified metabolite assigned E(5)M1. Eupatorin-5-methyl ether demonstrated a submicromolar IC50 in the CYP1-expressing cancer cell line MDA-MB 468, while it was considerably inactive in the normal cell line MCF-10A. Homology modeling in conjunction with molecular docking calculations were employed in an effort to rationalize the activity of these flavonoids based on their CYP1-binding mode. Taken together the data suggest that dietary flavonoids exhibit three distinct modes of action with regard to cancer prevention, based on their hydroxyl and methoxy decoration: (1) inhibitors of CYP1 enzymatic activity, (2) CYP1 substrates and (3) substrates and inhibitors of CYP1 enzymes.|Flos Chrysanthemi (the flower of Chrysanthemum morifolium Ramat.) is widely used in China as a food and traditional Chinese medicine for many diseases. Luteolin and apigenin are two main bioactive components in Flos Chrysanthemi, and chrysoeriol and diosmetin are two methylated metabolites of luteolin in vivo by cathechol-O-methyltransferase (COMT). However, there was /a/ lack of pharmacokinetic information of chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract (FCE). The present study aimed to develop an HPLC-UV method for simultaneous determination of rat plasma concentration of luteolin, apigenin, chrysoeriol and diosmetin and utilize it in pharmacokinetic study of the four compounds after orally giving FCE to rats. The method was successfully validated and applied to the pharmacokinetic study when oral administration of FCE to rats with or without co-giving a COMT inhibitor, entacapone. Chrysoeriol and diosmetin were detected in rat plasma after oral administration of FCE and their concentrations were significantly decreased after co-giving entacapone... In conclusion, a sensitive, accurate and reproducible HPLC-UV method for simultaneous determination of luteolin, apigenin, chrysoeriol and diosmetin in rat plasma were developed, pharmacokinetics of chrysoeriol and diosmetin combined with luteolin and apigenin were characterized after oral administration of FCE to rats, which gave us more information on pharmacokinetics and potential pharmacological effects of FCE in vivo.|Diosmetin has known human metabolites that include (2S,3S,4S,5R)-3,4,5-Trihydroxy-6-[5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxochromen-7-yl]oxyoxane-2-carboxylic acid.

Various types of tumors are known to overexpress enzymes belonging to the CYP1 family of cytochromes P450. The present study aimed to characterize the metabolism and further antiproliferative activity of the natural flavonoid diosmetin in the CYP1-expressing human hepatoma cell line HepG2. Diosmetin was converted to luteolin in HepG2 cells after 12 and 30 hr of incubation. In the presence of the CYP1A inhibitor alpha-naphthoflavone, the conversion of diosmetin to luteolin was attenuated. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed luteolin to be more cytotoxic than diosmetin. The antiproliferative effect of diosmetin in HepG2 cells was attributed to blockage at the G2/M phase as determined by flow cytometry. Induction of G2/M arrest was accompanied by up-regulation of phospho-extracellular-signal-regulated kinase (p-ERK), phospho-c-jun N-terminal kinase, p53 and p21 proteins. More importantly, induction of G2/M arrest and p53 and p-ERK up-regulation were reversed by the application of the CYP1 inhibitor alpha-naphthoflavone. Taken together, the data provide new evidence on the tumor-suppressing role of cytochrome P450 CYP1A enzymes and extend the hypothesis that the anticancer activity of dietary flavonoids is enhanced by P450-activation.|CYP1A1 and CYP1B1 are two extrahepatic enzymes that have been implicated in carcinogenesis and cancer progression. Selective inhibition of CYP1A1 and CYP1B1 by dietary constituents, notably the class of flavonoids, is a widely accepted paradigm that supports the concept of dietary chemoprevention. In parallel, recent studies have documented the ability of CYP1 enzymes to selectively metabolize dietary flavonoids to conversion products that inhibit cancer cell proliferation. In the present study /the authors/ have examined the inhibition of CYP1A1 and CYP1B1-catalyzed EROD activity by 14 different flavonoids containing methoxy- and hydroxyl-group substitutions as well as the metabolism of the monomethoxylated CYP1-flavonoid inhibitor acacetin and the poly-methoxylated flavone eupatorin-5-methyl ether by recombinant CYP1A1 and CYP1B1. The most potent inhibitors of CYP1-EROD activity were the methoxylated flavones acacetin, diosmetin, eupatorin and the di-hydroxylated flavone chrysin, indicating that the 4'-OCH(3) group at the B ring and the 5,7-dihydroxy motif at the A ring play a prominent role in EROD inhibition. Potent inhibition of CYP1B1 EROD activity was also obtained for the poly-hydroxylated flavonols quercetin and myricetin. HPLC metabolism of acacetin by CYP1A1 and CYP1B1 revealed the formation of the structurally similar flavone apigenin by demethylation at the 4'-position of the B ring, whereas the flavone eupatorin-5-methyl ether was metabolized to an as yet unidentified metabolite assigned E(5)M1. Eupatorin-5-methyl ether demonstrated a submicromolar IC50 in the CYP1-expressing cancer cell line MDA-MB 468, while it was considerably inactive in the normal cell line MCF-10A. Homology modeling in conjunction with molecular docking calculations were employed in an effort to rationalize the activity of these flavonoids based on their CYP1-binding mode. Taken together the data suggest that dietary flavonoids exhibit three distinct modes of action with regard to cancer prevention, based on their hydroxyl and methoxy decoration: (1) inhibitors of CYP1 enzymatic activity, (2) CYP1 substrates and (3) substrates and inhibitors of CYP1 enzymes.|The binding mechanism of molecular interaction between diosmetin and human serum albumin (HSA) in a pH 7.4 phosphate buffer was studied using atomic force microscopy (AFM) and various spectroscopic techniques including fluorescence, resonance light scattering (RLS), UV-vis absorption, circular dichroism (CD), and Fourier transform infrared (FT-IR) spectroscopy. Fluorescence data revealed that the fluorescence quenching of HSA by diosmetin was a static quenching procedure. The binding constants and number of binding sites were evaluated at different temperatures. The RLS spectra and AFM images showed that the dimension of the individual HSA molecules were larger after interaction with diosmetin. The thermodynamic parameters, /changes in enthalpy and entropy/ were calculated to be -24.56 kJ/mol and 14.67 J/mol/K, respectively, suggesting that the binding of diosmtin to HSA was driven mainly by hydrophobic interactions and hydrogen bonds. The displacement studies and denaturation experiments in the presence of urea indicated site I as the main binding site for diosmetin on HSA. The binding distance between diosmetin and HSA was determined to be 3.54 nm based on the Forster theory. Analysis of CD and FT-IR spectra demonstrated that HSA conformation was slightly altered in the presence of diosmetin.|The survival of osteoblasts is one of the determinants of the development of osteoporosis. This study /investigates/ the osteoblastic differentiation induced by diosmetin, a flavonoid derivative, in osteoblastic cell lines MG-63, hFOB, and MC3T3-E1 and bone marrow stroma cell line M2-10B4. Osteoblastic differentiation was determined by assaying alkaline phosphatase (ALP) activity and mineralization degree and measuring various osteoblast-related markers using ELISA. Expression and phosphorylation of Runt-related transcription factor 2 (Runx2), protein kinase Cdelta (PKCdelta), extracellular signal-regulated kinase (ERK), p38, and c-jun-N-terminal kinase (JNK) was assessed by immunoblot. Rac1 activity was determined by immunoprecipitation, and Runx2 activity was assessed by EMSA. Genetic inhibition was performed by small hairpin RNA plasmids or small interfering RNA (siRNA) transfection. Diosmetin exhibited an effect on osteoblastic maturation and differentiation by means of ALP activity, osteocalcin, osteopontin, and type I collagen production, as well as Runx2 upregulation. Induction of differentiation by diosmetin was associated with increased PKCdelta phosphorylation and the activations of Rac1 and p38 and ERK1/2 kinases. Blocking PKCdelta by siRNA inhibition significantly decreased osteoblastic differentiation by inhibiting Rac1 activation and subsequently attenuating the phosphorylation of p38 and ERK1/2. In addition, blocking p38 and ERK1/2 by siRNA transfection also suppressed diosmetin-induced cell differentiation. /This shows/ that diosmetin induced osteoblastic differentiation through the PKCdelta-Rac1-MEK3/6-p38 and PKCdelta-Rac1-MEK1/2- ERK1/2-Runx2 pathways and that it is a promising agent for treating osteoporosis.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/ALTERNATIVE and IN VITRO TESTS/ The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6alpha-hydroxy-paclitaxel as a probe reaction. Diosmetin and hesperetin inhibited 6alpha-hydroxy-paclitaxel production in a concentration-dependent manner, diosmetin being about 16-fold more potent than hesperetin (mean IC50) values 4.25 +/- 0.02 and 68.5 +/- 3.3 uM for diosmetin and hesperetin, respectively). Due to the low inhibitory potency of hesperetin, we characterized the mechanism of diosmetin-induced inhibition only. This flavonoid proved to be a reversible, dead-end, full inhibitor of CYP2C8, its mean inhibition constant (Ki) being 3.13 +/- 0.11 uM. Kinetic analysis showed that diosmetin caused mixed-type inhibition, since it significantly decreased the Vmax (maximum velocity) and increased the Km value (substrate concentration yielding 50% of Vmax) of the reaction. The results of kinetic analyses were consistent with those of molecular docking simulation, which showed that the putative binding site of diosmetin coincided with the CYP2C8 substrate binding site. The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with co-administered drugs metabolized by this CYP.|/ALTERNATIVE and IN VITRO TESTS/ The survival of osteoblasts is one of the determinants of the development of osteoporosis. This study /investigates/ the osteoblastic differentiation induced by diosmetin, a flavonoid derivative, in osteoblastic cell lines MG-63, hFOB, and MC3T3-E1 and bone marrow stroma cell line M2-10B4. Osteoblastic differentiation was determined by assaying alkaline phosphatase (ALP) activity and mineralization degree and measuring various osteoblast-related markers using ELISA. Expression and phosphorylation of Runt-related transcription factor 2 (Runx2), protein kinase Cdelta (PKCdelta), extracellular signal-regulated kinase (ERK), p38, and c-jun-N-terminal kinase (JNK) was assessed by immunoblot. Rac1 activity was determined by immunoprecipitation, and Runx2 activity was assessed by EMSA. Genetic inhibition was performed by small hairpin RNA plasmids or small interfering RNA (siRNA) transfection. Diosmetin exhibited an effect on osteoblastic maturation and differentiation by means of ALP activity, osteocalcin, osteopontin, and type I collagen production, as well as Runx2 upregulation. Induction of differentiation by diosmetin was associated with increased PKCdelta phosphorylation and the activations of Rac1 and p38 and ERK1/2 kinases. Blocking PKCdelta by siRNA inhibition significantly decreased osteoblastic differentiation by inhibiting Rac1 activation and subsequently attenuating the phosphorylation of p38 and ERK1/2. In addition, blocking p38 and ERK1/2 by siRNA transfection also suppressed diosmetin-induced cell differentiation. /This shows/ that diosmetin induced osteoblastic differentiation through the PKCdelta-Rac1-MEK3/6-p38 and PKCdelta-Rac1-MEK1/2- ERK1/2-Runx2 pathways and that it is a promising agent for treating osteoporosis.|/ALTERNATIVE and IN VITRO TESTS/ Flavonoids constitute a large class of polyphenolic compounds with cancer preventative properties. /This study/ examined the ability of the natural flavone diosmetin to inhibit proliferation of breast adenocarcinoma MDA-MB 468 and normal breast MCF-10A cells and found that this compound is selective for the cancer cells with slight toxicity in the normal breast cells... Diosmetin caused G1 arrest at 10 uM in MDA-MB 468 cells after 48 hr treatment whereas this effect was not observed in MCF-10A cells. /Data/ suggest that diosmetin exerts cytostatic effects in MDA-MB 468 cells, due to CYP1A1 and CYP1B1 catalyzed conversion to the flavone luteolin.|/ALTERNATIVE and IN VITRO TESTS/ The aim of this study was to assess the effects of diosmetin and hesperetin, two flavonoids present in various medicinal products, on CYP2C8 activity of human liver microsomes using paclitaxel oxidation to 6alpha-hydroxy-paclitaxel as a probe reaction. Diosmetin and hesperetin inhibited 6alpha-hydroxy-paclitaxel production in a concentration-dependent manner, diosmetin being about 16-fold more potent than hesperetin (mean IC50) values 4.25 +/- 0.02 and 68.5 +/- 3.3 uM for diosmetin and hesperetin, respectively). Due to the low inhibitory potency of hesperetin, /investigators/ characterized the mechanism of diosmetin-induced inhibition only. This flavonoid proved to be a reversible, dead-end, full inhibitor of CYP2C8, its mean inhibition constant (Ki) being 3.13 +/- 0.11 uM. Kinetic analysis showed that diosmetin caused mixed-type inhibition, since it significantly decreased the maximum velocity/(Vmax)/and increased /the/ substrate concentration yielding 50% of Vmax (Km) of the reaction. The results of kinetic analyses were consistent with those of molecular docking simulation, which showed that the putative binding site of diosmetin coincided with the CYP2C8 substrate binding site. The demonstration that diosmetin inhibits CYP2C8 at concentrations similar to those observed after in vivo administration (in the low micromolar range) is of potential clinical relevance, since it may cause pharmacokinetic interactions with co-administered drugs metabolized by this CYP.|For more Human Toxicity Excerpts (Complete) data for Diosmetin (7 total), please visit the HSDB record page.

diosmetin

Diosmetin is available in food supplements containing citrus bioflavonoids

...Polyamide column chromatography and UV spectrometry were used in the analysis of the constituents of the flowers, leaves and rhizomes of some species of Centranthus. Results showed that rutin, robinin, quercetin (I) and kaempferol (II) were identified in the leaves of Centranthus ruber DC var. albiflorus Zola. Luteolin, I and II were found in C. angustifolius (Miller) DC. leaves, and diosmetin, I and II in C. calcitrapa (L.) Dufresne leaves. Valepotriates were present in the methylene chloride extracts of the rhizomes, leaves and flowers of all species.|Simultaneous determination of diosmin and diosmetin in human plasma by ion trap liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry: Application to a clinical pharmacokinetic study...|The isolation and identification of 3 new flavanol 7-glucuronides, luteolin 7-glucuronide (luteolin 7-O-glucuronide), apigenin 7-glucuronide and diosmetin 7-glucuronide, from the seeds of Alyssum minimum are described.|From the leaves and twigs of Leptadenia reticulata, hentriacontanol, alpha-amyrin, beta-amyrin, and stigmasterol were isolated and identified. Two flavones, diosmetin and luteolin, were also isolated and characterized by chemical and spectral methods.

Diosmetin and hesperetin are the aglycones of the flavonoid glycosides diosmin and hesperidin which occur naturally in citrus fruit. A GC/MS method for the simultaneous determination of diosmetin and hesperetin in human plasma and urine has been developed and validated. The method was linear in the 2-300 ng/mL concentration range for both diosmetin and hesperetin in plasma and urine (r > 0.999). The precision of the method was better than 6.01 and 7.16% for diosmetin and hesperetin, respectively, and the accuracy was 96.76-100.40% and 95.00-105.50% for diosmetin and hesperetin, respectively. The lower limit of quantitation was found to be 2 ng/mL for both analytes in plasma and urine. Recovery of diosmetin, hesperetin and internal standard naringenin was greater than 82.5%. The method has been applied for the determination of diosmetin and hesperetin in plasma and urine samples obtained from a healthy male subject following a single oral 1000 mg dose of the flavonoid glycoside diosmin. The presence of hesperetin in plasma and urine samples indicates the metabolic reduction of diosmetin to its flavanone analogue hesperetin through reduction of the 2,3 double bond of the C-ring by the enzymes of bacteria of the intestinal microflora.|Diosmetin (3',5,7-trihydroxy-4'-methoxyflavone) is the aglycone of the flavonoid glycoside diosmin (3',5,7-trihydroxy-4'-methoxyflavone-7-ramnoglucoside). Diosmin is hydrolyzed by enzymes of intestinal micro flora before absorption of its aglycone diosmetin. A specific, sensitive, precise, accurate and robust HPLC assay for the simultaneous determination of diosmin and diosmetin in human plasma was developed and validated. Plasma samples were incubated with beta-glucuronidase/sulphatase. The analytes were isolated by liquid-liquid extraction with tert-butyl methyl ether at pH 2, and separated on a C(18) reversed-phase column using a mixture of methanol/1% formic acid (58:42, v/v) at a flow rate of 0.5 mL/min. APCI in the positive ion mode and multiple reaction monitoring (MRM) method was employed. The selected transitions for diosmin, diosmetin and the internal standard (7-ethoxycoumarin) at /mass to charge ration/ (m/z) were: 609.0 /to/ 463.0, 301.2 /to/ 286.1 and 191, respectively. A good linearity was found in the range of 0.25-500 ng/ml (R(2)>0.992) for both compounds. The intra-batch assay precision (CV) for diosmin and diosmetin ranged from 1.5% to 11.2% and from 2.8% to 12.5%, respectively, and the inter-batch precision were from 5.2% to 11.5% and 8.5% to 9.8%, respectively. The accuracy was well within the acceptable range the accuracies (from -2.7% to 4.2% and -1.6% to 3.5% for diosmin and diosmetin, respectively). The mean recoveries of diosmin, diosmetin and the internal standard were 87.5%, 89.2% and 67.2%. Stability studies showed that diosmin and diosmetin were stable in different conditions. Finally, the method was successfully applied to the pharmacokinetic study of diosmin in healthy volunteers following a single oral administration (Daflon).|HPLC determination in biological fluids.

Polyketides [PK] -> Flavonoids [PK12] -> Flavones and Flavonols [PK1211]