Apigenin

Metabolismus

• Metabolite Description

Apigenin is a plant-derived flavonoid that has significant promise as a skin cancer chemopreventive agent. Apigenin inhibits the expression of involucrin (hINV), a marker of keratinocyte differentiation, is increased by differentiating agents via a protein kinase Cdelta (PKCdelta), Ras, MEKK1, MEK3 cascade that increases AP1 factor level and AP1 factor binding to DNA elements in the hINV promoter. Apigenin suppresses the 12-O-tetradeconylphorbol-13-acetate-dependent increase in AP1 factor expression and binding to the hINV promoter and the increase in hINV promoter activity. Apigenin also inhibits the increase in promoter activity observed following overexpression of PKCdelta, constitutively active Ras, or MEKK1. The suppression of PKCdelta activity is associated with reduced phosphorylation of PKCdelta-Y311. Activation of hINV promoter activity by the green tea polyphenol, (-)-epigellocathecin-3-gallate, is also inhibited by apigenin, suggesting that the two chemopreventive agents can produce opposing actions in keratinocytes. (PMID: 16982614). Apigenin, a flavone abundantly found in fruits and vegetables, exhibits antiproliferative, anti-inflammatory, and antimetastatic activities through poorly defined mechanisms. This flavonoid provides selective activity to promote caspase-dependent-apoptosis of leukemia cells and uncover an essential role of PKCdelta during the induction of apoptosis by apigenin. (PMID: 16844095). Apigenin markedly induces the expression of death receptor 5 (DR5) and synergistically acts with exogenous soluble recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis in malignant tumor cells. On the other hand, apigenin-mediated induction of DR5 expression is not observed in normal human peripheral blood mononuclear cells. Moreover, apigenin does not sensitize normal human peripheral blood mononuclear cells to TRAIL-induced apoptosis. (PMID: 16648565).

Apigenin

Synonyma

• 4',5,7-trihydroxyflavone
• 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one
• Chamomile
• Spigenin
• Versulin
• 4',5,7-Trihydroxyflavone
• Apigenol
• Apigenine
• Pelargidenon 1449
• 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4-benzopyrone
• 2-(p-Hydroxyphenyl)-5,7-dihydroxychromone
• 5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one [109]

Použití

• Used to dye wool [108]
• Heřmánkový čaj:
• Soothing qualities as a sedative
• Mild analgesic
• Sleep medication [109]

Vznik

• Apigenin is the 3'-hydroxylated metabolite of chrysin [109]

Metabolismus

• The main in vitro metabolite of apigenin
• In rat liver Aroclor 1254-induced microsomes
• 3'-hydroxylated compound, luteolin

Výskyt

• Apigenin is found in many fruits and vegetables

• Bacopa Monnieri
• celeriac
• celery
• grapefruit
• plant-derived beverages
• onions
• oranges
• tea
• wheat sprouts
• wine and beer from natural ingredients
• red wine

Chamomile tea

• Abundant in the flowers of chamomile plants
• 68% of total flavonoids [108]
• Chamomile aromatic oil extracted from the flowers or leaves of the daisy-like plants including
• German chamomile (Matricaria recutita)
• Roman or English chamomile (Chamaemelum nobile) [109]
• Extracts, oils and teas made from chamomile

Parsley

• Appears to be absorbable by humans after intake of parsley (Petroselinum crispum)
• 20 g parsley- urinary excretion of apigenin was significantly higher
• Half-life for apigenin was calculated to be on the order of 12 hr
• Individual variation in the bioavailability and excretion of apigenin [109]
• Oral bolus of 2 g blanched parsley ( 65.8 +- 15.5 umol apigenin) per kilogram body weight
• Maximum apigenin plasma concentration of 127 +- 81 nmol/L reached after 7.2 +- 1.3 hr
• Plasma apigenin concentration
• Rose after bolus ingestion
• Fell within 28 hr under the detection limit (2.3 nmol/L) [109]
• Average apigenin content in 24-hour urine was 144 +- 110 nmol/24 hr
• Detected in red blood cells
• Without showing dose-response characteristics [109]

Chrysanthemum morifolium

• Extract (CME) (200 mg/kg)
• Luteolin and apigenin
• Plasma concentrations of luteolin and apigenin peak
• At 1.1 and 3.9 hr after dosing [109]
• AUC for luteolin and apigenin
• 23.03 and 237.6 ug h/mL [109]
• Total recovery of the dose was 37.9% luteolin
• 6.6% in urine
• 31.3% in feces [109]
• Total recovery of the dose was 45.2% apigenin
• 16.6% in urine
• 28.6% in feces [109]
• Cumulative luteolin and apigenin excreted in the bile was 2.05% and 6.34%
• Apigenin may be absorbed more efficiently than luteolin
• Luteolin and apigenin have a slow elimination phase
• Possible accumulation of the two flavonoids in the body can be hypothesized [109]

Hypericum perforatum

Naturally occurring glycosides formed by the combination of apigenin with sugars include:

Apiin (apigenin 7-O-apioglucoside)

• parsley
• celery

Apigetrin (apigenin 7-glucoside)

• Found in dandelion coffee
• Teucrium gnaphalodes

Vitexin (apigenin 8-C-glucoside)

• Vitexin inhibits thyroid peroxidase thus contributing to goiter

• Passion flower
• Vitex agnus-castus (chaste tree or chasteberry)
• Phyllostachys nigra bamboo leaves
• Pearl millet (Pennisetum millet)
• Hawthorn

Isovitexin (apigenin 6-C-glucosid, homovitexin, saponaretin)

• passion flower
• Cannabis
• Açaí palm

Rhoifolin (apigenin 7-O-neohesperidoside)

• Boehmeria nivea
• China grass or ramie (leaf)
• Citrus limon
• Canton lemon (leaf)
• Citrus x aurantium,
• Bigarade or bitter orange (plant)
• Citrus x paradisi
• Grapefruit (leaf)
• Ononis campestris
• Cammock (shoot)
• Sabal serratula
• Serenoa - sabal fruit (plant)

Schaftoside (apigenin 6-C-glucoside 8-C-arabinoside)

Účinky apigeninu

• Induces autophagy in leukemia cells
• Interfers with the action of the chemotherapy drug vincristine [108]
• Potent inhibitor of CYP2C9
• Apigenin dimers can reverse the highest level of drug resistance found in cancer stem cells [108]
• Prevent renal damage caused by ciclosporin in rats
• Reduced expression of the cell death mediator bcl-2
• Ciclosporin enhances the expression of transforming growth factor-beta in the rat kidney
• Accelerated apoptosis [108]
• Acts as a monoamine transporter activator
• Ligand for central benzodiazepine receptors that competitively inhibited the binding of flunitrazepam [108]
• Anxiolytic
• Slight sedative [108]
• Second-order positive modulatory activity at GABAA receptors
• Effects on adenosine receptors
• Blocks NMDA receptors [108]
• Nanomolar affinity for the opioid receptors
• Non-selective antagonist of all three opioid receptors [108]
• May be toxic to red blood cells [108]
• May also stimulate adult neurogenesis
• Promoting neuronal differentiation [108]
• Crosses the blood-brain barrier
• Has not demonstrated toxicity at high doses
• Effectiveness against a wide range of cancer types, while not showing toxicity to normal cells [108]
• Inhibits the expression of involucrin (hINV)
• Marker of keratinocyte differentiation [108]
• Suppression of PKCdelta activity
• Reduced phosphorylation of PKCdelta-Y311 [108]
• Activation of hINV promoter activity by the green tea polyphenol, (-)-epigellocathecin-3-gallate
• Is also inhibited by apigenin
• Can produce opposing actions in keratinocytes [108]
• Antimetastatic activities
• Promote caspase-dependent-apoptosis of leukemia cells
• Induces the expression of death receptor 5 (DR5)
• Synergistically acts with exogenous soluble recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
• Induce apoptosis in malignant tumor cells
• Not observed in normal human peripheral blood mononuclear cells
• Does not sensitize normal human peripheral blood mononuclear cells to TRAIL-induced apoptosis [108]
• Api caused a concentration-dependent increase in cyclic guanosine monophosphate levels
• Maximum effect at a concentration of 1 uM
• Induced hyperpolarization
• Blocked by the small and large conductance K(Ca) inhibitors apamin and iberiotoxin
• Activates small and large conductance K(Ca)
• To a hyperpolarization
• Followed by a Ca(2+) influx
• Increase of [Ca(2+)](i)
• Increased NO production
• Antiangiogenic effects of Api via Akt dephosphorylation [109]
• Inhibits the production of proinflammatory cytokines
• IL-1beta, IL-8, and TNF in LPS-stimulated human monocytes and mouse macrophages
• Even when apigenin is administered after LPS stimulation [109]
• Inhibits the transcriptional activity of NF-kappaB in LPS-stimulated mouse macrophages
• Regulates NF-kappaB activity through
• Hypophosphorylation of Ser536 in the p65 subunit
• Inactivation of the IKK complex stimulated by LPS [109]
• Inhibits in vivo LPS-induced TNF and the mortality induced by lethal doses of LPS [109]
• Causes G0-G1 phase arrest, decrease in total Rb protein and its phosphorylation at Ser780 and Ser807/811 in dose- and time-dependent fashion. Apigenin treatment caused increased phosphorylation of ERK1/2 and JNK1/2 and this sustained activation resulted in decreased ELK-1 phosphorylation and c-FOS expression thereby inhibiting cell survival. Use of kinase inhibitors induced ERK1/2 phosphorylation, albeit at different levels, and did not contribute to cell cycle arrest in comparison to apigenin treatment. Despite activation of MAPK pathway, apigenin caused a significant decrease in cyclin D1 expression that occurred simultaneously with the loss of Rb phosphorylation and inhibition of cell cycle progression. The reduced expression of cyclin D1 protein correlated with decrease in expression and phosphorylation of p38 and PI3K-Akt, which are regulators of cyclin D1 protein. Interestingly, apigenin caused a marked reduction in cyclin D1, D2 and E and their regulatory partners CDK 2, 4 and 6, operative in G0-G1 phase of the cell cycle. This was accompanied by a loss of RNA polymerase II phosphorylation, suggesting the effectiveness of apigenin in inhibiting transcription of these proteins. This study provides an insight into the molecular mechanism of apigenin in modulating various tyrosine kinases and perturbs cell cycle progression, suggesting its future development and use as anticancer agent in humans. [109]

The aim of this study was to clarify the anti-inflammatory mechanism of apigenin. Apigenin inhibited the collagenase activity involved in rheumatoid arthritis (RA) and suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) production in a dose dependent manner in RAW 264.7 macrophage cells. Pretreatment with apigenin also attenuated LPS-induced cyclooxygenase-2 (COX-2) expression. In addition, apigenin profoundly reduced the tumor necrosis factor-alpha (TNF-alpha)-induced adhesion of monocytes to HUVEC monolayer. Apigenin significantly suppressed the TNF-alpha-stimulated upregulation of vascular cellular adhesion molecule-1 (VCAM-1)-, intracellular adhesion molecule-1 (ICAM-1)-, and E-selectin-mRNA to the basal levels. Taken together, these results suggest that apigenin has significant anti-inflammatory activity that involves blocking NO-mediated COX-2 expression and monocyte adherence ... Abstract: PubMedLee JH et al; Arch Pharm Res 30(10):1318-27 (2007)Van Dross RT et al; Mol Carcinog 46(4):303-14 (2007)The goal of this study was to determine whether the antiproliferative action of these flavonoids on prostate (DU-145) and breast (MDA-MB-231) cancer cells expressing only estrogen receptor (ER) beta is mediated by this ER subtype. It was found that both genistein and apigenin, although not 17beta-estradiol, exhibited antiproliferative effects and proapoptotic activities through caspase-3 activation in these two cell lines. In yeast transcription assays, both flavonoids displayed high specificity toward ERbeta transactivation, particularly at lower concentrations. However, in mammalian assay, apigenin was found to be more ERbeta-selective than genistein, which has equal potency in inducing transactivation through ERalpha and ERbeta. Small interfering RNA-mediated downregulation of ERbeta abrogated the antiproliferative effect of apigenin in both cancer cells but did not reverse that of genistein ... The anticancer action of apigenin is mediated, in part, by ERbeta. The differential use of ERalpha and ERbeta signaling for transaction between genistein and apigenin demonstrates the complexity of phytoestrogen action in the context of their anticancer properties.[Mak P et al; Neoplasia 8(11):896-904 (2006)] Full text: PMC1716010 Abstract: PubMedBalasubramanian S et al; J Biol Chem 281(47):36162-72 (2006)Vargo MA et al; Biochem Pharmacol 72(6):681-92 (2006)Van Dross RT et al; Mol Carcinog 44(2):83-91 (2005)Liu LZ et al; Mol Pharmacol 68(3):635-43 (2005)Fang J et al; FASEB J 19(3):342-53 (2005)Way TD et al; FEBS Lett 579(1):145-52 (2005)Apigenin ... has been shown to induce cell growth-inhibition and cell cycle arrest in many cancer cell lines. One important effect of apigenin is to increase the stability of the tumor suppressor p53 in normal cells. Therefore, apigenin is expected to play a large role in cancer prevention by modifying the effects of p53 protein ... The influence of apigenin on cell growth and the cell cycle in p53-mutant cell lines /was assessed/. Treatment with apigenin resulted in growth-inhibition and G2/M phase arrest in two p53-mutant cancer cell lines, HT-29 and MG63. These effects were associated with a marked increase in the protein expression of p21/WAF1 ... p21/WAF1 mRNA expression was also markedly increased by treatment with apigenin in a dose- and time-dependent manner. However ... p21/WAF1 promoter activity following treatment with apigenin /was not detected/. Similarly, promoter activity from pG13-Luc, a p53-responsive promoter plasmid, was not activated by treatment with apigenin with or without p53 protein expression. These results suggest that there is a p53-independent pathway for apigenin in p53-mutant cell lines, which induces p21/WAF1 expression and growth-inhibition. Apigenin may be a useful chemopreventive agent not only in wild-type p53 status, but also in cancer with mutant p53. Abstract: PubMedTakagaki N et al; Int J Oncol 26(1):185-9 (2005)Bandyopadhyay S et al; Biochem Pharmacol 72(2):184-97 (2006) [109]