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Artemisia afra and luteolin

June 26, 2015 - 11:01 -- Pierre Lutgen

Luteolin (3′,4′,5′,7′-tetrahydroxyflavone) is a widespread flavonoid aglycon structurally related to quercetin. The ethnobotanical use of this flavone includes applications in the treatment of cough, diarrhea, dysentery, diabetes, cancer and malaria.

The effects of a range of common dietary flavonoids on the growth of Plasmodium falciparum has been studied by A M Lehane et al., (BMC Res Notes, 1-26, 2008). Among the following molecules: kaempferol, myricetin, quercetin,, isoquercitrin, acacetin, apigenin, baicalein, chrysin and luteolin, the latter was found to be the most active with IC50 values around 11 µM. Luteolin also was found to prevent the progression of parasite growth beyond the young trophozoite stage. The parasites are therefore unable to complete a full intra-erythrocytic cycle. A similar low IC50 had been found previously for luteolin extracted from S.parvifolia ( V Van Baren et al., Z Naturforschung C. 61, 2006, 180-192). The IC50 values of luteolin 7-O-β-glucopyranoside displayed against Plasmodium falciparum was 2.9 µg/ml (H Kirmizibekmez et al., Phytother Res 142-6, 2011, 142-6).

This strong antiplasmodial activity is eventually related to the inhibition of fatty acid biosynthesis by Plasmodium falciparum. These lipids are required for the detoxification by crystallization into hemozoin of heme resulting from hemoglobin digestion by the parasite. Apicomplexan parasites utilize a fatty acid synthesis pathway, independent of the human host and catalyzed by specific enzymes like FabG. These enzymes are a potential target of new antimalarials. Among 30 flavonoids studied (D Tazdemir et al., J Med Chem. 49, 2006, 3345-53) it was found that luteolin and quercetin had the lowest IC50 for the inhibition of these enzymes. In this same study these two flavonoids also showed in vitro activity in the submicromolar range against several strains of Plasmodium falciparum.

The antiplasmodial activity might also be related to the inhibition of alpha-glucosidase and amylase by luteolin (JS Kim et al., Biosc Biotechnol Biochem 64:11, 2458-2461, 2000). Among 40 flavonoides studied by these authors luteolin was the most potent. These enzymes convert carbohydrates into glucose required for the development and multiplication of parasites.

A recent paper from Portugal (RB Pereira et al., Molecules 18, 2013, 8858-8872) studied the synergisms and antagonisms of a series of flavonoids with glutathione (GSH) in the ability to trap free radicals. Some indeed showed antagonistic behavior. But luteolin, quercetin, catechin showed synergy. This is in line with a previous paper from Nigeria (T Sunmonu et al., Pakist J Nutrition, 11-7, 520-25, 2012) which also describes the antioxidant effect of the flavonoids in Artemisia afra which according to the authors fully justifies the traditional medicinal use of this plant in South Africa. A paper from Warsaw evaluates the antioxidant potential of flavonoids and finds that quercetin and luteolin are much stronger than apigenin (M Majewska et al., Acta Poloniae Pharmaceutica, 68, 611-15, 2011). This has been confirmed by the work of Yi et al., Chemistry Central Journal, 2013.

Luteolin is also a strong chelator of iron, it reduces the absorption of free iron from food, inhibiting the Fenton reaction which generates OH radicals (Ai-Hong-Yang et al., RSC Advances 48, 2014).

The flavonoid luteolin is found in all Artemisia species presenting an antimalarial activity. A. annua (Marco JA Sanz et al., Pharmazie 45-5, 1990, 382-383; B Sivanescu et al., Chem and Natur Compounds, 2010, 4, 468-71), A. absinthium (O Craciunescu et al., Chem Central J. 6-97, 2012), A. herba alba (K Seddik et al., J Med Plant Res. 4-13 2010 1273-80), A pontica, A.afra.

Salvia officinalis also contains luteolin. This plant has been known for its medicinal properties since ages (salvare, to heal, officinalis, medicinal). The University of Al Quds ( M Akkawi et al., Malaria J. 2012. 11-Suppl P3) has demonstrated that Salvia officinalis is a potential antimalarial drug. It inhibits the formation of β-hematin. Other medicinal herbs rich in luteolin are chamomile, rooibos, thyme. lemongrass. A study of 13 medicinal plants in Pakistan shows that luteolin is present in all of them, quercetin in 4, catechin in 3, kaempferol and rutin only in one ( AM Khan et al., Pak J Bot 44:4, 2012, 1241-45). An excellent comparison for polyphenols in A annua, A vulgaris and A absinthium is made by a study in Romania (B Sivanescu et al., Chem and Natur Compounds, 2010, 4, 468-71).

THE HIGHEST CONCENTRATION OF LUTEOLIN IN ALL MEDICINAL HERBS IS FOUND IN ARTEMISIA AFRA: 1.9 mg/g, (A Dube, Thesis, U Western Cape, 2006), 20 times more than in Artemisia annua. The author also found that luteolin present at high concentrations in the herb specimen studied stays stable after several processing operations. This to a large extent could explain the strong antiplasmodial, antiviral and anticancer properties of Artemisia afra. Hulls of peanuts also contain (1.3 mg/g), while it is absent in the kernels. (MM Win et al., Pak J Bot, 43-3, 2011, 1635-42). Some people mix Artemisia annua leaf powder with peanut butter for oral administration. It would eventually be beneficial to include some powder from the peanut hulls. Another abundant source of luteolin are the leaves of the oil palm tree (Elaeis guineensis) or Cichorium endivia.

The bioavaillabitly ot luteolin from plant extracts is high and may circulate in humans (MT Yasuda et al., J Agric Food Chem 2015 PMID 25843231). The metabolism of luteolin is much slower than for other flavonoids (S Labib PhD thesis, Würzburg 2006). It has anti-inflammatory properties at micromolar concentrations and reduces IL-6 production (S Jang et al., PNAS, 105-21, 2012, 7729-34) and IL-1 production (PL Moldovan, Mémoire, Université de Québec, Oct 2014). Luteolin inhibits gut inflammation ( Y Nishitani et al., Biofactors, 2013 Mar 5). Chamomille (Matriarca chamomilla) is a well known medicinal plant. Its anti-inflammatory properties are attributed to quercetin and luteolin ( H Ghavimi et al., Afr J Phar Pharmacol 6, 2012 508-511). Luteolin indeed lowers IL-6 production (S Jang et al. Proc Nat Acad Sc. 208, 125) and this reduces neuroinflammation and is responsible for broad antiulcer activities, especially gastric ulcer (OJ Ode et al., IOSR J Pharm. 2014, 4, 17-23). A similar inhibition effect for IL-6 and IL-8 was seen ( PM de Magalhaes et al., Food Chemistry, 28 Feb 2012) for Artemisia annua extract with low artemisinin content. Luteolin also has an excellent anti-oxidant properties (GB Sun et al., Toxicol Appl Pharmacol. 265, 2012, 229-40) by suppression of the NFкB pathway. When comparing the free radical scavenging activity of quercetin, rutin, luteolin and apigenin (K Horvathea, Neoplasma, 51-5, 2004, 395-9) it was found that luteolin and quercetin provided effective protection against oxidative attack. Apigenin had no protective effect and rutin was only marginal. The antioxidant potential of luteolin is twice stronger than that of Vitamin E.

Luteolin has some prophylactic activities against toxic substances causing renal lipidoperoxidation. Taking luteolin during 7 days before administering the toxic alleviates its toxicity, mainly by raising the glutathione level (S Sultana et al., Indian J Exp Biol. 47, 2009, 355-360). Artemisia afra has insecticidal properties. It is known as Wilde-als by the Afrikaans community.

Margaret Roberts (1990) lists many other interesting uses in her book, Indigenous Healing Plants that includes the use of Artemisia afra in natural insecticide sprays and as a moth repellent. When maize silks are infected by Fusarium graminearum the luteolin content in the plant rapidly increases (LM Reid et al., Can J Bot, Jan 7, 1992).

Luteolin also has a hepatoprotective effect, 4 times higher than quercetin an 11 times higher than rosmarinic acid (CF Lima et al., University of Porto, Portugal). The concentration of luteolin-7-glycoside is 10 times higher in the water extract of Salvia officinalis than in the methanol extract (CF Lima et al, Chemical Biological interactions, Preprint accepted 31 Jan 2007).

Numerous papers describe the inhibitory effect of luteolin on tumors and cancer. For example luteolin present in Pomegranate (Punica granatum) is active against human squameous liver and colon cancer cells (Lei wan et al., Int J Mol Sc, 2014, 15, 14949-966). It is not the purpose of the present document to review this important field of research. Just to mention the work (DM Harris et al., Metabolomics, March 2011) which shows that luteolin is stronger than quercetin or resveratrol in inhibiting fatty acid synthase, an enzyme which is particularly active in cancer cells. In this way luteolin contributes to control the glucose flux and entry. In a similar study on 27 flavonoids from Citrus plants against several tumor cell lines only 7 flavonoids were judged to be active and in the rank order of potency luteolin was the strongest (S Kawaii et al., Biosc Biotechnol Biochem. 1999, 63, 896-99). Topical application of luteolin causes significant reduction of skin tumor incidence and multiplicity in a mouse skin cancer model (Ueda et al., 2003). In cell culture studies, luteolin has been shown to be a potent inhibitor of cyclin-dependent kinases, to induce cell cycle arrest in human melanoma cells and apoptotic cell death in human myeloid leukemia cells (Huang et al., 1999; Ko et al., 2002). Luteolin also sensitizes cancer cell lines to TNFα-dependent apoptosis by inhibiting the NF-κB pathway (Shi et al., 2004). More recently it was confirmed that it is efficient against gastric cancer (Jun Lu et al., J of Translational Med. 2015, 13-42).

Luteolin has strong antinociceptive (analgesic) properties, sometimes more active than well-known analgesic drugs, such as acetyl salicylic acid, acetaminophen, dipyrone, indomethacin (LC Block et al., J Ethnopharmacol. May 1998, 35-39). Topical application of wormwood extract is relatively equal to morphine. ( M Shams, 2011 SHS Acta Horticulturae, IMAPS2010) The presence of luteolin may explain the antinociceptive properties in trials with mice and the antimalarial and antinociceptive effects noticed by Dr M Onimus during surgical interventions at Bangui (personal communication, available on request).

Several flavonoids like rutin, kaempferol, naringenin, quercetin reduce serum uric acid levels (J Huang et al., Food Chem Toxicol 2011, 49, 1943-7). Quercetin protects against renal uric acid disorder ( J Wang et al., Evid Based Complement Alternat Med, 2012 548430). Another study compared the inhibition of bovine xanthine oxidase of several natural compounds and found that luteolin had the strongest action. Contrary to previous reports curcumin had none (JM Pauff et al., J Nat Prod 2009, 72, 725-731). A Vietnamese study even found that luteolin was more potent than allopurinol i.e. had a 2 times lower IC50 (MTT Nguyen et al., Biol Pharm Bull 27, 2004, 1414-21). Several studies have shown that Artemisia plants have a strong inhibitory action on xanthine oxidase which is also a ROS producer. This is probably due to luteolin which binds strongly to xanthine oxidase (J Yan et al, Food Chemistry, 2013, 141, 3766-73). This eventually explains the strong antimalarial properties of Artemisia afra rich in luteolin.

Luteolin is a potent hypoglycemic agent and improves insulin sensitivity and attenuates diabetes associated cognitive decline (Y Liu et al., Brain Res Bull. Feb 13 2013) Luteolin has anti-estrogenic properties. Luteolin has an inhibitory effect against rotavirus infection which leads to severe diarrhea (K Knipping et al., Virol J. 9:137, Jul 2012). It has a bronchodilatory effect and is a traditional plant frequently used in steem inhalation ( J Mjigiza et al., J Ethnopharmacol 2013 Epub). It is also active against the hepatitis C virus by blocking the NS5A protein (R Katchatoorian et al., Virology, 2012, 433, 346-355).

Intestinal absorption of luteolin from aqueous plant extracts is up to 5 times greater than for the pure luteolin ( P Zhou et al., J Agric Food Chem. 9-56, 2008, 296-300). This was confirmed in another research work ( JT Mukinda et al., J Ethnopharmacol 130-3, 2010, 439-49). The same effect has been observed for Artemisia annua extract versus pure artemisinin. As substances like luteolin or artemisinin are sparingly soluble in water it is recommended for therapeutic purposes to use dried herb powder (totum) rather than infusion. Luteolin also increases the bioavailability of other molecules, for example rosmarinic acid (PL Falé et al., Food Funct 2013, 4:3, 426-431)

No toxic effect was noticed for high doses of luteolin administered to rodents ( JT Mukinda, Thesis, University of Western Cape)