Skip to main content
Log in

Artemisinin production in Artemisia annua: studies in planta and results of a novel delivery method for treating malaria and other neglected diseases

  • Published:
Phytochemistry Reviews Aims and scope Submit manuscript

Abstract

Artemisia annua L. produces the sesquiterpene lactone, artemisinin, a potent antimalarial drug that is also effective in treating other parasitic diseases, some viral infections and various neoplasms. Artemisinin is also an allelopathic herbicide that can inhibit the growth of other plants. Unfortunately, the compound is in short supply and thus, studies on its production in the plant are of interest as are low cost methods for drug delivery. Here we review our recent studies on artemisinin production in A. annua during development of the plant as it moves from the vegetative to reproductive stage (flower budding and full flower formation), in response to sugars, and in concert with the production of the ROS, hydrogen peroxide. We also provide new data from animal experiments that measured the potential of using the dried plant directly as a therapeutic. Together these results provide a synopsis of a more global view of regulation of artemisinin biosynthesis in A. annua than previously available. We further suggest an alternative low cost method of drug delivery to treat malaria and other neglected tropical diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Acton N, Klayman DL (1985) Artemisitene, a new sesquiterpene lactone endoperoxide from Artemisia annua. Planta Med 51:441–442

    Article  PubMed  CAS  Google Scholar 

  • Alin MH, Bjorkman A (1994) Concentration and time dependency of artemisinin efficacy against Plasmodium falciparum in vitro. Am J Trop Med Hyg 50:771–776

    PubMed  CAS  Google Scholar 

  • Alin MH, Ashton M, Kihamia CM, Mtey GJ, Bjorkman A (1996) Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients. Trans R Soc Trop Med Hyg 90:61–65

    Article  CAS  Google Scholar 

  • Arsenault PR, Wobbe KK, Weathers PJ (2008) Recent advances in artemisinin production through heterologous expression. Curr Medicin Chem 15:2886–2896

    Article  CAS  Google Scholar 

  • Arsenault PR, Vail D, Wobbe KK, Erickson K, Weathers PJ (2010a) Reproductive development modulates artemisinin related gene expression and metabolite levels in Artemisia annua. Submitted for publication

  • Arsenault PR, Vail D, Wobbe KK, Weathers PJ (2010b) Effect of sugars on artemisinin production in Artemisia annua L.: transcript and metabolite measurements. Submitted for publication

  • Ashton M, Hai TN, Sy ND, Huong DX, Huong NV, Nieu NT, Cong LD (1998) Artemisinin pharmacokinetics is time-dependent during repeated oral administration in healthy male adults. Drug Metab Dispos 26:25–27

    PubMed  CAS  Google Scholar 

  • Baraldi R, Isacchi B, Predieri S, Marconi G, Vincieri FF, Bili AR (2008) Distribution of artemisinin and bioactive flavonoids from Artemisia annua L. during plant growth. Biochem System Ecol 36:340–348

    Article  CAS  Google Scholar 

  • Bilia AR, Lazari D, Messori L, Taglioli V, Temperini C, Vincieri FF (2002) Simple and rapid physico-chemical methods to examine action of antimalarial drugs with hemin: its application to Artemisia annua constituents. Life Sci 70:769–778

    Article  PubMed  CAS  Google Scholar 

  • Bilia AR, de Malgalhães PM, Bergonzi MC, Vincieri FF (2006) Simultaneous analysis of artemisinin and flavonoids of several extracts of Artemisia annua L. obtained form a commercial sample and a selected cultivar. Phytomed 13:487–493

    Article  CAS  Google Scholar 

  • Bouwmeester HJ, Wallaart TE, Janssen MH, van Loo B, Jansen BJ, Posthumus MA, Schmidt CO, De Kraker JW, Konig WA, Franssen MC (1999) Amorpha-4, 11-diene synthase catalyses the first probable step in artemisinin biosynthesis. Phytochem 52:843–854

    Article  CAS  Google Scholar 

  • Brown GD, Sy LK (2007) In vivo transformations of artemisinic acid in Artemisia annua plants. Tetrahedron 63:9548–9566

    Article  CAS  Google Scholar 

  • Covello PS (2008) Making artemisinin. Phytochemistry 69:2881–2885

    Article  PubMed  CAS  Google Scholar 

  • Covello PS, Teoh KH, Polichuk DR, Reed DW (2007) Functional genomics and the biosynthesis of artemisinin. Phytochemistry 68:1864–1871

    Article  PubMed  CAS  Google Scholar 

  • De Ridder S, van der Kooy F, Verpoorte R (2008) Artemisia annua as a self-treatment for malaria in developing countries. J Ethnopharmacol 120:302–314

    Article  PubMed  Google Scholar 

  • de Vries PJ, Dien TK (1996) Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs 52:818–836

    Article  PubMed  Google Scholar 

  • Dien TK, de Vries PJ, Khanh NX, Koopmans R, Binh LN, Duc DD, Kager PA, van Boxtel CJ (1997) Effect of food intake on pharmacokinetics of oral artemisinin in healthy Vietnamese subjects. Antimicrob Agents Chemother 41:1069–1072

    PubMed  CAS  Google Scholar 

  • Duke SO, Vaughn KC, Croom EM, ElSohly HN (1987) Artemisinin, a constituent of annual wormwood (Artemisia annua) is a selective phytotoxin. Weed Sci 35:499–505

    CAS  Google Scholar 

  • Efferth T (2007) William Schwabe Award 2006: antiplasmodial and antitumor activity of artemisinin–from bench to bedside. Planta Med 73:299–309

    Article  PubMed  CAS  Google Scholar 

  • Fabricant DS, Farnsworth NR (2001) The value of plants used in traditional medicine for drug discovery. Environ Health Perspectives 109:69–75

    Article  CAS  Google Scholar 

  • Ferreira JFS, Janick J (1995) Floral morphology of Artemisia annua with special reference to trichomes. Int J Plant Sci 156:807–815

    Article  Google Scholar 

  • Ferreira JFS, Janick J (1996) Roots as an enhancing factor for the production of artemisinin in shoot cultures of Artemisia annua. Plant Cell Tiss Organ Cult 44:211–217

    Article  CAS  Google Scholar 

  • Ferreira JFS, Laughlin JC, Delabays N, de Magalhães PM (2005) Cultivation and genetics of Artemisia annua L. for increased production of the antimalarial artemisinin. Plant Genet Resour 3:206–229

    Article  CAS  Google Scholar 

  • Gilbert B, Alves LF (2003) Synergy in plant medicines. Curr Medicin Chem 10:13–20

    Article  CAS  Google Scholar 

  • Gollop R, Farhi S, Peri A (2001) Regulation of the leucoanthocyanidin dioxygenase gene expression in Vitis vinifera. Plant Sci 161:579–588

    Article  CAS  Google Scholar 

  • Gollop R, Even S, Colova-Solova V, Peri A (2002) Expression of the grape dihydroflavanol reductase gene and analysis of its promoter region. J Exp Bot 53:1397–1409

    Article  PubMed  CAS  Google Scholar 

  • Graham IA, Denby KJ, Leaver CJ (1994) Carbon catabolite repression regulates glyoxylate cycle gene expression in cucumber. Plant Cell 6:761–772

    Article  PubMed  CAS  Google Scholar 

  • Grove N, Bowles D, Craft JC, Brewer T (2007) Innovative new approaches to reduce economic access barriers to artemisinin-based combination therapy. Eur J Trop Med Internatl Health 12(Supplement 1):68

    Google Scholar 

  • Haynes RK (2006) From artemisinin to new artemisinin antimalarials: biosynthesis, extraction, old and new derivatives, stereochemistry and medicinal chemistry requirements. Curr Top Med Chem 6:509–537

    Article  PubMed  CAS  Google Scholar 

  • Kharasch N, Thyagarajan BS (1983) Structural basis for biological activities of dimethyl sulfoxide. Annal NY Acad Sci 411:391–402

    Article  CAS  Google Scholar 

  • Koobkokkraud T, Chochai A, Kerdmanee C, De-eknamkul W (2007) TLC-densitometric analysis of artemisinin for the rapid screening of high-producing plantlets of Artemisia annua L. Phtochem Anal 18:229–234

    Article  Google Scholar 

  • Kumar S, Gupta SK, Singh P, Bajpai MM, Gupta D, Singh D, Gupta AK, Ram G, Shasany AK, Sharma S (2004) High yields of artemisinin by multi-harvest of Artemisia annua crops. Indust Crops Products 19:77–90

    Article  CAS  Google Scholar 

  • Li Q-G, Peggins JO, Fleckenstein LL, Masonic K, Heiffer MH, Brewer TG (1998) The pharmacokinetics and bioavailability of dihydroartemisinin, arteether, artemether, artesunic acid and artelinic acid in rats. J Pharm Pharmacol 50:173–182

    Article  PubMed  CAS  Google Scholar 

  • Liu KC-SC, Yang S-L, Roberts MF, Elford BC, Phillipson JD (1992) Antimalarial activity of Artemisia annua flavonoids from whole plants and cell cultures. Plant Cell Rep 11:637–640

    Article  CAS  Google Scholar 

  • Lommen WJ, Shenk E, Bouwmeester HJ, Verstappen FW (2006) Trichome dynamics and artemisinin accumulation during development and senescence of Artemisia annua leaves. Planta Med 72:336–345

    Article  PubMed  CAS  Google Scholar 

  • Mannan A, Liu C, Arsenault P, Towler M, Vail D, Lorence A, Weathers P (2009) DMSO stimulates production of artemisinin suggesting that the sesquiterpene may also function as a ROS sink in Artemisia annua. Plant Cell Rep. Accepted for publication

  • Mathers CD, Loncar D (2006) Projections of global mortality, burden of disease from 2002 to 2030. PLoS Med 3:e442

    Article  PubMed  Google Scholar 

  • Mishina Y, Krishna S, Haynes RK, Meade JC (2007) Artemisinins inhibit Trypanosome cruzi and Trypanosoma crucei rhodesiense in vitro growth. Antimicrob Agents Chemother 51:1852–1854

    Article  PubMed  CAS  Google Scholar 

  • Olsson ME, Olofsson LM, Lindahl A-L, Lundgren A, Brodelius M, Brodelius PE (2009) Localization of enzymes of artemisinin biosynthesis to the apical cells of glandular trichomes of Artemisia annua L. Phytochem 70:1123–1128

    Article  CAS  Google Scholar 

  • Picaud S, Olofsson L, Brodelius M, Brodelius PE (2005) Expression, purification, and characterization of recombinant amorpha-4, 11-diene synthase from Artemisia annua L. Arch Biochem Biophys 436:215–226

    Article  PubMed  CAS  Google Scholar 

  • Raskin I, Ribnicky DM, Komarnytsky S, Ilic N, Poulev A, Borisjuk N, Brinker A, Moreno DA, Ripoll C, Yakoby N, O’Neal JM, Cornwell T, Pastor I, Fridlender B (2002) Plants and human health in the twenty-first century. Trends Biotechnol 20:522–531

    Article  PubMed  CAS  Google Scholar 

  • Rath K, Taxis K, Walz G, Gleiter CH, Li SM, Heide L (2004) Pharmacokinetic study of artemisinin after oral intake of a traditional preparation of Artemisia annua L. (Annual Wormwood). Am J Trop Med Hyg 70:128–132

    PubMed  Google Scholar 

  • Rathore D, McCutchan TF, Sullivan M, Kumar S (2005) Antimalarial drugs: current status and new developments. Expert Opin Investig Drugs 14:871–883

    Article  PubMed  CAS  Google Scholar 

  • Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MC, Withers ST, Shiba Y, Sarpong R, Keasling JD (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440:940–943

    Article  PubMed  CAS  Google Scholar 

  • Rodeiro I, Donato MT, Jimenez N, Garrido G, Molina-Torres J, Menendez R, Castell JV, Gomez-Lechon MJ (2009) Inhibition of human P450 enzymes by natural extracts used in traditional medicine. Phytother Res 23:279–282

    Article  PubMed  CAS  Google Scholar 

  • Schramek N, Wang H, Romisch-Margl W, Keil B, Radykewicz T, Winzenhorlein B, Beerhues L, Bacher A, Rohdich F, Gershenzon J, Liu B, Eisenreich W (2010) Artemisinin biosynthesis in growing plants of Artemisia annua. A 13CO2 study. Phytochem 71:179–187

    Article  CAS  Google Scholar 

  • Sen R, Bandyopadhyay S, Dutta A, Mandal G, Ganguly S, Saha P, Chatterjee M (2007) Artemisinin triggers induction of cell-cycle arrest and apoptosis in Leishmania donovani promastigotes. J Med Microbiol 56:1213–1218

    Article  PubMed  CAS  Google Scholar 

  • Solfanelli C, Poggi A, Loreti E, Alpi A, Perata P (2006) Sucrose-specific induction of the anthocyanin biosynthetic pathway in Arabidopsis. Plant Physiol 140:634–646

    Article  Google Scholar 

  • Sy L-K, Brown GD (2002) The mechanism of the spontaneous autoxidation of dihydroartemisinic acid. Tetrahedron 58:897–908

    Article  CAS  Google Scholar 

  • Tellez MR, Canel C, Rimando AM, Duke SO (1999) Differential accumulation of isoprenoids in glanded and glandless Artemisia annua L. Photochem 52:1035–1040

    Article  CAS  Google Scholar 

  • Teoh KH, Polichuk DR, Reed DW, Nowak G, Covello PS (2006) Artemisia annua L. (Asteraceae) trichome-specific cDNAs reveal CYP71AV1, a cytochrome P450 with a key role in the biosynthesis of the antimalarial sesquiterpene lactone artemisinin. FEBS Lett 580:1411–1416

    Article  PubMed  CAS  Google Scholar 

  • Teoh KH, Polichuk DR, Reed DW, Covello PS (2009) Molecular cloning of an aldehyde dehydrogenase implicated in artemisinin biosynthesis in Artemisia annua. Botany 87:635–642

    Article  CAS  Google Scholar 

  • Titulaer HA, Zuidema J, Kager PA, Wetsteyn JC, Lugt CB, Merkus FW (1990) The pharmacokinetics of artemisinin after oral, intramuscular and rectal administration to volunteers. J Pharm Pharmacol 42:810–813

    Article  PubMed  CAS  Google Scholar 

  • Towler MJ, Weathers PJ (2007) Evidence of artemisinin production from IPP stemming from both the mevalonate and the nonmevalonate pathways. Plant Cell Rep 26:2129–2136

    Article  PubMed  CAS  Google Scholar 

  • Utzinger J, Xiao S, Keiser J, Chen M, Zheng J, Tanner M (2001) Current progress in the development and use of artemether for chemoprophylaxis of major human schistosome parasites. Curr Medicin Chem 8:1841–1860

    CAS  Google Scholar 

  • Vitrac X, Larronde F, Krisa S, Decendit A, Deffieux G, Merillon JM (2000) Sugar sensing and Ca2+-calmodulin requirement in Vitis vinifera cells producing anthocyanins. Phytochem 53:659–665

    Article  CAS  Google Scholar 

  • Wallaart TE, Van Uden W, Lubberink HGM, Woerdenbag HJ, Pras N, Quax WJ (1999) Isolation and identification of dihydroartemisinic acid from Artemisia annua and its possible role in the biosynthesis of artemisinin. J Nat Prod 62:430–433

    Article  PubMed  CAS  Google Scholar 

  • Wallaart TE, Pras N, Beekman AC, Quax WJ (2000) Seasonal variation of artemisinin and its biosynthetic precursors in plants of Artemisia annua of different geographical origin: proof for the existence of chemotypes. Planta Med 66:57–62

    Article  PubMed  CAS  Google Scholar 

  • Wallaart TE, Bouwmeester HJ, Hille J, Popping L, Maijers NC (2001) Amorpha-4, 11-diene synthase: cloning and functional expression of a key enzyme in the biosynthetic pathway of the novel antimalarial drug artemisinin. Planta 212:460–465

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Weathers PJ (2007) Sugars proportionately affect artemisinin production. Plant Cell Rep 26:1073–1081

    Article  PubMed  Google Scholar 

  • Wang H, Ge L, Ye HC, Chong K, Liu BY, Li GF (2004) Studies of the effects of fpf1 gene on Artemisia annua flowering time and on the linkage between flowering and artemisinin biosynthesis. Planta Med 70:347–352

    Article  PubMed  CAS  Google Scholar 

  • Weathers PJ, Wyslouzil BE, Wobbe KK, Kim YJ, Yigit E (1999) The biological response of hairy roots to O2 levels in bioreactors. In Vitro Cell Dev Biol Plant 35:286–289

    Article  CAS  Google Scholar 

  • WHO (2005) Meeting on the production of artemisinin and artemisinin-based combination therapies. June 6–7, Arusha, United Republic of Tanzania

  • WHO (2006) http://www.who.int/medicines/publications/traditional/ArtemisiaMonograph.pdf

  • Widmer V, Handloser D, Reich E (2007) Quantitative HPTLC analysis of artemisinin in dried Artemisia annua L.: a practical approach. J Liq Chromatog Relat Technol 30:2209–2219

    Article  CAS  Google Scholar 

  • Willcox M (2009) Artemisia species: from traditional medicines to modern antimalarials–and back again. J Alternat Complement Med 15:101–109

    Article  Google Scholar 

  • Willcox M, Falquet J, Ferreira JFS, Gilbert B, Hsu E, Melillo de Magalhães P, Plaizier-Vercammen J, Sharma VP, Wright CW (2007) Artemisia annua as a herbal tea for malaria. Afr J Trad Complement Alternat Med 4:121–123

    Google Scholar 

  • Woerdenbag HJ, Luers J, van Uden W, Pras N, Malingre T, Alfermann A (1993) Production of the new antimalarial drug artemisinin in shoot cultures of Artemisia annua L. Plant Cell Tiss Organ Cult 32:247–257

    Article  CAS  Google Scholar 

  • Zhang Y, Teoh KH, Reed DW, Maes L, Goossens A, Olson DJH, Ross ARS, Covello PS (2008) The molecular cloning of artemisinic aldehyde ∆11(13) reductase and its role in glandular trichome-dependent biosynthesis of artemisinin in Artemisia annua. J Biol Chem 283:21501–21508

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Thanks to Professor Carole Cramer, Arkansas Bioscience Institute, for suggesting the mouse feeding experiments. Approval for animal studies was obtained from the Institutional Animal Care and Use Committee (IACUC) of Arkansas State University. Support was provided in part by NIH 2R15GM069562-02 and the Arkansas Biosciences Institute, the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pamela J. Weathers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weathers, P.J., Arsenault, P.R., Covello, P.S. et al. Artemisinin production in Artemisia annua: studies in planta and results of a novel delivery method for treating malaria and other neglected diseases. Phytochem Rev 10, 173–183 (2011). https://doi.org/10.1007/s11101-010-9166-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11101-010-9166-0

Keywords

Navigation