Skip to main content
SpringerLink
Log in

Scopolamine: a journey from the field to clinics

  • Published:
Phytochemistry Reviews Aims and scope Submit manuscript

Abstract

Tropane alkaloids are present in many different plants of the Solanaceae family and widely known for their anticholinergic properties. Among them, most valued and increasingly demanded is scopolamine, also known under the name of hyoscine, which is used as pharmaceutical active substance in the treatment of postoperative nausea and vomiting, motion sickness and gastrointestinal, renal and biliary spasms for instance. It naturally occurs in various plant genera, e.g. Anisodus, Anthocercis, Atropa, Brugmansia, Datura, Duboisia, Hyoscyamus, Mandragora and Scopolia and the purified substance has a long history of use dating back to the nineteenth century. Until today, the supply in scopolamine is mainly covered by large scale field plant cultivation of hybrids between Duboisia myoporoides and Duboisia leichhardtii. Biotechnological approaches optimising the alkaloid biosynthesis, for example the use of callus cultures or genetically transformed hairy root cultures, are not competitive by now. The aim of this review is to give a comprehensive overview regarding the current knowledge on botanical origin, pharmacology, biosynthesis as well as agricultural and biotechnological production of scopolamine.

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

Access this article

Log in via an institution

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
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

ArgDC:

Arginine decarboxylase

CNS:

Central nervous system

Cyp80F:

Cytochrome P450 80F1

E. coli :

Escherichia coli

GST-tag:

Gluthation-S-transferase-tag

HIS-tag:

Polyhistidine-tag

H6H/h6h :

Hyoscyamine 6β-hydroxylase (enzyme/gene)

mAChR:

Muscarinic acetylcholine receptors

MPO:

N-methylputrescine oxidase

OrnDC:

Ornithine decarboxylase

PMT/pmt :

Putrescine N-methyltransferase (enzyme/gene)

S. cerevisiae :

Saccharomyces cerevisiae

SAM:

S-adenosylmethionine

TR-1/tr-1 :

Tropinone-reductase I (enzyme/gene)

TR-2/tr-2 :

Tropinone-reductase I (enzyme/gene)

References

  • Adamse P, van Egmond HP (2010) Tropane alkaloids in food. RIKILT—Institute of Food Safety. https://www.researchgate.net/publication/254834358. Cited 20 Apr 2016

  • Alaghemand A, Ghorbanpour M, Asli DE et al (2013) Influence of urea fertilization on tropane alkaloids content of Henbane (Hyoscyamus niger L.) under hydroponic culture conditions. Adv Environ Biol 7(2):301–307

    Google Scholar 

  • Al-Humaid AI (2004) Effects of compound fertilization on growth and alkaloids of Datura plants. J Plant Nutr 27(12):2203–2219

    Article  CAS  Google Scholar 

  • Apfel CC, Zhang K, George E et al (2010) Transdermal scopolamine for the prevention of postoperative nausea and vomiting: a systematic review and meta-analysis. Clin Ther 32(12):1987–2002

    Article  CAS  PubMed  Google Scholar 

  • Armstrong DW, Han SM, Han YI (1987) Separation of optical isomers of Scopolamine, Cocaine, Homatropine, and Atropine. Anal Biochem 167:261–264

    Article  CAS  PubMed  Google Scholar 

  • Barr RG (2006) Tiotropium for stable chronic obstructive pulmonary disease: a meta-analysis. Thorax 61(10):854–862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Belabbassi O, Khelifi-Slaoui M, Zaoui D et al (2016) Synergistic effects of polyploidization and elicitation on biomass and hyoscyamine content in hairy roots of Datura stramonium. Biotechnol Agron Soc Environ 20(3):408–416

    Google Scholar 

  • Berger M (2011) Kleines Lexikon der Nachtschattengewächse. Nachtschatten Verlag, Solothurn

    Google Scholar 

  • Beyer J, Drummer OH, Maurer HH (2009) Analysis of toxic alkaloids in body samples. Forensic Sci Int 185(1–3):1–9

    Article  CAS  PubMed  Google Scholar 

  • Bimmerle G (1993) “Truth” Drugs in Interrogation. Center for the study of intelligence. CIA historical review programme. https://www.cia.gov/library/center-for-the-study-of-intelligence/kent-csi/vol5no2/html/v05i2a09p_0001.htm. Cited 20 Apr 2016

  • Biondi S, Fornalé S, Oksman-Caldentey K et al (2000) Jasmonates induce over-accumulation of methylputrescine and conjugated polyamines in Hyoscyamus muticus L. root cultures. Plant Cell Rep 19(7):691–697

    Article  CAS  Google Scholar 

  • Bymaster FP, McKinzie DL, Felder CC et al (2003) Use of M1–M5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system. Neurochem Res 28(3/4):437–442

    Article  CAS  PubMed  Google Scholar 

  • Cao Y-D, He Y-C, Li H et al (2015) Efficient biosynthesis of rare natural product scopolamine using E. coli cells expressing a S14P/K97A mutant of hyoscyamine 6β-hydroxylase AaH6H. J Biotechnol 211:123–129

    Article  CAS  PubMed  Google Scholar 

  • Cardillo AB, Talou J, Giulietti AM (2008) Expression of Brugmansia candida Hyoscyamine 6β-hydroxylase gene in Saccharomyces cerevisiae and its potential use as biocatalyst. Microb Cell Fact 7(1):17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cardillo AB, Otálvaro AÁM, Busto VD et al (2010) Scopolamine, anisodamine and hyoscyamine production by Brugmansia candida hairy root cultures in bioreactors. Process Biochem 45(9):1577–1581

    Article  CAS  Google Scholar 

  • Carter AJ (2003) Myths and mandrakes. J Roy Soc Med 96:144–147

    Article  PubMed  PubMed Central  Google Scholar 

  • Carvalho EB, Curtis WR (1998) Characterization of fluid-flow resistance in root cultures with a convective flow tubular bioreactor. Biotechnol Bioeng 60(3):375–384

    Article  CAS  PubMed  Google Scholar 

  • Caulfield MP, Birdsall NJM (1998) International union of pharmacology. XVII. classification of muscarinic acetylcholine receptors. Pharmacol Rep 50(2):279–290

    CAS  Google Scholar 

  • Chand S, Basu P (1998) Embryogenesis and plant regeneration from callus cultures derived from unpollinated ovaries of Hyoscyamus muticus L. Plant Cell Rep 17(4):302–305

    Article  CAS  Google Scholar 

  • Choi O, Choo CH, Cho SC (1964) The studies on the residual accommodation of Koreans: II. The residual accommodation under 0.5% scopolamine and 1% cyclogyl cycloplegia. Yonsei Med J 5(1):62–64

    Article  CAS  PubMed  Google Scholar 

  • Christen P, Roberts MF, Phillipson JD et al (1989) High-yield production of tropane alkaloids by hairy-root cultures of a Datura candida hybrid. Plant Cell Rep 8:75–77

    Article  CAS  PubMed  Google Scholar 

  • Corallo CE, Whitfield A, Wu A (2009) Anticholinergic syndrome following an unintentional overdose of scopolamine. Ther Clin Risk Manag 5:719–723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cusido RM, Palazón J, Pinol T et al (1999) Datura metel: in vitro production of tropane alkaloids. Planta Med 65:144–148

    Article  CAS  PubMed  Google Scholar 

  • De Luca V, St Pierre B (2000) The cell and developmental biology of alkaloid biosynthesis. Trends Plant Sci 5(4):1360–1385

    Google Scholar 

  • Dehghan E, Häkkinen ST, Oksman-Caldentey K-M et al (2012) Production of tropane alkaloids in diploid and tetraploid plants and in vitro hairy root cultures of Egyptian henbane (Hyoscyamus muticus L.). Plant Cell, Tissue and Organ Culture (PCTOC) 110(1):35–44

  • Dobo P, Fodor G, Janzsó G et al (1959) The Stereochemistry of the Tropane Alkaloids. Part XII. The Total Synthesis of Scopolamine. J Chem Soc:3461–3465

  • Dräger B (2006) Tropinone reductases, enzymes at the branch point of tropane alkaloid metabolism. Phytochemistry 67(4):327–337

    Article  PubMed  CAS  Google Scholar 

  • Dupraz J-M, Christen P, Kapetanidis I (1994) Tropane alkaloids in transformed roots of Datura quercolia. Planta Med 60:158–162

    Article  CAS  PubMed  Google Scholar 

  • EFSA (2013) Scientific opinion on tropane alkaloids in food and feed. EFSA Journal http://www.efsa.europa.eu/de/efsajournal/pub/3386. Cited 16 Febr 2016

  • Endo T, Yasuyuku Y (1985) Alkaloid production in cultured roots of three species of Duboisia. Phytochemistry 24(6):1233–1236

    Article  CAS  Google Scholar 

  • El Imam YMA, Evan WC (1984) Tropane alkaloids of species of Anthocercis Cyphanthera and Crenidium. Planta Med 50(1):86–87

    Article  PubMed  Google Scholar 

  • Evans WC, Ramsey KPA (1981) Tropane alkaloids from Anthocercis and Anthotroche. Phytochemistry 20:497–499

    Article  CAS  Google Scholar 

  • Evans WC, Ramsey KPA (1983) Alkaloids of the Solanaceae tribe Anthocecideae. Phytochemistry 22(10):2219–2225

    Article  CAS  Google Scholar 

  • Evans WC, Wellendorf M (1959) The alkaloids of the roots of Datura. J Chem Soc:1406–1409

  • Evans WC, Ghani A, Woolley VA (1972) Alkaloids of Solandra species. Phytochemistry 11:470–472

    Article  CAS  Google Scholar 

  • Ferrie AMR (2009) Current Status of Doubled Haploids in Medicinal Plants. In: Touraev A, Forster BP, Jain SM (eds) Advances in haploid production in higher plants. Springer Verlag, Berlin Heidelberg

    Google Scholar 

  • Finkel R, Cubeddu LX, Clark MA (eds) (2009) Lippincott’s Illustrated Reviews: Pharmacology, 4th edn. Lippincott Williams & Wilkins, Florida

    Google Scholar 

  • Fodor G, Kovács Ö (1953) The Stereochemistry of the Tropane Alkaloids. Part III. The Configuration of Scopolamine and of Valeroidine. J Chem Soc:2341-2344

  • Foley P (2006) Duboisia myoporoides: the medical career of a native Australian plant. Hist Rec Aust Sci 17:31–69

    Article  Google Scholar 

  • Gadamer J, Hammer F (1921) Beiträge zur Kenntnis des Scopolins. Arch Pharm 259(1–4):110–135

    Article  CAS  Google Scholar 

  • Geis G (1959) In Scopolamine Veritas. J Crim L & Criminology 50(4):347–357

    Google Scholar 

  • Gerarde J (1597) The Herball or Generall Historie of Plantes. Virtuelle Fachbibliothek Biologie. www.BioLib.de. Cited 18 Apr 2016

  • Godara R, Katoch M, Katoch R et al (2014) In Vitro Acaricidal Activity of Atropa belladonna and Its Components, Scopolamine and Atropine, against Rhipicephalus (Boophilus) microplus. Sci World J 2014:1–6

    Article  Google Scholar 

  • Griffin WJ, Lin GD (2000) Chemotaxonomy and geographical distribution of tropane alkaloids. Phytochemistry 53:623–637

    Article  CAS  PubMed  Google Scholar 

  • Grynkiewicz G, Gadzikowska M (2008) Tropane alkaloids as medicinally useful natural products and their synthetic derivatives as new drugs. Pharmacol Rep 60:439–463

    CAS  PubMed  Google Scholar 

  • Gyermek L (1997) Pharmacology of Antimuscarinic Agents. In: Kane H, Didier D, Boyd D, Luong K (eds) Handbooks in Pharmacology and Toxicology. CRC Press, Boca Raton

    Google Scholar 

  • Hall RCW, Popkin MK, Mchenry LE (1977) Angel’s Trumpet Psychosis: a Central Nervous System Anticholinergic Syndrom. Am J Psychiat 143(3):312–314

    Google Scholar 

  • Hashimoto T, Yamada Y (1994) Alkaloid biogenesis: molecular aspects. Annu Rev Plant Physiol Plant Mol Biol 45:257–285

    Article  CAS  Google Scholar 

  • Hashimoto T, Yukimune Y, Yamada Y (1989) Putrescine and putrescine N-methyltransferase in the biosynthesis of tropane alkaloids in cultured roots of Hyoscyamus albus. Planta 178:123–130

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto T, Hayashi A, Amano Y et al (1991) Hyoscyamine 6β-hydroxylase, an enzyme involved in tropane alkaloid biosynthesis, is lokalized at the pericycle of the root. J Biol Chem 266(7):4648–4653

    CAS  PubMed  Google Scholar 

  • Hashimoto T, Nakajima K, Ongena G et al (1992) Two Tropinone Reductases with Distinct Stereospecificities from Cultured Roots of Hyoscyamus niger. Plant Physiol 100(2):836–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hashimoto T, Matsuda J, Yamada Y (1993a) Two-step epoxidation of hyoscyamine to scopolamine is catalyzed by bifunctional hyoscyamine 6β-hydroxylase. FEBS Lett 329(1/2):35–39

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto T, Yun D-J, Yamada Y (1993b) Production of tropane alkaloids in genetically engineered root cultures. Phytochemistry 32(3):713–718

    Article  CAS  Google Scholar 

  • Heim WG, Sykes KA, Hildreth SB et al (2007) Cloning and characterization of a Nicotiana tabacum methylputrescine oxidase transcript. Phytochemistry 68(4):454–463

    Article  CAS  PubMed  Google Scholar 

  • Hibi N, Fujita T, Hatano M et al (1992) Putrescine N-Methyltransferase in cultured roots of Hyoscyamus albus. Plant Physiol 100:826–835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hills KL, Bottomley W, Mortimer PI (1953) Occurrence of Nicotine together with Hyoscine in Duboisia myoporoides R. Br. Nature 171(4349):435

    Article  CAS  PubMed  Google Scholar 

  • Humphrey AD, O’Hagan D (2001) Tropane alkaloid biosynthesis. A century old problem unresolved. Nat Prod Rep 18(5):494–502

    Article  CAS  PubMed  Google Scholar 

  • Ikenaga T, Hama K, Takemoto S et al (1985) Seasonal Variations of Tropane Alkaloids Content in Duboisia. Jpn J Trop Agr 29(4):229–230

    CAS  Google Scholar 

  • Jackson BP, Berry MI (1979) Mandragora—taxonomy and chemistry of the European species. In: Hawkes JG, Lester RN, Skelding AD (eds) The biology and taxonomy of the Solanaceae. Press, London, Acad, pp 505–512

    Google Scholar 

  • Jaffe RJ, Novakovic V, Peselow ED (2013) Scopolamine as an Antidepressant. Clin Neuropharmacol 36(1):24–26

    Article  CAS  PubMed  Google Scholar 

  • Jaremicz Z, Luczkiewicz M, Kokotkiewicz A et al (2014) Production of tropane alkaloids in Hyoscyamus niger (black henbane) hairy roots grown in bubble-column and spray bioreactors. Biotechnol Lett 36(4):843–853

    Article  CAS  PubMed  Google Scholar 

  • Jaziri M, Legros M, Homes J et al (1988) Tropine alkaloids production by hairy root cultures of Datura stramonium and Hyoscyamus niger. Phytochemistry 27(2):419–420

    Article  CAS  Google Scholar 

  • Jouhikainen K, Lindgren L, Jokelainen T et al (1999) Enhancement of scopolamine production in Hyoscyamus muticus L. hairy root cultures by genetic engineering. Planta 208:545–551

    Article  CAS  Google Scholar 

  • Kai G, Chen J, Li L et al (2007) Molecular Cloning and Characterization of a New cDNA Encoding Hyoscyamine 6β-hydroxylase from Roots of Anisodus acutangulus. J Biochem Mol Biol 40(5):715–722

    CAS  PubMed  Google Scholar 

  • Kai G, Liu Y, Wang X et al (2011a) Functional identification of hyoscyamine 6β-hydroxylase from Anisodus acutangulus and overproduction of scopolamine in genetically-engineered Escherichia coli. Biotechnol Lett 33(7):1361–1365

    Article  CAS  PubMed  Google Scholar 

  • Kai G, Yang S, Luo X et al (2011b) Co-expression of AaPMT and AaTRI effectively enhances the yields of tropane alkaloids in Anisodus acutangulus hairy roots. BMC Biotechnol 11(1):43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kai G, Zhang A, Guo Y et al (2012) Enhancing the production of tropane alkaloids in transgenic Anisodus acutangulus hairy root cultures by over-expressing tropinone reductase I and hyoscyamine-6β-hydroxylase. Mol BioSyst 8(11):2883

    Article  CAS  PubMed  Google Scholar 

  • Kamada H, Okamura N, Satake M et al (1986) Alkaloid production by hairy root cultures in Atropa belladonna. Plant Cell Rep 5:239–242

    Article  CAS  PubMed  Google Scholar 

  • Kholodenko BN, Cascante M, Hoek JB et al (1998) Metabolic design: how to engineer a living cell to desired metabolite concentrations and fluxes. Biotechnol Bioeng 59(2):239–247

    Article  CAS  PubMed  Google Scholar 

  • Kim Y, Kim J, Kim OJ et al (2014) Intoxication by angel’s trumpet: case report and literature review. BMC Res Notes 7

  • Kintz P, Villain M, Barguil Y et al (2006) Testing for atropine and scopolamine in hair by LC-MS-MS after Datura inoxia abuse. J Anal Toxicol 30(7):454–457

    Article  CAS  PubMed  Google Scholar 

  • Knab T (1977) Notes Concerning Use of Solandra among the Huichol. Econ Bot 31:80–86

    Article  Google Scholar 

  • Koleva II, van Beek TA, Soffers AEMF et al (2012) Alkaloids in the human food chain - Natural occurrence and possible adverse effects. Mol Nutr Food Res 56(1):30–52

    Article  CAS  PubMed  Google Scholar 

  • Lavania UC, Srivastava S (1991) Enhanced productivity of tropane alkaloids and fertility in artificial autotetraploids of Hyoscyamus niger L. Euphytica 52(2):73–77

    CAS  Google Scholar 

  • Lee O-S, Kang Y-M, Jung H-Y et al (2005) Enhanced production of tropane alkaloids in Scopolia parviflora by introducing the PMT (putrescine N-methyltransferase) gene. Vitro Cell Dev-Pl 41(2):167–172

    Article  CAS  Google Scholar 

  • Leete E, Marion L, Spenser ID (1954) Biogenesis of Hyoscyamine. Nature 174(4431):650–651

    Article  CAS  PubMed  Google Scholar 

  • Levin DA (1983) Polyploidy and Novelty in Flowering Plants. Am Nat 122(1):1–25

    Article  Google Scholar 

  • Li R, Reed DW, Liu E, Nowak J, Pelcher LE, Page JE, Covello PS (2006) Functional genomic analysis of alkaloid biosynthesis in Hyoscyamus niger reveals a cytochrome P450 involved in littorine rearrangement. Chem Biol 13(5):513–520

    Article  CAS  PubMed  Google Scholar 

  • Luanratana O, Griffin WJ (1980a) Cultivation of a Duboisia hybrid. Part A. Nutritional requirements and effects of growth regulators on alkaloid content. J Nat Prod 43(5):546–551

    Article  CAS  Google Scholar 

  • Luanratana O, Griffin WJ (1980b) Cultivation of a Duboisia hybrid. Part B. Alkaloid variation in a commercial plantation: effects of seasonal change, soil fertility, and cytokinins. J Nat Prod 43(5):552–558

    Article  CAS  Google Scholar 

  • Luanratana O, Noymuang W, Buasang W et al (1990) Seasonal variation of alkaloids in Thai grown Duboisia myoporoides and Duboisia hybrid. Planta Med 56:640

    Article  Google Scholar 

  • Maldonado-Mendoza IE, Ayora-Talavera TR, Loyola-Vargas VM (1993) Establishment of hairy root cultures of Datura stramonium. Plant Cell Tiss Org 33:321–329

    Article  CAS  Google Scholar 

  • Mangathayaru K (2013) Pharmacognosy: An Indian perspective. Pearson Education India, New Delhi

    Google Scholar 

  • Mano Y, Nabeshima S, Matsui C et al (1986) Production of Tropane Alkaloids by Hairy Root Cultures of Scopolia japonica. Agr Biol Chem Tokyo 50(11):2715–2722

    CAS  Google Scholar 

  • Mano Y, Ohkawa H, Yamada Y (1989) Production of tropane alkaloids by hairy root cultures of Duboisia leichhardtii transformed by Agrobacterium rhizogenes. Plant Sci 59:191–201

    Article  CAS  Google Scholar 

  • Mato A, Limeres J, Tomás I et al (2010) Management of drooling in disabled patients with scopolamine patches. Brit J Clin Pharmaco 69(6):684–688

    Article  Google Scholar 

  • Matsuda J, Okabe S, Hashimoto T et al (1991) Molecular cloning of hyoscyamine 6β-hydroxylase, a 2-oxoglutarate-dependent dioxygenase, from cultured roots of Hyoscyamus niger. J Biol Chem 266(15):9460–9464

    CAS  PubMed  Google Scholar 

  • Meinwald J (1953) The Stereochemistry of Scopolamine. J Chem Soc 1953:712–713

    Google Scholar 

  • Min J, Jung H, Kang S et al (2007) Production of tropane alkaloids by small-scale bubble column bioreactor cultures of Scopolia parviflora adventitious roots. Bioresource Technol 98(9):1748–1753

    Article  CAS  Google Scholar 

  • Moyano E, Fornalé S, Palazón J et al (2002) Alkaloid production in Duboisia hybrid hairy root cultures overexpressing the pmt gene. Phytochemistry 59:697–702

    Article  CAS  PubMed  Google Scholar 

  • Moyano E, Jouhikainen K, Tammela P et al (2003) Effect of pmt gene overexpression on tropane alkaloid production in transformed root cultures of Datura metel and Hyoscyamus muticus. J Exp Bot 54(381):203 ± 211

  • Moyano E, Palazón J, Bonfill M et al (2007) Biotransformation of hyoscyamine into scopolamine in transgenic tobacco cell cultures. J Plant Physiol 164(4):521–524

    Article  CAS  PubMed  Google Scholar 

  • Munoz O, Casale JF (2003) Tropane Alkaloids from Latua pubiflora. Z Naturforsch 58c:626-628

  • Nachum Z, Shupak A, Gordon CR (2006) Transdermal Scopolamine for Prevention of Motion Sickness. Clin Pharmacokinet 45(6):543–566

    Article  CAS  PubMed  Google Scholar 

  • Nakajima K, Hashimoto T (1999) Two tropinone reductases, that catalyze opposite stereospecific reductions in tropane alkaloid biosynthesis, are lokalized in plant root with different cell-specific patterns. Plant Cell Physiol 40(11):1099–1107

    Article  CAS  PubMed  Google Scholar 

  • Nejadhabibvash F, Rahmani F, Heidari R et al (2012) Study of inheritance and environment on tropane alkaloids within Hyoscyamus species. Austr J Crop Sci 6(10):1428–1434

    CAS  Google Scholar 

  • Nisar A, Malik AH, Zargar MA (2013) Atropa acuminata Royle Ex Lindl. blunts production of pro-inflammatory mediators eicosanoids, leukotrienes, cytokines in vitro and in vivo models of acute inflammatory responses. J Ethnopharmacol 147(3):584–594

    Article  CAS  PubMed  Google Scholar 

  • Nocquet P-A (2016) Opatz T (2016) Total Synthesis of (±)-Scopolamine: challenges of the Tropane Ring. Eur J Org Chem 6:1156–1164

    Article  CAS  Google Scholar 

  • Oksman-Caldentey K-M (2007) Tropane and Nicotine Alkaloid Biosynthesis-Novel Approaches Towards Biotechnological Production of Plant-Derived Pharmaceuticals. Curr Pharm Biotechnol 8:203–210

    Article  CAS  PubMed  Google Scholar 

  • Olmstead RG, Bohs L, Migid HA et al (2008) A molecular phylogeny of the Solanaceae. Taxon 57(4):1159

    Google Scholar 

  • OSAC (2014) Colombia 2014 Crime and Safety Report: Bogota. Product of the research and information support center. https://www.osac.gov/pages/ContentReportDetails.aspx?cid=15445. Cited 18 Apr 2016

  • Osbaldeston TA (ed) (2000) De Materia Medica (by) Pedanius Dioscorides. Ibidis, Johannesburg

    Google Scholar 

  • Palazón J, Moyano E, Cusidó RM et al (2003) Alkaloid production in Duboisia hybrid hairy roots and plants overexpressing the h6h gene. Plant Sci 165(6):1289–1295

    Article  CAS  Google Scholar 

  • Palazón J, Navarro-Ocaña A, Hernandez-Vazquez L et al (2008) Application of metabolic engineering to the production of scopolamine. Molecules 13(8):1722–1742

    Article  PubMed  CAS  Google Scholar 

  • Parr AJ (1989) The production of secondary metabolites by plant cell cultures. J Biotechnol 10:1–26

    Article  CAS  Google Scholar 

  • Payne J, Hamill JD, Robins RJ et al (1987) Production of hyoscyamine by ‘hairy root’ cultures of Datura stramonium. Planta Med 53(5):474–478

    Article  CAS  PubMed  Google Scholar 

  • Perez LM, Farriols C, Puente V et al (2010) The use of subcutaneous scopolamine as a palliative treatment in Parkinson’s disease. Palliat Med 25(1):92–93

    Article  PubMed  Google Scholar 

  • Perger ARV (1864) Deutsche Pflanzensagen. Schaber Verlag, Stuttgart

    Google Scholar 

  • Phillipson JD, Handa SS (1976) Hyoscyamine N-Oxide in Atropa belldonna. Phytochemistry 15:605–608

    Article  CAS  Google Scholar 

  • Pietsch J, Koch I, Hermanns-Clausen M et al (2009) Pediatric plant exposures in Germany, 1998–2004. Clin Toxicol 46(7):686–691

    Article  Google Scholar 

  • Pitta-Alavarez SI, Giulietti AM (1995) Advantages and limitations in the use of hairy root cultures for the production of tropane alkaloids: use of Anti-Auxins in the maintenance of normal root morphology. In Vitro Cell Dev Bio 31:215–220

    Article  Google Scholar 

  • Pitta-Alvarez SI, Giulietti AM (1999) Influence of chitosan, acetic acid and citric acid on growth and tropane alkaloid production in transformed roots of Brugmansia candida. Effect of medium pH and growth phase. Plant Cell Tiss Org 59:31–38

    Article  CAS  Google Scholar 

  • Pitta-Alvarez SI, Spollansky TC, Giulietti AM (2000) The influence of different biotic and abiotic elicitors on the production and profile of tropane alkaloids in hairy root cultures of Brugmansia candida. Enzyme Microb Tech 26:252–258

    Article  CAS  Google Scholar 

  • Plowman T, Gyllenhaal LO, Lindgren JE (1971) Latua pubiflora magic plant from Southern Chile. Bot Mus Leafl Harv Univ 23(2):61–92

    CAS  Google Scholar 

  • Rahman L, Kitamura Y, Yamaguchi J et al (2006) Exogenous plant H6H but not bacterial HCHL gene is expressed in Duboisia leichhardtii hairy roots and affects tropane alkaloid production. Enzyme Microb Technol 39(6):1183–1189

    Article  CAS  Google Scholar 

  • Rätsch C (2012) Enzyklopädie der psychoaktiven Pflanzen: Botanik. AT Verlag, Aurau, Ethnopharmakologie und Anwendung

    Google Scholar 

  • Renner UD, Oertel R, Kirch W (2005) Pharmacokinetics and pharmacodynamics in clinical use of scopolamine. Ther Drug Monit 27(5):655–665

    Article  CAS  PubMed  Google Scholar 

  • Richter U, Rothe G, Fabian A-K et al (2005) Overexpression of tropinone reductases alters alkaloid composition in Atropa belladonna root cultures. J Exp Bot 56(412):645–652

    Article  CAS  PubMed  Google Scholar 

  • Ripperger H (1995) (S)-scopolamine and (S)-norscopolamine from Atropanthe sinensis. Planta Med 61(3):292–293

    PubMed  Google Scholar 

  • Robins RJ, Parr AJ, Walton NJ (1991) Studies on the biosynthesis of tropane alkaloids in Datura stramonium L. transformed root cultures. Planta 183:196–201

    Article  CAS  PubMed  Google Scholar 

  • Robins RJ, Bachmann P, Woolley JG (1994) Biosynthesis of hyoscyamine involves an intramolecular rearrangement of littorine. J Chem Soc Perkin Trans 1:615–619

    Article  Google Scholar 

  • Robins RJ, Chesters NCJE, O’Hagan D, Parr AJ, Walton NJ, Woolley JG (1995) The biosynthesis of hyoscyamine—the process by which littorine rearranges to hyoscyamine. J Chem Soc Perkin Trans 1:481–485

    Article  Google Scholar 

  • Robinson R (1917) A synthesis of tropinone. J Chem Soc 111:762–768

    Article  CAS  Google Scholar 

  • Romek KM, Remaud GS, Silvestre V et al (2016) Non-statistical13C fractionation distinguishes co-incident and divergent steps in the biosynthesis of the alkaloids nicotine and tropine. J Biol Chem 291(32):16620–16629

    Article  CAS  PubMed  Google Scholar 

  • Rosenblum EI (1954) Alkaloid variation in wild and cultivated Duboisia leichhardtii F. Muell. Appl Sci 5:51–62

    CAS  Google Scholar 

  • Ryan SM, DeBoer KD, Hamill JD (2015) Alkaloid production and capacity for methyljasmonate induction by hairy roots of two species in Tribe Anthocercideae, family Solanaceae. Funct Plant Biol 42(8):792

    Article  CAS  Google Scholar 

  • Samoryadov BA, Minina SA (1971) Isolation of hyoscyamine and scopolamine from the epigeal part of Scopolia tangutica. Chem Nat Compd 7(2):205–206

    Article  Google Scholar 

  • Sato F, Hashimoto T, Hachiya A et al (2001) Metabolic engineering of plant alkaloid biosynthesis. Proc Natl Acad Sci USA 98(1):367–372

    Article  CAS  PubMed  Google Scholar 

  • Sauerwein M, Shimomura K (1991) Alkaloid production in hairy roots of Hyoscyamus albus transformed with Agrobacterium rhizogenes. Phytochemistry 30(10):3277–3280

    Article  CAS  Google Scholar 

  • Schmidt E (1892) Mitteilungen aus dem pharmaceutisch-chemischen Institut der Universität Marburg. 40. Ueber Scopolamin (Hyoscin). Arch Pharm 230(1–4):207–231

    Article  Google Scholar 

  • Schmidt E, Henschke H (1888) Über die Alkaloide der Wurzel von Scopolia japonica. Arch Pharm 226(5):185–203

    Article  Google Scholar 

  • Sevón N, Oksman-Caldentey K-M (2002) Agrobacterium rhizogenes-mediated transformation: root cultures as a source of alkaloids. Planta Med 68(10):859–868

    Article  PubMed  Google Scholar 

  • Sevón N, Hiltunen R, Oksman-Caldentey K-M (1998) Somaclonal variation in transformed roots and protoplast-derived hairy root clones of Hyoscyamus muticus. Planta Med 64:37–41

    Article  PubMed  Google Scholar 

  • Shepard GH (2009) Psychoactive Botanicals in Ritual, Religion and Shamanism. In: Elisabetsky E, Etkin NL (eds) Ethnopharmacology—Vol. II. EOLSS Publications, Paris, France

  • Smolenski SJ, Crane FA, Voigt RF (1967) Effects of the ratio of calcium to potassium in the nutrient medium on the growth and alkaloid production of Atropa belladonna. J Pharm Sci 56(5):599–602

    Article  CAS  PubMed  Google Scholar 

  • Soni P, Siddiqui AA, Dwivedi J et al (2012) Pharmacological properties of Datura stramonium L. as a potential medicinal tree: an overview. Asian Pac. J Trop Biomed 2(12):1002–1008

    Article  CAS  Google Scholar 

  • Staba J, Jindra A (1968) Datura tissue cultures: production of minor alkaloids from Chlorophyllous and Nonchlorophyllous Strains. J Pharm Sci 57(4):701–704

    Article  CAS  PubMed  Google Scholar 

  • Staskin DR, Zoltan E (2007) Anticholinergics and central nervous system effects: are we confused? Rev Urol 9(4):191–196

    PubMed  PubMed Central  Google Scholar 

  • Stohs SJ (1969) Production of scopolamine and hyoscyamine by Datura stramonium L Suspension Cultures. J Pharm Sci 58(6):703–705

    Article  CAS  PubMed  Google Scholar 

  • Strang CE, Renna JM, Amthor FR et al (2010) Muscarinic acetylcholine receptor localization and activation effects on Ganglion response properties. Invest Ophthalmol Vis Sci 51(5):2778–2789

    Article  PubMed  PubMed Central  Google Scholar 

  • Subroto MA, Kwok KH, Hamill JD et al (1996) Coculture of genetically transformed roots and shoots for synthesis, translocation, and biotransformation of secondary metabolites. Biotechnol Bioeng 49(5):481–494

    Article  CAS  PubMed  Google Scholar 

  • Suzuki K, Yamada Y, Hashimoto T (1999) Expression of Atropa belladonna Putrescine N-Methyltransferase gene in root pericycle. Plant Cell Physiol 40(3):289–297

    Article  CAS  PubMed  Google Scholar 

  • Tabata M, Yamamoto H, Hiraoka N et al (1972) Organization and alkaloid production in tissue cultures of Scopolia parviflora. Phytochemistry 11:949–955

    Article  CAS  Google Scholar 

  • Takeuchi I, Suzuki T, Kishi T et al (2015) Effect of Scopolamine Butylbromide on Clozapine-induced Hypersalivation in Schizophrenic Patients: a Case Series. Clin Psychopharmacol Neurosci 13(1):109–112

    Article  PubMed  PubMed Central  Google Scholar 

  • Thearle J, Pearn J (1982) The history of hyoscine. Hist Sci Med 17(2):257–261

    PubMed  Google Scholar 

  • Tytgat GN (2007) Hyoscine Butylbromide. A Review of its Use in the Treatment of Abdominal Cramping and Pain. Drugs 67(9):1343–1357

    Article  CAS  PubMed  Google Scholar 

  • Tytgat GN (2008) Hyoscine butylbromide—a review on its parenteral use in acute abdominal spasm and as an aid in abdominal diagnostic and therapeutic procedures. Curr Med Res Opin 24(11):3159–3173

    Article  CAS  PubMed  Google Scholar 

  • Ungricht S, Knapp S, Press JR (1998) A revision of the genus Mandragora (Solanaceae). Bull Nat Hist Mus Bot Ser 28(1):17–40

    Google Scholar 

  • Volpicelli LA, Levey AI (2004) Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus. Prog Brain Res 145:59–66

    Article  CAS  PubMed  Google Scholar 

  • Walton NJ, Robins RJ, Peerless ACJ (1990) Enzymes of N-methylputrescine biosynthesis in relation to hyoscyamine formation in transformed root cultures of Datura stramonium and Atropa belladonna. Planta 182:136–141

    Article  CAS  PubMed  Google Scholar 

  • West FR Jr, Mika ES (1957) Synthesis of Atropine by Isolated Roots and Root-Callus Cultures of Belladonna. Bot Gaz 119(1):50–54

    Article  CAS  Google Scholar 

  • White FF, Nester EW (1980) Hairy root: plasmid encodes virulence traits in Agrobacterium rhizogenes. J Bacteriol 141(3):1134–1141

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wildiers H, Dhaenekint C, Demeulenaere P et al (2009) Atropine, Hyoscine Butylbromide, or Scopolamine Are Equally Effective for the Treatment of Death Rattle in Terminal Care. J Pain Symptom Manag 38(1):124–133

    Article  CAS  Google Scholar 

  • Williams C (2013) Medicinal Plants in Australia. Rosenberg Publishing, Dural, An Antipodean Apothecary

    Google Scholar 

  • Willstätter R (1901) Umwandlung von Tropidin in Tropin. Ber Deut Chem Ges 34(2):3163–3165

    Article  Google Scholar 

  • Willstätter R, Berner E (1923) Hydrolyse des Scopolamins. Ber Deut Chem Ges 56:1079–1082

    Article  Google Scholar 

  • Wink M (1987) Physiology of the Accumulation of Secondary Metabolites with Special Reference to Alkaloids. In: Constabel F, Vasil I (eds) Cell culture and somatic cell genetics of plants. Academic Press, San Diego, pp 17–41

    Google Scholar 

  • Witkin JM, Overshiner C, Li X et al (2014) M1 and M2 Muscarinic Receptor Subtypes Regulate Antidepressant-Like Effects of the Rapidly Acting Antidepressant Scopolamine. J Pharmacol ExpTherap 351(2):448–456

    Article  CAS  Google Scholar 

  • Yukimune Y, Hara Y, Yamada Y (1994) Tropane Alkaloid Production in Root Cultures of Duboisia myoporoides Obtained by Repeated Selection. Biosci Biotech Biochem 58(8):1443–1446

    Article  CAS  Google Scholar 

  • Yun D-J, Hashimoto T, Yamada Y (1992) Metabolic engineering of medicinal plants: transgenic Atropa belladonna with an improved alkaloid composition. Appl Biol Sci 89:11799–11803

    CAS  Google Scholar 

  • Zabetakis I, Edwards R, O’Hagan D (1999) Elicitation of tropane alkaloid biosynthesis in transformed root cultures of Datura stramonium. Phytochemistry 50(1):53–56

    Article  CAS  Google Scholar 

  • Zárate R, el Jaber-Vazdekis N, Medina B et al (2006) Tailoring Tropane Alkaloid Accumulation in Transgenic Hairy Roots of Atropa baetica by Over-expressing the Gene Encoding Hyoscyamine 6β-hydroxylase. Biotechnol Lett 28(16):1271–1277

    Article  PubMed  CAS  Google Scholar 

  • Zenkteler M (1971) In vitro production of haploid plants from pollen grains of Atropa belladonna L. Experientia 27:1087

    Article  Google Scholar 

  • Zhang L, Ding R, Chai Y et al (2004) Engineering tropane biosynthetic pathway in Hyoscyamus niger hairy root cultures. Proc Natl Acad Sci USA 101(17):6786–6791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Kai G-Y, Lu B-B, Zhang H-M, Tang K-X, Jiang J-H, Chen WS (2005) Metabolic Engineering of Tropane Alkaloid Biosynthesis in Plants. J Integr Plant Biol 47(2):136–143

    Article  CAS  Google Scholar 

  • Zhang L, Yang B, Lu B et al (2007) Tropane alkaloids production in transgenic Hyoscyamus niger hairy root cultures over-expressing Putrescine N-methyltransferase is methyl jasmonate-dependent. Planta 225(4):887–896

    Article  CAS  PubMed  Google Scholar 

  • Ziegler J, Facchini PJ (2008) Alkaloid biosynthesis: metabolism and trafficking. Annu Rev Plant Biol 59(1):735–769

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The research from the DISCO project leading to these results has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement 613513. This work is furthermore supported financially by Boehringer Ingelheim Pharma GmbH & Co. KG.. The authors are grateful to Andreas Rothauer for literature supply and proof reading of the manuscript.

Author information

Authors and Affiliations

  1. Boehringer Ingelheim Pharma GmbH und Co. KG, Binger Str. 173, 55216, Ingelheim am Rhein, Germany

    Sophie Friederike Ullrich & Hansjörg Hagels

  2. Department of Technical Biochemistry, Technical University of Dortmund, Emil-Figge-Str. 66, 44227, Dortmund, Germany

    Sophie Friederike Ullrich & Oliver Kayser

Authors
  1. Sophie Friederike Ullrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hansjörg Hagels
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oliver Kayser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oliver Kayser.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ullrich, S.F., Hagels, H. & Kayser, O. Scopolamine: a journey from the field to clinics. Phytochem Rev 16, 333–353 (2017). https://doi.org/10.1007/s11101-016-9477-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11101-016-9477-x

Keywords

Search

Navigation