Abstract
Although Cannabis sativa synthesizes a wide rangeof phytochemicals, much attention has been primarily given to twophytocannabinoids, Δ9-tetrahydocannabinol (THC) andcannabidiol (CBD), due to their distinctive activities in humans.These bioactivities can be further enhanced through the interactionof THC and CBD with other phytocannabinoids or non-phytocannabinoidchemicals, such as terpenes and flavonoids, a phenomenon that is termedthe entourage effect. Flavonoid metabolism in C. sativa and the entourage effect are currently understudied. This mini-reviewexamines recent advances in the biosynthesis and bioactivities ofcannflavins, which are prenylated (C5) and geranylated (C10) flavonesthat are relatively unique to C. sativa. We alsodiscuss the rapidly developing omics tools that enable discoveriesin flavonoid metabolism in C. sativa and manipulationof flavonoid production through biotechnology. These advances setthe stage for interrogating the health benefits of C. sativa flavonoids, deciphering the contribution of flavonoids to the entourageeffect, and developing drugs.
1. Introduction
Cannabis sativa L. belongs to the Cannabaceae family that contains the genera Cannabis and Humulus (Hop), as well as eight genera that were previouslyclassified as Celtidaceae.1 In the formal botanical nomenclature of C. sativa, this single species of the Cannabis genus containstwo subspecies, each with two varieties. These include C.sativa subsp. sativa var. sativa, C. sativa subsp. sativa var. spontanea, C. sativa subsp. indica var. indica, and C. sativa subsp. indica var. kafiristanica.1 Aside from the botanical classification, it has been proposedthat, instead of the commonly used designations of “cultivars”and “strains”, C. sativa should becategorized as chemovars according to the chemical profiles of phytocannabinoidsand terpenes in flowers.2
Among thechemicals produced in C. sativa, twophytocannabinoids, the psychoactive compound Δ9-tetrahydocannabinol(THC) and the medicinally important, but nonpsychoactive, compoundcannabidiol (CBD), have been intensively studied for their structures,biosynthesis, and biological activities. Additional phytocannabinoids,and other classes of plant chemicals, such as terpenes, flavonoids,and alkaloids, have also been identified in C. sativa.3 These other plant chemicals exert synergisticeffects to enhance the bioactivities of phytocannabinoids, known as“the entourage effect”.4 However,the underlying mechanisms of the entourage effect are not well understood.As such, studies on non-phytocannabinoid compounds, such as terpenesand flavonoids, are valuable for developing therapeutics in C. sativa.
More than 20 flavonoids have been identifiedin C. sativa, most of which are flavone (apigeninand luteolin) and flavonol(kaempferol and quercetin) aglycones and glycosides.5,6 Interestingly, three prenylated/geranylated flavones, cannflavinA, B, and C, were isolated in C. sativa (Figure 1A). It is worth notingthat, although cannflavins are often referred to as flavonoids uniqueto C. sativa, cannflavin A has also been identifiedin Mimulus bigelovii, a plant in the Phrymaceae family.7 Since biosynthesis of the coreflavonoid skeleton in plants and bioactivities of the common flavonesand flavonols have been widely studied and reported, this mini-reviewwill focus on the biosynthesis and bioactivities of the relativelyunique cannflavins as well as the applications of C. sativa flavonoids.
Figure 1.
Open in a new tab
2. Biosynthesisof Cannflavins in C. sativa
The phenylpropanoidand flavonoid biosynthetic pathways build thecore skeletons of flavonoids in C. sativa (Figure 1B).3,8 Genes encoding two enzymes in the phenylpropanoid biosynthetic pathway,phenylalanine ammonia-lyase (PAL) and p-coumaroyl:CoA ligase (4CL), were isolated in C. sativa var.Futura by searching expressed sequence tags (ESTs) using homologous PAL and 4CL sequences from other plants.9 Conversion of p-coumaroyl CoAto luteolin (a flavone) encompasses condensation with three moleculesof malonyl CoA to form naringenin chalcone by chalcone synthase (CHS),ring closure of naringenin chalcone to generate naringenin by chalconeisomerase (CHI), formation of apigenin from naringenin by flavonesynthase (FNS), and 3-hydroxylation of apigenin to derive luteolinby flavonoid 3′-hydroxylase (F3′H) (Figure 1B). Based on their chemicalstructures, cannflavin A and B could be derived from luteolin throughtransferring a methyl group to the 3′-O positionby a methyltransferase activity as well as a geranyl (C10) group (forcannflavin A) or a prenyl/dimethylallyl (C5) group (for cannflavinB) to the C6-position by a prenyltransferase activity (Figure 1B). Candidate methyltransferasesand prenyltransferases responsible for these reactions were identifiedfrom a draft C. sativa genome assembly based on sequencehomology to previously characterized enzymes and phylogenetic analysis.8 Upon functional characterization using purifiedrecombinant proteins, it was shown that a regiospecific O-methyltransferase (CsOMT21) methylates the 3′-O position of luteolin and forms chrysoeriol, and a prenyltransferase(CsPT3) adds a geranyl or a prenyl group to chrysoerioland produces cannflavin A and B.8 However,the function of CsOMT21 and CsPT3in cannflavin biosynthesis has not been demonstrated in a plant system.
To date, flavonoid identification in C. sativa has focused on plants that are grown under nonstressed conditions.While flavonoids are present in most tissues studied in C.sativa, including seedlings, leaves, flowers, and fruits,they are undetectable in roots and seeds.9−11 In additionto the tissue-specific distribution, flavonoid profiles were alsoshown to vary in bracts during plant development.11 As many flavonoids possess protective functions for plants,their production is responsive to environmental factors, which isalso observed in C. sativa. For example, cannflavinA accumulation is determined not only by the genetic background,but as a response to temperature, solar radiation, rainfall, and humidityin the environment.12 Moreover, higherelevation positively impacts the content of cannflavin A, B, and Cin cloned (i.e., genetically identical) C. sativa plants grown at different altitudes.13 With these observations taken into consideration, it is temptingto postulate that, aside from the flavonoids that have already beenisolated in C. sativa tissues, some yet unidentifiedflavonoids may only be produced under specific environmental conditions,such as biotic and abiotic stresses. It is also possible that certainflavonoids only accumulate in significant quantities in specific C. sativa chemovars, such as cannflavin C that was isolatedand identified from a high THC chemovar.6 As such, unraveling the identity of additional flavonoids, particularlythose unique to C. sativa, will facilitate a comprehensiveunderstanding of the biosynthesis and functions of flavonoids in thisimportant plant.
3. Bioactivities of Cannflavins
Besides the antioxidative effects that cannflavins share with manyother flavonoids, a relatively well-studied bioactivity for cannflavinsis their anti-inflammatory properties. An intriguing observation wasfirst reported in 1981, showing that compounds present in a phytocannabinoid-freeextract of C. sativa leaves could be involved inthe production or release of prostaglandin E2 (PGE2) in mice.14 Further work showed that cannflavins in ethanolicextracts of C. sativa leaves inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA; a proinflammatoryagent)-induced PGE2 production in cultured human rheumatoid synovialcells.15 Chemical structures of cannflavinA and B were subsequently solved using nuclear magnetic resonance(NMR) and demonstrated to be prenylated/geranylated flavones.16 More recently, it was shown in in vitro enzyme assays that cannflavin A and B exert anti-inflammatory activitiesby inhibiting the microsomal PGE2 synthase-1 and the 5-lipoxygenaseactivities, leading to reduced PGE2 and leukotriene production, respectively.17 Cannflavin A and B show promise as an anti-inflammatorytherapeutic agent because they were about 30 times more effectivethan aspirin in inhibiting PGE2 release when assayed in human rheumatoidcells.16 An additional advantage is thatcannflavin A only weakly inhibits cyclooxygenases (COXs) COX-1 andCOX-2, and therefore can circumvent the adverse side effects exhibitedby COX inhibitors (anti-inflammatory drugs), such as gastrointestinalerosion.17
The neuroprotective roleof cannflavin A was explored in neuronalPC12 cells.18 At 10 μM or lower concentrations,cannflavin A enhanced the viability of neuronal PC12 cells againstamyloid β (Aβ)-induced cytotoxicity by reducing Aβ1–42 aggregation and fibril formation.18 Anticancer activities were reported for a synthetic 8-prenylatedisomer of cannflavin B, isocannflavin B (FBL-03G; caflanone) (Figure 1A). IsocannflavinB suppressed the proliferation of estrogen-dependent T47-D human breastcancer cells through a G0/G1 cell cycle arrest.19 It also increased apoptosis in two pancreatic cancer celllines Panc-02 and Ptf1/p48-Cre (KPC).20 Treatment with isocannflavin B caused a delay in both local andmetastatic tumor progression and increased survival in mice with pancreaticcancer.20 These reports suggest the potentialof isocannflavin B as an anticancer drug, though translational studiesshould be undertaken to determine its activities in humans.
A combination of in vitro bioassays and in silico molecular docking analysis established antiparasiticactivities of cannflavins. Cannflavin A (IC50 = 4.5 μg/mL)and cannflavin B (IC50 = 5 μg/mL) exhibited moderateanti-leishmanial activities against a culture of Leishmaniadonovani promastigotes.6 The bioassayresults were corroborated by strong docking energy (−144.0kJ/mol) of cannflavin A to one of the protein targets in L.donovani, Leishmania pteridine reductase1.21 Besides L. donovani, cannflavin A also showed moderate inhibitory activity against theparasite Trypanosoma brucei brucei with an IC50 value of 1.9 μg/mL.7 Themechanistic basis for the antiparasitic effects of cannflavins remainsto be elucidated.
To date, only molecular docking/computationalanalysis has beenemployed to evaluate the antiviral activities of cannflavins. CannflavinA showed a relatively high binding affinity (−9.7 kcal/mol)and high reactivity (energy gap between highest occupied molecularorbital and lowest unoccupied molecular orbital = 0.114 kcal/mol)against HIV-1 protease, an enzyme that renders human immunodeficiencyviruses (HIV) infectious, as determined by the density functionaltheory (DFT) analysis.22 A molecular dockingstudy of multiple protein targets of Dengue virus revealed cannflavinA as a strong docking ligand (docking energy = −125.7 kJ/mol)for the Dengue virus envelope protein.23 Cannflavin A is also among the phytochemicals that are predictedto show efficient docking to the helicase (RNA site) (−131.7kJ/mol), helicase (ATP site) (−134.6 kJ/mol), methyltransferase(−126.9 kJ/mol), and RNA-dependent RNA polymerase (−120.3kJ/mol) of Zika virus.24 Although the computationalanalysis suggests cannflavins as potential antiviral drug leads, furtherempirical evidence is still needed to precisely determine their bioactivities.
To investigate the microbial metabolism of cannflavins, cannflavinA and B were fermented with Mucor ramannianus (ATCC9628) and Beauveria bassiana (ATCC 13144), whichresulted in 6″S,7″-dihydroxycannflavinA, 6″S,7″-dihydroxycannflavin A 7-sulfate,and 6″S,7″-dihydroxycannflavin A 4′-O-α-l-rhamnopyranoside from cannflavin A,and cannflavin B 7-O-β-d-4′″-O-methylglucopyranoside and cannflavin B 7-sulfate fromcannflavin B.25 However, these microbialtransformed metabolites do not possess the antimicrobial and antiparasiticactivities reported for cannflavin A and B.25
Whether and how the geranylation and prenylation at C6 ofcannflavinA and B and at C8 of cannflavin C and isocannflavin B (differentially)contribute to their anti-inflammatory, neuroprotective, anticancer,antiparasitic, and antiviral activities should be further investigated.Insights into the structure–function relationship of theseprenylated/geranylated flavones will inform the effective developmentof therapeutics. Furthermore, microbial degradation products of cannflavinsin humans need to be elucidated to better understand drug metabolismand biological functions of cannflavins in humans.
4. Biotechnology of C. sativa Flavonoids
Molecularand genetic studies in C. sativa havelagged behind many other plant species due to its historically prohibitedstatus. However, the advancements in omics methods and the availabilityof genome and transcriptome sequences in the public domain have largelyfacilitated molecular studies in C. sativa. A draftgenome of cultivated C. sativa was released in 2011,although it was not assembled to the chromosomal level.26 Recently, a high-quality (scaffold size = 83Mb; N50 = 513.57 kb) reference genomeof a wild C. sativa variety was obtained using PacBio,a single-molecule real-time sequencing technology, and Hi-C, a next-generationsequencing technology for chromosome conformation capture.27 With the assistance of transcriptome sequencing,38,828 protein-coding genes were delineated, over 98% of which werefunctionally annotated.27 In the past fewyears, there have also been increasing efforts in sequencing the transcriptomesof multiple chemovars and wild C. sativa. As of January2021, 59 C. sativa-related bioprojects (sets of experimentaldata) have been registered in the National Center for BiotechnologyInformation (NCBI) Sequence Read Archive (SRA) database, a repositoryof high-throughput sequencing data. Of these bioprojects, 37 containgenome or transcriptome sequences of plant materials. These bioprojectsaim to discover genes responsible for the biosynthesis of C. sativa phytochemicals, to elucidate the evolution andgenetic diversity of C. sativa accessions, or toexamine changes in transcriptomes when C. sativa plantsare exposed to abiotic stresses. These sequencing data collectivelyare invaluable for gene discovery, biological application, and geneticimprovement of C. sativa.
Indeed, the utilityof C. sativa genome sequenceshas already been demonstrated in cloning genes encoding the prenyltransferaseand methyltransferase enzymes for cannflavin biosynthesis.8 On the other hand, transcriptome data that arepublicly available or generated in individual research groups willbe useful for elucidating the flavonoid biosynthetic and regulatorygenes using gene coexpression analysis. In addition to transcriptomicanalysis, integrated analysis of transcriptome, metabolome, and proteomedata can be utilized to reveal genes responsible for the spatial andtemporal distribution of flavonoids in C. sativa regulatedby plant development and/or the environment. Because it is an integralpart of the complex metabolic network, understanding the control offlavonoid production will have implications in the accumulation ofphytocannabinoids and other non-phytocannabinoid chemicals in C. sativa. Moreover, understanding the control of stress-inducedflavonoids will facilitate the development of environmentally resilient C. sativa plants.
The bioactivities of cannflavinsand other flavonoids make thema desirable bioproduct that will require the biosynthesis of a largeamount of flavonoids for downstream applications. However, flavonoidsare present at low levels in C. sativa tissues grownunder normal conditions. Overexpressing the biosynthetic and regulatorygenes of flavonoids can potentially increase their accumulation in C. sativa, though it is currently challenging to transformand propagate C. sativa plants. To this end, cellsuspension and hairy root tissue cultures and heterologous expressionsystems have been developed for C. sativa, whichcan be utilized for the production of flavonoids and functional genomicsof flavonoid metabolism.28
5. Future Perspectives
Non-phytocannabinoid constituents of C. sativa are a rapidly growing area of research that holdsgreat promise.Future studies should further investigate how flavonoid metabolismin C. sativa responds to various biotic and abioticstresses, facilitating the discovery of regulatory factors, e.g.,transcription factors and miRNAs, to further enhance flavonoid accumulation.The isolation and characterization of cannflavin biosynthetic genespave the way for reconstructing the entire pathway in plant culturesor heterologous systems, e.g. bacteria and yeast, for manufacturingcannflavins. Additional considerations should be given to increasingthe overall carbon flux to the flavonoid pathway in C. sativa by overexpressing upstream biosynthetic genes in a plant systemor feeding of substrates in heterologous expression systems. Overall,scaling up cannflavin production is crucial for studying drug metabolismin preclinical drug development and clinical studies to elucidatethe clinically relevant bioactivities of C. sativa flavonoids and interrogate the entourage effect in C. sativa.
Acknowledgments
We thank Cody Bekkeringfor critical reading ofthe manuscript.
Biographies
Johanna L. Bautista is a Ph.D.student in the Plant Biology Programat the University of California, Davis, under the supervision of Prof.Dr. Li Tian. Her research interest is mainly the study of the metabolicregulation of phenolic compounds from medicinal plants. She receivedher bachelor’s degree from California State University, LosAngeles.
Dr. Shu Yu is currently a postdoctoral researcher withexpertisein biochemistry and plant breeding in Department of Plant Sciencesat University of California, Davis. She received Ph.D. in Horticultureand Agronomy from University of California, Davis in 2019. After Ph.D.,she continued her research studies with Dr. Li Tian. Her researchfocuses on carotenoid metabolism and provitamin A biofortificationin wheat.
Li Tian received her Ph.D. in Plant Biology at MichiganState Universityand obtained postdoctoral training in natural product biochemistryat the Samuel Roberts Noble Foundation. She joined the faculty atthe University of California, Davis in 2008. She is currently an AssociateProfessor in the Department of Plant Sciences and a member of theFood for Health Institute. Her research group is interested in understandinghow phytonutrients (e.g., phenolics) are made in plants using molecular,genetic, and biochemical tools. They also examine how accumulationof phytonutrients in plants is controlled by different factors undervarious environmental conditions. Their long-term goal is to applythe knowledge obtained from these investigations to improve the nutritionalvalue and agronomic performance of crop plants.
Author Contributions
# J.L.B. and S.Y.contributed equally.
The authors declare nocompeting financial interest.
References
- McPartland J. M.Cannabissystematics at the levels of family, genus, and species. Cannabis Cannabinoid Res.2018, 3, 203–212. 10.1089/can.2018.0039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hazekamp A.; Fischedick J. T.Cannabis- from cultivar to chemovar. Drug Test. Anal.2012, 4, 660–667. 10.1002/dta.407. [DOI] [PubMed] [Google Scholar]
- Pollastro F.; Minassi A.; Fresu L. G.Cannabisphenolics and their bioactivities. Curr. Med.Chem.2018, 25, 1160–1185. 10.2174/0929867324666170810164636. [DOI] [PubMed] [Google Scholar]
- Ben-Shabat S.; Fride E.; Sheskin T.; Tamiri T.; Rhee M. H.; Vogel Z.; Bisogno T.; De Petrocellis L.; Di Marzo V.; Mechoulam R.An entourage effect: inactive endogenousfatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoidactivity. Eur. J. Pharmacol.1998, 353, 23–31. 10.1016/S0014-2999(98)00392-6. [DOI] [PubMed] [Google Scholar]
- Flores-Sanchez I. J.; Verpoorte R.Secondarymetabolism in cannabis. Phytochem. Rev.2008, 7, 615–639. 10.1007/s11101-008-9094-4. [DOI] [Google Scholar]
- Radwan M. M.; Elsohly M. A.; Slade D.; Ahmed S. A.; Wilson L.; El-Alfy A. T.; Khan I. A.; Ross S. A.Non-cannabinoidconstituents from a high potency Cannabis sativa variety. Phytochemistry2008, 69, 2627–2633. 10.1016/j.phytochem.2008.07.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Salem M. M.; Capers J.; Rito S.; Werbovetz K. A.Antiparasiticactivity of C-geranyl flavonoids from Mimulus bigelovii. Phytother. Res.2011, 25, 1246–1249. 10.1002/ptr.3404. [DOI] [PubMed] [Google Scholar]
- Rea K. A.; Casaretto J. A.; Al-Abdul-Wahid M. S.; Sukumaran A.; Geddes-McAlister J.; Rothstein S. J.; Akhtar T. A.Biosynthesis ofcannflavins A and B from Cannabis sativa L. Phytochemistry2019, 164, 162–171. 10.1016/j.phytochem.2019.05.009. [DOI] [PubMed] [Google Scholar]
- Docimo T.; Consonni R.; Coraggio I.; Mattana M.Early phenylpropanoidbiosynthetic steps in Cannabis sativa: link betweengenes and metabolites. Int. J. Mol. Sci.2013, 14, 13626–13644. 10.3390/ijms140713626. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Frassinetti S.; Moccia E.; Caltavuturo L.; Gabriele M.; Longo V.; Bellani L.; Giorgi G.; Giorgetti L.Nutraceuticalpotential of hemp (Cannabis sativa L.) seeds andsprouts. Food Chem.2018, 262, 56–66. 10.1016/j.foodchem.2018.04.078. [DOI] [PubMed] [Google Scholar]
- Flores-Sanchez I. J.; Verpoorte R.PKS activitiesand biosynthesis of cannabinoids andflavonoids in Cannabis sativa L. plants. Plant Cell Physiol.2008, 49, 1767–1782. 10.1093/pcp/pcn150. [DOI] [PubMed] [Google Scholar]
- Calzolari D.; Magagnini G.; Lucini L.; Grassi G.; Appendino G. B.; Amaducci S.High added-value compounds from Cannabis threshingresidues. Ind. Crops Prod.2017, 108, 558–563. 10.1016/j.indcrop.2017.06.063. [DOI] [Google Scholar]
- Giupponi L.; Leoni V.; Pavlovic R.; Giorgi A.Influence of altitudeon phytochemical composition of hemp inflorescence: A metabolomicapproach. Molecules2020, 25, 1381. 10.3390/molecules25061381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fairbairn J. W.; Pickens J. T.Activity of cannabis in relationto its delta’-trans-tetrahydro-cannabinolcontent. Br. J. Pharmacol.1981, 72, 401–409. 10.1111/j.1476-5381.1981.tb10990.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barrett M. L.; Gordon D.; Evans F. J.Isolationfrom Cannabis sativa L. of cannflavin-a novel inhibitorof prostaglandin production. Biochem. Pharmacol.1985, 34, 2019–2024. 10.1016/0006-2952(85)90325-9. [DOI] [PubMed] [Google Scholar]
- Barrett M. L.; Scutt A. M.; Evans F. J.CannflavinA and B, prenylated flavonesfrom Cannabis sativa L. Experientia1986, 42, 452–453. 10.1007/BF02118655. [DOI] [PubMed] [Google Scholar]
- Werz O.; Seegers J.; Schaible A. M.; Weinigel C.; Barz D.; Koeberle A.; Allegrone G.; Pollastro F.; Zampieri L.; Grassi G.; Appendino G.Cannflavinsfrom hemp sprouts, a novel cannabinoid-free hemp food product, targetmicrosomal prostaglandin E2 synthase-1 and 5-lipoxygenase. PharmaNutrition2014, 2, 53–60. 10.1016/j.phanu.2014.05.001. [DOI] [Google Scholar]
- Eggers C.; Fujitani M.; Kato R.; Smid S.Novel cannabisflavonoid,cannflavin A displays both a hormetic and neuroprotective profileagainst amyloid β-mediated neurotoxicity in PC12 cells: Comparisonwith geranylated flavonoids, mimulone and diplacone. Biochem. Pharmacol.2019, 169, 113609. 10.1016/j.bcp.2019.08.011. [DOI] [PubMed] [Google Scholar]
- Brunelli E.; Pinton G.; Bellini P.; Minassi A.; Appendino G.; Moro L.Flavonoid-induced autophagy in hormone sensitive breast cancer cells. Fitoterapia2009, 80, 327–332. 10.1016/j.fitote.2009.04.002. [DOI] [PubMed] [Google Scholar]
- Moreau M.; Ibeh U.; Decosmo K.; Bih N.; Yasmin-Karim S.; Toyang N.; Lowe H.; Ngwa W.Flavonoidderivativeof cannabis demonstrates therapeutic potential in preclinical modelsof metastatic pancreatic cancer. Front. Oncol.2019, 9, 660. 10.3389/fonc.2019.00660. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ogungbe I. V.; Erwin W. R.; Setzer W. N.Antileishmanialphytochemical phenolics:molecular docking to potential protein targets. J. Mol. Graphics Modell.2014, 48, 105–117. 10.1016/j.jmgm.2013.12.010. [DOI] [PubMed] [Google Scholar]
- Akhtar A.; Hussain W.; Rasool N.Probing the pharmacologicalbindingproperties, and reactivity of selective phytochemicals as potentialHIV-1 protease inhibitors. Univ. Sci.2019, 24, 441–464. 10.11144/Javeriana.SC24-3.artf. [DOI] [Google Scholar]
- Powers C. N.; Setzer W. N.An in-silico investigation of phytochemicalsas antiviral agents against Dengue fever. Comb.Chem. High Throughput Screening2016, 19, 516–536. 10.2174/1386207319666160506123715. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Byler K. G.; Ogungbe I. V.; Setzer W. N.In-silicoscreening for anti-Zikavirus phytochemicals. J. Mol. Graphics Modell.2016, 69, 78–91. 10.1016/j.jmgm.2016.08.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ibrahim A. K.; Radwan M. M.; Ahmed S. A.; Slade D.; Ross S. A.; ElSohly M. A.; Khan I. A.Microbialmetabolism of cannflavinA and B isolated from Cannabis sativa. Phytochemistry2010, 71, 1014–1019. 10.1016/j.phytochem.2010.02.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- vanBakel H.; Stout J. M.; Cote A. G.; Tallon C. M.; Sharpe A. G.; Hughes T. R.; Page J. E.The draft genomeand transcriptome of Cannabis sativa. Genome Biol.2011, 12, R102. 10.1186/gb-2011-12-10-r102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gao S.; Wang B.; Xie S.; Xu X.; Zhang J.; Pei L.; Yu Y.; Yang W.; Zhang Y.A high-quality referencegenome of wild Cannabis sativa. Hortic. Res.2020, 7, 73. 10.1038/s41438-020-0295-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Andre C. M.; Hausman J.-F.; Guerriero G.Cannabissativa:The plant of the thousand and one molecules. Front. Plant Sci.2016, 7, 19. 10.3389/fpls.2016.00019. [DOI] [PMC free article] [PubMed] [Google Scholar]
