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The Inheritance of Chemical Phenotype in Cannabis Sativa L

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The Inheritance of Chemical Phenotype in Cannabis Sativa L Euphytica (2009) 165:293–311 DOI 10.1007/s10681-008-9787-1 The inheritance of chemical phenotype in Cannabis sativa L. (III): variation in cannabichromene proportion E. P. M. de Meijer · K. M. Hammond · M. Micheler Received: 21 April 2008 / Accepted: 7 August 2008 / Published online: 23 August 2008 Springer Science+Business Media B.V. 2008 Abstract The mechanism that controls the propor- Keywords Cannabichromene · Cannabis · tion of cannabichromene (CBC), a potential pharma- Chemotype · Genotype · Ontogeny · Plasticity ceutical, in the cannabinoid fraction of Cannabis sativa L. is explored. As with tetrahydrocannabinol (THC) and cannabidiol (CBD), CBC is an enzymatic conver- Introduction sion product of the precursor cannabigerol (CBG). CBC is reported to dominate the cannabinoid fraction Cannabinoid biogenesis of juveniles and to decline with maturation. This ontog- eny was conWrmed in inbred lines with diVerent mature Cannabis plants synthesise and accumulate cannabi- chemotypes. A consistent CBC presence was found in noids as carboxylic acids (e.g., cannabichromenic early leaves from a diverse clone collection, suggesting acid, CBCA). In this paper these compounds will be that CBC synthase is encoded by a Wxed locus. Mor- indicated by the abbreviations for their neutral forms. phological variants possessing a ‘prolonged juvenile The most common cannabinoids, those with a pentyl chemotype’ (PJC), a substantial proportion of CBC side chain, are cannabidiol (CBD; Adams et al. 1940; persisting up to maturity, are presented. PJC is associ- Mechoulam and Shvo 1963), delta 9-tetrahydrocan- ated with a reduced presence of Xoral bracts, bracte- nabinol (THC; Gaoni and Mechoulam 1964a), canna- oles, and capitate-stalked trichomes. Genetic factors bichromene (CBC; Gaoni and Mechoulam 1966) and causing these features were independent of the allelic cannabigerol (CBG; Gaoni and Mechoulam 1964b). chemotype locus B that was previously postulated and The Wrst speciWc step in the pentyl cannabinoid regulates THC and CBD synthesis and CBG accumula- biosynthesis is the condensation of geranylpyrophos- tion. In contrast to previously described Cannabis phate (GPP) with olivetolic acid (OA) into CBG. This chemotypes, the cannabinoid composition of PJCs reaction is catalysed by the enzyme geranylpyrophos- showed plasticity in that reduced light levels increased phate:olivetolate geranyltransferase (GOT; Fellermeier the CBC proportion. The ability of PJC plants to enable and Zenk 1998). CBG is the direct precursor for each the production of pharmaceutical raw material with of the compounds THC (Taura et al. 1995), CBD high CBC purity is demonstrated. (Taura et al. 1996) and CBC (Gaoni and Mechoulam 1966; Morimoto et al. 1997, 1998). The diVerent conversions of CBG are enzymatically catalysed, & E. P. M. de Meijer ( ) · K. M. Hammond · M. Micheler and for each reaction an enzyme has been identiWed: GW Pharmaceuticals plc., Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ, UK THC acid synthase (Taura et al. 1995), CBD acid e-mail: [email protected] synthase (Taura et al. 1996) and CBC acid synthase 123 294 Euphytica (2009) 165:293–311 (Morimoto et al. 1997, 1998). Cannabinoids with pro- true-breeding, strongly THC predominant plant has a W pyl side chains, as identi ed by Vree et al. (1971) and BT/BT genotype and plants with substantial propor- de Zeeuw et al. (1972), result if GPP condenses with tions of both CBD and THC are heterozygous BD/BT. divarinic acid instead of OA, into cannabigerovarin de Meijer and Hammond (2005) concluded that plants (CBGV). The three cannabinoid synthase enzymes accumulating the precursor CBG have a mutation of are not selective for the length of the alkyl side chain BD called B0, in the homozygous state, which encodes and convert CBGV into the propyl homologues of for a poorly functional CBD synthase. The genetic CBD, THC and CBC, which are indicated as cannabi- control of the CBC biosynthesis remains to be clari- divarin (CBDV), delta 9-tetrahydrocannabivarin Wed. de Meijer et al. (2003) brieXy addressed two (THCV) and cannabichromevarin (CBCV), respec- options: a further allele BC at the B locus, encoding tively (Shoyama et al. 1984). CBC synthase, or the involvement of a completely Cannabinoids are deposited in the non-cellular, diVerent locus that may or may not be allelic. secretory cavity of glandular trichomes. Sirikantara- mas et al. (2005) conWrmed the presence of the central The occurrence of cannabichromene in Cannabis precursor CBG and an exclusive THC synthase activ- chemotypes ity in the secretory cavity and concluded that this is not only the site of THC accumulation but also of its To discriminate between quantitative and qualitative biosynthesis. As THC, CBD and CBC all result from aspects of cannabinoid accumulation, de Meijer et al. CBG conversions, it was suggested that CBD and (2003) considered the yield of a certain cannabinoid CBC are also synthesised in the secretory cavity. as a complex trait. In this view, quantitative yield Mahlberg and Kim (2004) report that glandular tric- components, including the total cannabinoid content, homes are exclusively specialised to synthesise high are polygenic, not related to speciWc metabolic amounts of cannabinoids and that other tissues contain pathways and are heavily aVected by the environ- only very low levels. They recognised three types of ment. In contrast, the cannabinoid composition glandular trichomes: the small bulbous and the large strictly depends on the metabolic pathways followed capitate-sessile form that are both present on leaf sur- by the plant to convert common precursors into spe- faces throughout the plant and the large capitate- ciWc end products. This paper focuses on chemotype stalked form that develops after Xower initiation on in the latter qualitative sense of the proportions of the inXorescence bracts (small leaves) and bracteoles pertinent cannabinoids within the total cannabinoid (structures enclosing the ovary). These authors report fraction. that the cannabinoid content of capitate-stalked glands According to several reports, chemotypes with high is about 20 times that of capitate-sessile glands. proportions of CBC appear to be a juvenile expression. According to Taura et al. (1995, 1996), CBD and Shoyama et al. (1975), Rowan and Fairbairn (1977) THC synthase are very similar in respect of their and Vogelmann et al. (1988) reported a shift from high Y a nity for CBG (Km values 134 and 137 M, respec- CBC proportions, or even CBC predominance in tively) and their catalytic capacity (turnover number young seedlings or cuttings towards a strong THC pre- ¡1 Y kcat, 0.19 and 0.20 s , respectively). The a nity of dominance in the same plants at maturity. Morimoto CBC acid synthase for the CBG substrate is higher et al. (1997, 1998) reported a development from strong (Km =23M) than that of CBD and THC synthase CBC predominance to strong CBD predominance. but, in contrast, its catalytic capacity is lower The proportion of CBC in the total cannabinoid ¡1 X (kcat =0.04s ) (Morimoto et al. 1998). fraction may also vary under the in uence of photo- It has been previously concluded that the inheri- period and light quality. Valle et al. (1978) compared tance of CBD and THC composed chemotypes is the cannabinoid composition of Xowering plants controlled by a monogenic, co dominant mechanism grown under a 10 and 12 h photoperiod, respectively, (de Meijer et al. 2003). A single locus referred to as and found that the 12 h treatment increased THC con- B, with two alleles, BD and BT, encoding CBD and tent and decreased CBC content. Mahlberg and THC synthase respectively, was postulated. Accord- Hemphill (1983) examined the eVect of light on the ing to this model, a true-breeding, strongly CBD pre- cannabinoid composition of the vegetative leaves of a dominant plant has a BD/BD genotype at the B locus, a THC predominant strain. Unlike THC production, 123 Euphytica (2009) 165:293–311 295 CBC production was maintained at comparable or THC/CBC plants with CBC proportions ranging from greater levels under light-stressed conditions than in 7% to 58%. daylight controls. As a result, the CBC/THC ratio increased signiWcantly under light-stress. It was con- Aim of this work cluded that the processes of both synthesis and accu- mulation of CBC are independent of those for THC. This paper aims to extend the genetic model for In mature inXorescences of drug, Wbre and undo- chemotype inheritance in Cannabis (de Meijer et al. mesticated strains from a wide range of origins, CBC 2003; de Meijer and Hammond 2005), by exploring commonly occurs as a minor constituent beside much the mechanisms that control the CBC proportion in more substantial proportions of THC and/or CBD. In the cannabinoid fraction. To this purpose breeding reports on large-scale germplasm evaluations, mature experiments were conducted with chemotypes char- plants are usually characterised by the contents of the acterised by contrasting CBC proportions at maturity. major cannabinoids CBD and THC, whereas CBC is With the focus on CBC, a study of the ontogenetically often neglected (e.g., Small and Beckstead 1973; de and environmentally induced variation in chemotype Meijer et al. 1992; Small and Marcus 2003). Turner also appeared essential. and Hadley (1973) however, found that certain drug strains are devoid of CBD and have CBC as a minor component beside THC. Baker et al. (1983) reported Materials and methods on the minor presence of CBC in CBD-predominant plants from Sri Lanka and India. Beutler and Der Chemotype monitoring Marderosian (1978) analysed samples from Mexican and Siberian plants and their cross progeny. They Table 1 presents Wve female inbred lines that were found a constant presence of CBC in all plants, occu- grown for periodic assessments of their cannabinoid pying a 3–9% proportion of the total cannabinoid contents. Up to Wve seedlings per line were evaluated fraction. Hillig and Mahlberg (2004) examined the under similar glasshouse conditions.
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