Microbial Biotransformation of Cannabidiol (CBD) from Cannabis sativa

Abstract

Microbial biotransformation of cannabidiol was assessed using 31 different microorganisms. Only Mucor ramannianus (ATCC 9628), Beauveria bassiana (ATCC 7195), and Absidia glauca (ATCC 22 752) were able to metabolize cannabidiol. M. ramannianus (ATCC 9628) yielded five metabolites, namely, 7,4″β-dihydroxycannabidiol (1), 6β,4″β-dihydroxycannabidiol (2), 6β,2″β-dihydroxycannabidiol (3), 6β,3″α-dihydroxycannabidiol (4), and 6β,7,4″β-trihydroxycannabidiol (5). B. bassiana (ATCC 7195) metabolized cannabidiol to afford six metabolites identified as 7,3″-dihydroxycannabidivarin (6), 7-hydroxycannabidivarin-3″-carboxylic acid (7), 3″-hydroxycannabidivarin (8), 4″β-hydroxycannabidiol (9), and cannabidivarin-3″-carboxylic acid (10) along with compound 1. Incubation of cannabidiol with A. glauca (ATCC 22 752) yielded three metabolites, 6α,3″-dihyroxycannabidivarin (11), 6β,3″-dihyroxycannabidivarin (12), and compound 6. All compounds were evaluated for their antimicrobial and antiprotozoal activity.

Key words

cannabidiol - biotransformation - metabolites - antimicrobial - Cannabis sativa - Cannabaceae

Publikationsverlauf

Eingereicht: 20. Juli 2020

Angenommen nach Revision: 26. März 2021

Artikel online veröffentlicht:
26. April 2021

• References

• 1 Blanton HL, Brelsfoard J, DeTurk N, Pruitt K, Narasimhan M, Morgan DJ, Guindon J. Cannabinoids: current and future options to treat chronic and chemotherapy-induced neuropathic pain. Drugs 2019; 79: 969-995
• 2 Fraguas-Sánchez A, Fernández-Carballido A, Torres-Suárez A. Phyto-, endo-and synthetic cannabinoids: promising chemotherapeutic agents in the treatment of breast and prostate carcinomas. Expert Opin Investig Drugs 2016; 25: 1311-1323
• 3 Snider S, Consroe P. Beneficial and adverse effects of cannabidiol in a parkinson patient with sinemet-induced dystonic dyskinesia. Neurology 1985; 35: 201
• 4 Calderon B, Sayre T. Cannabidiol use in older adults. US Pharm 2020; 45: 34-38
• 5 Dash R, Ali MC, Jahan I, Munni YA, Mitra S, Hannan MA, Timalsina B, Oktaviani DF, Choi HJ, Moon IS. Roles of cannabidiol in reversing proteinopathies. Preprints 2020;
• 6 Bih CI, Chen T, Nunn AV, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics 2015; 12: 699-730
• 7 Consroe P, Sandyk R, Snider SR. Open label evaluation of cannabidiol in dystonic movement disorders. Int J Neurosci 1986; 30: 277-282
• 8 Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev 2014; 2014 (03) CD009270
• 9 Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, Roberts C. Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial. Epilepsia 2019; 60: 294-302
• 10 Kaplan JS, Stella N, Catterall WA, Westenbroek RE. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A 2017; 114: 11229-11234
• 11 Corroon J, Kight R. Regulatory status of cannabidiol in the United States: A perspective. Cannabis Cannabinoid Res 2018; 3: 190-194
• 12 Massi P, Vaccani A, Bianchessi S, Costa B, Macchi P, Parolaro D. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci 2006; 63: 2057-2066
• 13 Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio MP, Parolaro D. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther 2004; 308: 838-845
• 14 Solinas M, Massi P, Cinquina V, Valenti M, Bolognini D, Gariboldi M, Monti E, Rubino T, Parolaro D. Cannabidiol, a non-psychoactive cannabinoid compound, inhibits proliferation and invasion in U87-MG and T98G glioma cells through a multitarget effect. PLoS One 2013; 8: e76918
• 15 Vaccani A, Massi P, Colombo A, Rubino T, Parolaro D. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 2005; 144: 1032-1036
• 16 World Health Organization. Global tuberculosis report 2019. Accessed November 1, 2020 at: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-report-2019
• 17 Honeyborne I, Lipman M, Zumla A, McHugh TD. The changing treatment landscape for MDR/XDR-TB-can current clinical trials revolutionise and inform a brave new world?. Int J Infect Dis 2019; 80: S23-S28
• 18 Huang P, Xie F, Ren B, Wang Q, Wang J, Wang Q, Abdel-Mageed WM, Liu M, Han J, Oyeleye A. Anti-MRSA and anti-TB metabolites from marine-derived Verrucosispora sp. MS100047. Appl Microbiol Biotechnol 2016; 100: 7437-7447
• 19 Appendino G, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod 2008; 71: 1427-1430
• 20 Clark AM, McChesney JD, Hufford CD. The use of microorganisms for the study of drug metabolism. Med Res Rev 1985; 5: 231-253
• 21 Robertson LW, Lyle MA, Billets S. Biotransformation of cannabinoids by Syncephalastrum racemosum . Biomed Mass Spectrom 1975; 2: 266-271
• 22 Robertson LW, Koh SW, Huff SR, Malhotra RK, Ghosh A. Microbiological oxidation of the pentyl side chain of cannabinoids. Experientia 1978; 34: 1020-1022
• 23 Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci 2011; 89: 165-170
• 24 Harvey DJ, Mechoulam R. Metabolites of cannabidiol identified in human urine. Xenobiotica 1990; 20: 303-320
• 25 Ujváry I, Hanuš L. Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res 2016; 1: 90-101
• 26 Ibrahim AK, Radwan MM, Ahmed SA, Slade D, Ross SA, El Sohly MA, Khan IA. Microbial metabolism of cannflavin A and B isolated from Cannabis sativa . Phytochemistry 2010; 71: 1014-1019
• 27 Herath W, Mikell JR, Hale AL, Ferreira D, Khan IA. Microbial metabolism part 9. Structure and antioxidant significance of the metabolites of 5,7-dihydroxyflavone (chrysin), and 5-and 6-hydroxyflavones. Chem Pharm Bull 2008; 56: 418-422
• 28 Ibrahim A, Khalifa SI, Khafagi I, Youssef DT, Khan S, Mesbah M, Khan I. Microbial metabolism of biologically active secondary metabolites from Nerium oleander L. Chem Pharm Bull 2008; 56: 1253-1258
• 29 Hoye TR, Jeffrey CS, Shao F. Mosher ester analysis for the determination of absolute configuration of stereogenic (chiral) carbinol carbons. Nat Protoc 2007; 2: 2451-2458
• 30 Ross SA, ElSohly MA, Sultana GN, Mehmedic Z, Hossain CF, Chandra S. Flavonoid glycosides and cannabinoids from the pollen of Cannabis sativa L. Phytochem Anal 2005; 16: 45-48
• 31 Merkus FW. Cannabivarin and tetrahydrocannabivarin, two new constituents of hashish. Nature 1971; 232: 579-580
• 32 Nilsson I, Agurell S, Nilsson JLG, Widman M, Leander K. Two cannabidiol metabolites formed by rat liver. J Pharm Pharmacol 1973; 25: 486-487
• 33 Kusumi T, Fukushima T, Ohtani I, Kakisawa H. Elucidation of the absolute configurations of amino acids and amines by the modified Mosherʼs method. Tetrahedron Lett 1991; 32: 2939-2942
• 34 Bharate SB, Khan SI, Yunus NA, Chauthe SK, Jacob MR, Tekwani BL, Khan IA, Singh IP. Antiprotozoal and antimicrobial activities of O-alkylated and formylated acylphloroglucinols. Bioorg Med Chem 2007; 15: 87-96