Abstract
Cannabinoids are terpenophenolic compounds consisting of an aromatic polyketide and derived from the geranyl diphosphate C10 terpenoid unit. They are the active constituents in Cannabis sativa and have been utilized in a number of cannabis-based medicines. Biotransformation of cannabinoids is an important field of xenobiochemistry and toxicology and the study of the metabolism of these compounds can lead to the discovery of new compounds, unknown metabolites with unique structures and new therapeutic entities. Different fungi, bacteria, plants and animal cells have been used for the regio- and stereoselective transformation of cannabinoids. All of the above mentioned organisms have distinct enzymes which catalyze the conversion of a specific cannabinoid at different positions and thus provide a variety of derivatives. All organisms are able to transform the alkyl side chain where as mammalians are unique in the formation of the carboxy derivatives. This review article assesses the current knowledge on the biotransformation of tetrahydrocannabinol and with particular focus on ∆9-THC.
References
Abbott BJ, Fukuda DS, Archer RA (1977) Microbiological transformation of cannabinoids. Experientia 33:718–720
BenZvi Z, Burstein S (1974) 7-Oxo-delta1-tetrahydrocannabinol: a novel metabolite of Δ1-tetrahydrocannabinol. Res Commun Chem Pathol Pharmacol 8:223–229
Benzvi Z, Burstein S (1975) Transformation of Δ1-tetrahydrocannabinol (THC) by rabbit liver-microsomes. Biochem Pharmacol 24:1130–1131
BenZvi Z, Burstein S, Zikopoulos J (1974) Metabolism of Δ1-tetrahydrocannabinol by mouse hepatic microsomes: identification of 6alpha-hydroxytetrahydrocannabinol. J Pharm Sci 63:1173–1174
Billy RM, David RC, William RP, Rita LB, Raj KR (1995) Pharmacological evaluation of dimethylheptyl analogs of Δ9-THC: reassessment of the putative three-point cannabinoid-receptor interaction. Drug Alcohol Depen 37:231–240
Binder M (1976) Microbial transformation of (−)-D 1–3, 4-trans-tetrahydrocannabinol by Cunninghamella blakesleeana Lender. Helv Chima Acta 59:1674
Binder M, Meisenberg G (1978) Microbial transformation of cannabinoids 2. A screening of different microorganisms. Eur J Appl Microbiol Biotechnol 5:37–50
Binder M, Popp A (1980) Microbial transformation of cannabinoids. Part 3: major metabolites of (3R,4R) -Δ1-tetrahydrocannabinol. Helv Chima Acta 63:2515–2518
Bornheim LM, Lasker JM, Raucy JL (1992) Human hepatic-microsomal metabolism of Δ1-tetrahyrocannabinol. Drug Metab Dispos 20:241–246
Braemer R, Paris M (1987) Biotransformation of cannabinoids by a cell suspension culture of Cannabis sativa L. Plant Cell Rep 6:150–152
Brown NK, Harvey DJ (1988a) In vivo metabolism of the methyl homologues of Delta-8-tetrahydrocannabinol, Delta-9-tetrahydrocannabinol and abn-delta-8-tetrahydrocannabinol in the mouse. Biomed Environ Mass Spectrom 15:389–398
Brown NK, Harvey DJ (1988b) Metabolism of n-hexyl-homologues of Δ8-tetrahydrocannabinol and Δ9-tetrahydrocannabinol in the mouse. Eur J Drug Metab Pharmacokinet 13:165–176
Brown NK, Harvey DJ (1988c) In vivo metabolism of the n-propyl homologs of Δ8- and Δ9-tetrahydrocannabinol in the mouse. Biomed Environ Mass Spectrom 15:403–410
Burstein S, Kupfer D (1971a) Hydroxylation of trans-∆1-tetrahydrocannabinol by hepatic microsomal oxygenase. Ann NY Acad Sci 191:61–67
Burstein SH, Kupfer D (1971b) Hydroxylation of trans-1-tetrahydrocannabinol by a hepatic microsomal monooxygenase. Chem Biol Interact 3:316
Burstein S, Shoupe TS (1981) Metabolic pathways for the transformation of Δ1-tetrahydrocannabinol in mouse hepatic microsomes. Drug Metab Dispos 9:94–96
Burstein S, Rosenfeld J, Wittstruck T (1972) Isolation and characterization of two major urinary metabolites of Δ1-Tetrahydrocannabinol. Science 176:422–423
Carter GT, Weydt P (2002) Cannabis: old medicine with new promise for neurological disorders. Curr Opin Investig Drugs 3:437–440
Christie RM, Rickards RW, Watson WP (1978) Microbial transformation of cannabinoids. 1. Metabolism of (−)-Δ9-6a, 10a, 10a-trans-tetra-hydrocannabinol by Chaetomium-globosum. Aust J Chem 31:1799–1807
Gaoni Y, Mechoulam R (1964) Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. J Am Chem Soc 86:1646–1647
Gaoni Y, Mechoulam R (1966) Cannabichromene, a new active principle in hashish. Chem Commun 1:20–21
Halldin MM, Widman M, Martin B (1979) The importance of side-chain hydroxylated metabolites of Δ6-tetrahydrocannabinol in rhesus monkey. Acta Pharm Suec 16:34–40
Halldin MM, Andersson LK, Widman M, Hollister LE (1982a) Further urinary metabolites of Δ1-tetrahydrocannabinol in man. Arznei-Forschung 32:1135–1138
Halldin MM, Carlsson S, Kanter SL, Widman M, Agurell S (1982b) urinary metabolites of Δ1-tetrahydrocannabinol in man. Arznei-Forschung 32:764
Halldin MM, Widman M, Vonbahr C, Lindgren JE, Martin BR (1982c) Identification of invitro metabolites of Δ1-tetrahydrocannabinol formed by human livers. Drug Metab Dispos 10:297–301
Harvey DJ (1989) Further studies on the oxidative cleavage of the pentyl side-chain of cannabinoids: identification of new biotransformation pathways in the metabolism of 3′-hydroxy-delta-9-tetrahydrocannabinol by the mouse. Xenobiotica 19:1437–1447
Harvey DJ (1990) Oxidative cleavage of the pentyl side-chain of cannabinoids. Identification of new biotransformation pathways in the metabolism of 4′-hydroxy-Δ9-tetrahydrocannabinol in the mouse. Drug Metab Dispos 18:350–355
Harvey DJ, Paton WD (1976) Characterization of three monohydroxyacid and two dihydroxyacid metabolites of Δ1-tetrahydrocannabinol in mouse liver. Res Commun Chem Pathol Pharmacol 13:585–599
Harvey DJ, Paton WD (1978) Identification of six 4″-hydroxy - metabolites of Δ1-tetrahydrocannabinol in mouse liver. Res Commun Chem Pathol Pharmacol 21:435
Harvey DJ, Paton WD (1979) The metabolism of deuterium-labeled analogs of Δ1-, Δ6-, and Δ7-tetrahydrocannabinol and the use of deuterium labeling. Recent Dev Mass Spectrom Biochem Med 2:127–147
Harvey DJ, Paton WD (1980) Identification of in vivo liver metabolites of Δ6-tetrahydrocannabinol produced by the mouse. Drug Metab Dispos 8:178–186
Harvey DJ, Paton WD (1981) In vivo metabolism of Δ6-tetrahydrocannabinol by the guinea pig : identification of two new hydroxyacid and ketoacid metabolites. Res Commun Subst Abuse 2:193–201
Harvey DJ, Paton WD (1986) Metabolism of cannabinoids. Rev Biochem Toxicol 6:221–264
Harvey DJ, Martin BR, Paton WD (1977) Identification of di- and tri-substituted hydroxy and ketone metabolites of Δ1-tetrahydrocannabinol in mouse liver. J Pharm Pharmacol 29:482–486
Harvey DJ, Martin BR, Paton WD (1978a) Identification and measurement of cannabinoids and their in vivo metabolites in liver by gas chromatography-mass spectrometry. Adv Biosci 22–23:45–62
Harvey DJ, Martin BR, Paton WD (1978b) Comparative in vivo metabolism of Δ1-tetrahydrocannabinol (Δ1-THC), cannabidiol (CBD) and cannabinol (CBN) by several species. Recent Dev Mass Spectrom Biochem Med 1:161–184
Harvey DJ, Martin BR, Paton WD (1980a) Identification of in vivo liver metabolites of Δ1-tetrahydrocannabinol, cannabidiol and cannabinol produced by the guinea pig. J Pharm Pharmacol 32:262
Harvey DJ, Leuschner JTA, Paton WD (1980b) Influence of 6β-hydroxylation on the metabolism of Δ1-tetrahydrocannabinol: switching of the major site of biotransformation from C-7 to the side-chain. Res Commun Subst 1:159–167
Harvey DJ, Gill EW, Slater M, Paton WD (1980c) Identification of the in vivo liver metabolites of (–)-Δ7- tetrahydrocannabinol produced by the mouse. Drug Metab Dispos 8:439–445
Jones G, Widman M, Agurell S, Lindgren JE (1974) Monohydroxylated metabolites of Δ1-tetrahydrocannabinol in mouse brain. Comparison with vitro liver metabolites. Acta Pharm Suec 11:283–294
Just WW, Erdmann G, Thel S, Werner G, Wiechmann M (1975) Metabolism and autoradiographic distribution of Δ8- and Δ9-tetrahydrocannabinol in some organs of monkey Callithrix jaccus. N-S Arch Pharmacol 287:219–225
Kanter SL, Hollister LE (1978) Marihuana metabolism in urine of man. 9. Identification of Δ9-tetrahydrocannabinol-11-oic acid by thin-layer chromatography. J Chromatogr 151:225–227
Matsunaga T, Iwawaki Y, Watanabe K, Yamamoto I, Kageyama T, Yoshimura H (1995) Metabolism of delta-9-tetrahydrocannabinol by cytochrome P450 isozymes purified from hepatic microsomes of monkeys. Life Sci 56:2089–2095
Mechoulam R, Goani Y (1967) Recent advances in the chemistry of hashish. Fortschr Chem Org Naturst 25:175–213
Narimatsu S, Matsubara K, Shimonishi T, Watanabe K, Yamamoto I, Yoshimura H (1988) Enzymatic oxidation of 7-hydroxylated Δ8-tetrahydrocannabinol to 7- oxo-Δ8-tetrahydrocannabinol by hepatic microsomes of the guinea pig. Drug Metab Dispos 16:156–161
Narimatsu S, Watanabe K, Yamamoto I, Yoshimura H (1991) Sex difference in the oxidative metabolism of Δ9-tetrahydrocannabinol in the rat. Biochem Pharmacol 41:1187–1194
Nilsson IM, Agurell S, Nilsson JL, Ohlsson A, Sandberg F, Wahlqvist M (1970) Δ1-tetrahydrocannabinol: structure of a major metabolite. Science 168:1228–1229
Nordqvist M, Agurell S, Binder M, Nilsson I (1974) Structure of an acidic metabolite of Δ1-tetrahydrocannabinol isolated from rabbit urine. J Pharm Pharmacol 26:471
Nordqvist M, Lindgren JE, Agurell S (1979a) Acidic metabolites of Δ1-tetrahydrocannabinol isolated from rabbit urine. J Pharm Pharmacol 31:231
Nordqvist M, Agurell S, Rydberg M, Falk L, Ryman T (1979b) More acidic metabolites of Δ1-tetrahydrocannabinol isolated from rabbit urine. J Pharm Pharmacol 31:238–243
Pars HG, Howes JF (1977) Potential therapeutic agents derived from the cannabinoid nucleus. Adv Drug Res 11:97–189
Rashidi H, Akhtar MT, Kooy FVD, Verpoorte R, Duetz WA (2009) Hydroxylation and further oxidation of Δ9-tetrahydrocannabinol by alkane-degrading bacteria. Appl Environ Microbiol 75:7135–7141
Robertson LW, Lyle MA (1975) Biotransformation of cannabinoids by Syncephalastrum racemosum. Biol Mass Spectrom 2:266–271
Robertson LW, Huff SR, Ghosh A, Malhotra R (1978a) Acidic biotransromation products of cannabinoids produced by Mycobacterium rohodchrous. Lloydia 41:659
Robertson LW, Koh SW, Huff SR, Malhotra RK, Ghosh A (1978b) Microbiological oxidation of pentyl side-chain of cannabinoids. Experientia 34:1020–1022
Russo EB (2007) History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers 4:1614–1648
Scotter EL, Abood ME, Glass M (2010) The endocannabinoid system as a target for the treatment of neurodegenerative disease. Br J Pharmacol 160:480–498
Sirikantaramas S, Taura F, Morimoto S, Shoyama Y (2007) Recent advances in Cannabis sativa research: biosynthetic studies and its potential in biotechnology. Curr Pharm Biotechnol 8:237–243
Tanaka H, Morimoto S, Shoyama Y (1993) Cannabis, 21. Biotransformation of Cannabinol to its glycosides by in vitro plant tissue. J Nat Prod 56:2068–2072
Tanaka H, Takahashi RN, Morimoto S, Shoyama Y (1997) A new Cannabinoid, Δ6-Tetrahydrocannabinol 2′-O-beta-D-glucopyranoside, Biotransformed by Plant Tissue. J Nat Prod 60:168–170
Vidic HJ, Hoyer GA, Kieslich K, Rosenberg D (1976) Microbiological transformations of nonsteroidal structures, IX. Microbiological hydroxylation of Δ8-tetrahydrocannabinol. Chem Ber 109:3606–3614
Wall ME (1971) The in vitro metabolism of tetrahydrocannabinol (THC). Ann NY Acad Sci 191:23
Wall ME, Brine DR (1976) Identification of cannabinoids and metabolites in biological materials by combined gas-liquid chro-matography-mass spectrometry. In: Nahas GG (ed) Marihuana: chemistry, biochemistry, and cellular effects. Springer, New York, p 51
Wall ME, Perez-Reyes M (1981) The metabolism of Δ9-tetrahydrocannabinol and related cannabinoids in man. J Clin Pharmacol 21:178–189
Wall ME, Brine DR, Brine GA, Pitt CG, Freudenthal RI, Christensen HD (1970) Isolation, structure, and biological activity of several metabolites of Δ9-tetrahydrocannabinol. J Am Chem Soc 92:3466–3468
Wall ME, Brine DR, Pitt CG, Perez-Reyes M (1972) Identification of Δ9-tetrahydrocannabinol and metabolites in man. J Am Chem Soc 94:8579–8581
Watanabe K, Yamamoto I, Oguri K, Yoshimura H (1979) Microsomal oxygenase catalyzed oxidation of 11-hydroxy -Δ8-tetrahydrocannabinol to 11-oxo-Δ8-tetrahydrocannabinol. Biochem Biophys Res Commun 88:178–182
Watanabe K, Yamamoto I, Oguri K, Yoshimura H (1980) Identification and determination of 11-oxo-Δ8-tetrahydrocannabinol as an intermediate metabolite of Δ8-tetrahydrocannabinol in the mouse brain and liver. J Pharmacobiodyn 3:686–691
Watanabe K, Matsunaga T, Narimatsu S, Yamamoto I, Imaoka S, Funae Y, Yoshimura H (1991) Catalytic activity of cytochrome P450 isozymes purified from rat liver in converting 11-oxo-Δ8-tetrahydrocannabinol to Δ8-tetrahydrocannabinol-11-oic acid. Biochem Pharmacol 42:1255–1259
Widman M, Nordqvist M, Dollery CT, Briant RH (1975) Metabolism of Δ1-tetrahydrocannabinol by the isolated perfused dog lung. Comparison with in vitro liver metabolism. J Pharm Pharmacol 27:842
Widman M, Halldin MM, Martin B (1979) In vitro metabolism of tetrahydrocannabinol by rhesus monkey liver and human liver. Adv Biosci 22–23:101–103
Williams PL, Moffat AC (1980) Identification in human urine of Δ9-tetrahydrocannabinol-11-oic acid glucuronide: a tetrahydrocannabinol metabolite. J Pharm Pharmacol 32:445–448
Yamamoto I, Watanabe K, Narimatsu S, Yoshimura H (1995) Recent advances in the metabolism of cannabinoids. Int J Biochem Cell Biol 27:741–746
Yamamoto I, Watanabe K, Matsunaga T, Kimura T, Funahashi T, Yoshimura H (2003) Pharmacology and toxicology of major constituents of marijuana-on the metabolic activation of cannabinoids and its mechanism. Toxicology 22:577–589
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Akhtar, M.T., Shaari, K. & Verpoorte, R. Biotransformation of Tetrahydrocannabinol. Phytochem Rev 15, 921–934 (2016). https://doi.org/10.1007/s11101-015-9438-9
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DOI: https://doi.org/10.1007/s11101-015-9438-9