Abstract
PurposeThe purpose of the present study was to identify the structures of cannabidiol (CBD) metabolites during CO formation by human liver microsomes and human recombinant cytochrome P450 (CYP) enzymes.MethodsCBD was NADPH-dependently metabolized by human liver microsomes and human recombinant CYP enzymes. Less-polar metabolites were analyzed by gas chromatography–mass spectrometry monitoring, and their estimated molecular ions were m/z 286, 358 and 481 after non-derivatization, trimethylsilylation and pentafluorobenzyl oxime formation, respectively.ResultsWe tentatively identified novel decarbonylated metabolites of CBD as keto-enol tautomers. Among eight major recombinant human CYP enzymes, only CYP3A4 catalyzed the formation of decarbonylated metabolites.ConclusionsCBD was biotransformed to two decarbonylated metabolites, an enol-form (cyclopentadienol structure), and a keto-form (cyclopentenone structure) by human liver microsomes and CYP3A4.
Highlights
Cannabidiol (CBD), one of the major phytocannabinoids in cannabis, has a variety of pharmacological effects, such as anticonvulsant, antiemetic, antioxidant, and anxiolytic effects, as well as barbiturate-induced sleep prolongationShizuo Narimatsu: Deceased on 6 November 2017.Hidetoshi Yoshimura: Deceased on 11 July 2018.[1–3], this phytocannabinoid lacks psychoactivity, which is associated with its lower affinity for the C B1 cannabinoid receptor [4]
The primary metabolic reactions of CBD are allylic hydroxylations at the 6- and 7-positions that are catalyzed by cytochrome P450 (CYP) enzymes mainly expressed in the liver
It was speculated that CO could be formed from CBD by CYP enzymes, in which the phenolic hydroxyl groups of CBD are a possible source for the CO formation, a counterpart metabolite of CBD after CO formation had not
Summary
Cannabidiol (CBD), one of the major phytocannabinoids in cannabis, has a variety of pharmacological effects, such as anticonvulsant, antiemetic, antioxidant, and anxiolytic effects, as well as barbiturate-induced sleep prolongationShizuo Narimatsu: Deceased on 6 November 2017.Hidetoshi Yoshimura: Deceased on 11 July 2018.[1–3], this phytocannabinoid lacks psychoactivity, which is associated with its lower affinity for the C B1 cannabinoid receptor [4]. Cannabidiol (CBD), one of the major phytocannabinoids in cannabis, has a variety of pharmacological effects, such as anticonvulsant, antiemetic, antioxidant, and anxiolytic effects, as well as barbiturate-induced sleep prolongation. Shizuo Narimatsu: Deceased on 6 November 2017. Hidetoshi Yoshimura: Deceased on 11 July 2018. CBD is metabolized in experimental animals and humans in vitro, as well as in vivo [12–15]. The primary metabolic reactions of CBD are allylic hydroxylations at the 6- and 7-positions that are catalyzed by cytochrome P450 (CYP) enzymes mainly expressed in the liver. Our previous study showed that CYP3A4 and CYP2C19 have major roles in the metabolism of CBD in human liver microsomes [16]. We demonstrated that CBD generated CO during mouse liver microsomal metabolism [17, 18]. It was speculated that CO could be formed from CBD by CYP enzymes, in which the phenolic hydroxyl groups of CBD are a possible source for the CO formation, a counterpart metabolite of CBD after CO formation had not
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