Comparative Metabolomic Profiling of the Metabolic Differences of Δ9-Tetrahydrocannabinol and Cannabidiol
Qianru Rao,
Ting Zhang,
Manyun Dai,
Bin Li,
Qianlun Pu,
Min Zhao,
Yan Cheng,
Dongmei Yan,
Qi Zhao,
Zhanxuan E. Wu,
Fei Li
Affiliations
Qianru Rao
Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
Ting Zhang
Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
Manyun Dai
Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
Bin Li
Academician Workstation, Jiangxi University of Chinese Medicine, Nanchang 330004, China
Qianlun Pu
Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
Min Zhao
Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
Yan Cheng
Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
Dongmei Yan
Academician Workstation, Jiangxi University of Chinese Medicine, Nanchang 330004, China
Qi Zhao
Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
Zhanxuan E. Wu
Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
Fei Li
Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
More than one hundred cannabinoids have been found in cannabis. Δ9-Tetrahydrocannabinol (THC) is the recognized addictive constituent in cannabis; however, the mechanisms underlying THC-induced toxicity remain elusive. To better understand cannabis-induced toxicity, the present study compared the metabolic pathways of THC and its isomer cannabidiol (CBD) in human and mouse liver microsomes using the metabolomic approach. Thirty-two metabolites of THC were identified, including nine undescribed metabolites. Of note, two glutathione (GSH) and two cysteine (Cys) adducts were found in THC’s metabolism. Molecular docking revealed that THC conjugates have a higher affinity with GSH and Cys than with the parent compound, THC. Human recombinant cytochrome P450 enzymes, and their corresponding chemical inhibitors, demonstrated that CYP3A4 and CYP1B1 were the primary enzymes responsible for the formation of THC-GSH and THC-Cys, thus enabling conjugation to occur. Collectively, this study systematically compared the metabolism of THC with the metabolism of CBD using the metabolomic approach, which thus highlights the critical role of metabolomics in identifying novel drug metabolites. Moreover, this study also facilitates mechanistic speculation in order to expand the knowledge of drug metabolism and safety.
