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Comparative Metabolomic Profiling of the Metabolic Differences of Δ9-Tetrahydrocannabinol and Cannabidiol

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 me...

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Autores principales: Rao, Qianru, Zhang, Ting, Dai, Manyun, Li, Bin, Pu, Qianlun, Zhao, Min, Cheng, Yan, Yan, Dongmei, Zhao, Qi, Wu, Zhanxuan E., Li, Fei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657426/
https://www.ncbi.nlm.nih.gov/pubmed/36364400
http://dx.doi.org/10.3390/molecules27217573
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author Rao, Qianru
Zhang, Ting
Dai, Manyun
Li, Bin
Pu, Qianlun
Zhao, Min
Cheng, Yan
Yan, Dongmei
Zhao, Qi
Wu, Zhanxuan E.
Li, Fei
author_facet Rao, Qianru
Zhang, Ting
Dai, Manyun
Li, Bin
Pu, Qianlun
Zhao, Min
Cheng, Yan
Yan, Dongmei
Zhao, Qi
Wu, Zhanxuan E.
Li, Fei
author_sort Rao, Qianru
collection PubMed
description 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.
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spelling pubmed-96574262022-11-15 Comparative Metabolomic Profiling of the Metabolic Differences of Δ9-Tetrahydrocannabinol and Cannabidiol Rao, Qianru Zhang, Ting Dai, Manyun Li, Bin Pu, Qianlun Zhao, Min Cheng, Yan Yan, Dongmei Zhao, Qi Wu, Zhanxuan E. Li, Fei Molecules Article 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. MDPI 2022-11-04 /pmc/articles/PMC9657426/ /pubmed/36364400 http://dx.doi.org/10.3390/molecules27217573 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rao, Qianru
Zhang, Ting
Dai, Manyun
Li, Bin
Pu, Qianlun
Zhao, Min
Cheng, Yan
Yan, Dongmei
Zhao, Qi
Wu, Zhanxuan E.
Li, Fei
Comparative Metabolomic Profiling of the Metabolic Differences of Δ9-Tetrahydrocannabinol and Cannabidiol
title Comparative Metabolomic Profiling of the Metabolic Differences of Δ9-Tetrahydrocannabinol and Cannabidiol
title_full Comparative Metabolomic Profiling of the Metabolic Differences of Δ9-Tetrahydrocannabinol and Cannabidiol
title_fullStr Comparative Metabolomic Profiling of the Metabolic Differences of Δ9-Tetrahydrocannabinol and Cannabidiol
title_full_unstemmed Comparative Metabolomic Profiling of the Metabolic Differences of Δ9-Tetrahydrocannabinol and Cannabidiol
title_short Comparative Metabolomic Profiling of the Metabolic Differences of Δ9-Tetrahydrocannabinol and Cannabidiol
title_sort comparative metabolomic profiling of the metabolic differences of δ9-tetrahydrocannabinol and cannabidiol
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9657426/
https://www.ncbi.nlm.nih.gov/pubmed/36364400
http://dx.doi.org/10.3390/molecules27217573
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