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Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration

The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury–acetaminophen (APAP)–in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabid...

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Autores principales: Ewing, Laura E., McGill, Mitchell R., Yee, Eric U., Quick, Charles M., Skinner, Charles M., Kennon-McGill, Stefanie, Clemens, Melissa, Vazquez, Joel H., McCullough, Sandra S., Williams, D. Keith, Kutanzi, Kristy R., Walker, Larry A., ElSohly, Mahmoud A., James, Laura P., Gurley, Bill J., Koturbash, Igor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630875/
https://www.ncbi.nlm.nih.gov/pubmed/31212965
http://dx.doi.org/10.3390/molecules24122256
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author Ewing, Laura E.
McGill, Mitchell R.
Yee, Eric U.
Quick, Charles M.
Skinner, Charles M.
Kennon-McGill, Stefanie
Clemens, Melissa
Vazquez, Joel H.
McCullough, Sandra S.
Williams, D. Keith
Kutanzi, Kristy R.
Walker, Larry A.
ElSohly, Mahmoud A.
James, Laura P.
Gurley, Bill J.
Koturbash, Igor
author_facet Ewing, Laura E.
McGill, Mitchell R.
Yee, Eric U.
Quick, Charles M.
Skinner, Charles M.
Kennon-McGill, Stefanie
Clemens, Melissa
Vazquez, Joel H.
McCullough, Sandra S.
Williams, D. Keith
Kutanzi, Kristy R.
Walker, Larry A.
ElSohly, Mahmoud A.
James, Laura P.
Gurley, Bill J.
Koturbash, Igor
author_sort Ewing, Laura E.
collection PubMed
description The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury–acetaminophen (APAP)–in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.) acetaminophen (APAP) administration (400 mg/kg) on day 4 resulted in overt toxicity with 37.5% mortality. No mortality was observed in mice treated with 290 mg/kg of CBD+APAP (MED of 25 mg/kg of CBD) or APAP alone. Following CRCE/APAP co-administration, microscopic examination revealed a sinusoidal obstruction syndrome-like liver injury–the severity of which correlated with the degree of alterations in physiological and clinical biochemistry end points. Mechanistically, glutathione depletion and oxidative stress were observed between the APAP-only and co-administration groups, but co-administration resulted in much greater activation of c-Jun N-terminal kinase (JNK). Strikingly, these effects were not observed in mice gavaged with 290 mg/kg CBD in CRCE followed by APAP administration. These findings highlight the potential for CBD/drug interactions, and reveal an interesting paradoxical effect of CBD/APAP-induced hepatotoxicity.
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spelling pubmed-66308752019-08-19 Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration Ewing, Laura E. McGill, Mitchell R. Yee, Eric U. Quick, Charles M. Skinner, Charles M. Kennon-McGill, Stefanie Clemens, Melissa Vazquez, Joel H. McCullough, Sandra S. Williams, D. Keith Kutanzi, Kristy R. Walker, Larry A. ElSohly, Mahmoud A. James, Laura P. Gurley, Bill J. Koturbash, Igor Molecules Article The goal of this study was to investigate the potential for a cannabidiol-rich cannabis extract (CRCE) to interact with the most common over-the-counter drug and the major known cause of drug-induced liver injury–acetaminophen (APAP)–in aged female CD-1 mice. Gavaging mice with 116 mg/kg of cannabidiol (CBD) [mouse equivalent dose (MED) of 10 mg/kg of CBD] in CRCE delivered with sesame oil for three consecutive days followed by intraperitoneally (i.p.) acetaminophen (APAP) administration (400 mg/kg) on day 4 resulted in overt toxicity with 37.5% mortality. No mortality was observed in mice treated with 290 mg/kg of CBD+APAP (MED of 25 mg/kg of CBD) or APAP alone. Following CRCE/APAP co-administration, microscopic examination revealed a sinusoidal obstruction syndrome-like liver injury–the severity of which correlated with the degree of alterations in physiological and clinical biochemistry end points. Mechanistically, glutathione depletion and oxidative stress were observed between the APAP-only and co-administration groups, but co-administration resulted in much greater activation of c-Jun N-terminal kinase (JNK). Strikingly, these effects were not observed in mice gavaged with 290 mg/kg CBD in CRCE followed by APAP administration. These findings highlight the potential for CBD/drug interactions, and reveal an interesting paradoxical effect of CBD/APAP-induced hepatotoxicity. MDPI 2019-06-17 /pmc/articles/PMC6630875/ /pubmed/31212965 http://dx.doi.org/10.3390/molecules24122256 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ewing, Laura E.
McGill, Mitchell R.
Yee, Eric U.
Quick, Charles M.
Skinner, Charles M.
Kennon-McGill, Stefanie
Clemens, Melissa
Vazquez, Joel H.
McCullough, Sandra S.
Williams, D. Keith
Kutanzi, Kristy R.
Walker, Larry A.
ElSohly, Mahmoud A.
James, Laura P.
Gurley, Bill J.
Koturbash, Igor
Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration
title Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration
title_full Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration
title_fullStr Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration
title_full_unstemmed Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration
title_short Paradoxical Patterns of Sinusoidal Obstruction Syndrome-Like Liver Injury in Aged Female CD-1 Mice Triggered by Cannabidiol-Rich Cannabis Extract and Acetaminophen Co-Administration
title_sort paradoxical patterns of sinusoidal obstruction syndrome-like liver injury in aged female cd-1 mice triggered by cannabidiol-rich cannabis extract and acetaminophen co-administration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630875/
https://www.ncbi.nlm.nih.gov/pubmed/31212965
http://dx.doi.org/10.3390/molecules24122256
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