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Molecules. 2019 Jun 17;24(12). pii: E2256. doi: 10.3390/molecules24122256.

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.

Author information

1
Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. LEEwing@uams.edu.
2
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. LEEwing@uams.edu.
3
Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. MRMcgill@uams.edu.
4
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. MRMcgill@uams.edu.
5
Center for Dietary Supplements Research, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. MRMcgill@uams.edu.
6
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. EYee@uams.edu.
7
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. QuickCharlesM@uams.edu.
8
Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. CMSkinner@uams.edu.
9
Center for Dietary Supplements Research, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. CMSkinner@uams.edu.
10
Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. SKennonmcgill@uams.edu.
11
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. MMClemens@uams.edu.
12
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. JVazquez@uams.edu.
13
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. McCulloughSandraS@uams.edu.
14
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. McCulloughSandraS@uams.edu.
15
Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. WilliamsDavidK@uams.edu.
16
Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. kristy.kutanzi@gmail.com.
17
National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA. lwalker@olemiss.edu.
18
ElSohly Laboratories, Inc. (ELI), Oxford, MS 38677, USA. lwalker@olemiss.edu.
19
National Center for Natural Products Research, University of Mississippi, University, MS 38677, USA. melsohly@olemiss.edu.
20
ElSohly Laboratories, Inc. (ELI), Oxford, MS 38677, USA. melsohly@olemiss.edu.
21
Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, University, MS 38677, USA. melsohly@olemiss.edu.
22
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. jameslaurap@uams.edu.
23
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. jameslaurap@uams.edu.
24
Center for Dietary Supplements Research, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. GurleyBillyJ@uams.edu.
25
Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. GurleyBillyJ@uams.edu.
26
Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. ikoturbash@uams.edu.
27
Center for Dietary Supplements Research, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. ikoturbash@uams.edu.

Abstract

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.

KEYWORDS:

acetaminophen; cannabidiol; liver injury; natural products; phytochemical; sinusoidal obstruction syndrome

PMID:
31212965
DOI:
10.3390/molecules24122256
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