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. 2024 Oct:192:114909.
doi: 10.1016/j.fct.2024.114909. Epub 2024 Aug 9.

Inter-strain variability in responses to a single administration of the cannabidiol-rich cannabis extract in mice

Laura E Ewing  1 , Ryan J Harpenau  1 , Charles M Skinner  2 , Kirsten Clement  1 , Charles M Quick  3 , Eric U Yee  3 , D Keith Williams  4 , Larry A Walker  5 , Mahmoud A ElSohly  6 , Bill J Gurley  7 , Igor Koturbash  8
Affiliations

Inter-strain variability in responses to a single administration of the cannabidiol-rich cannabis extract in mice

Laura E Ewing et al. Food Chem Toxicol. 2024 Oct.

Abstract

Cannabidiol (CBD) has gained widespread popularity; however, its pharmacological and toxicological profiles in the context of human genetic diversity remain largely unexplored. Here, we investigated the variability in metabolism and toxicity of CBD-rich cannabis extract (CRCE) in genetically diverse mouse models: C57BL/6J, B6C3F1/J, and NZO/HlLtJ strains. Mice received a single dose of CRCE containing 57.9% CBD at dosages of 0, 246, 738, and 2460 mg/kg of CBD. At 24 h after treatment, no appreciable histomorphological changes were detected in the liver. Plasma bilirubin levels increased markedly in all strains at the highest CBD dose. Mice in all treatment groups displayed significant but distinct increases in ALT and AST levels. While B6C3F1/J and NZO/HlLtJ mice had negligible plasma CBD levels at 738 mg/kg, C57BL/6J mice exhibited levels exceeding 7000 ng/mL. At 2460 mg/kg, high CBD concentrations were found in B6C3F1/J and C57BL/6J mice, but markedly lower levels were seen in NZO/HlLtJ mice. Gene expression profiling showed significant increases in Cyp2b10 across all strains but varying responses in Cyp1a1 expression, indicating strain-specific CYP dysregulation. Genetically diverse mice exhibited differential pharmacological and toxicological responses to CRCE, suggesting a high potential for inter-individual variability in the pharmacology and toxicology of CBD in humans.

Keywords: Cannabidiol-rich cannabis extract; Cytochromes; Genetic diversity; Hepatotoxicity; Metabolism; Mouse model.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
Body weight (A), liver-to (B), heart-to (C), and kidney-to (D) body weight changes 24 hours after single gavage with CRCE in three mouse strains. Organ body weight percentages were calculated based on pre-gavage body weight since the majority of mice lost weight. Data are presented as mean ± 95% confidence interval (n=6/group) and are analyzed with a two-way ANOVA followed by Bonferroni multiple comparison correction, if applicable, comparing strains at each dose. *, p < .05; **, p < .01; ***.
Fig. 2.
Fig. 2.
Liver function analysis 24 hours after single gavage with CRCE in three mouse strains: bilirubin (A); alanine amino transferase, ALT (B); aspartate amino transferase, AST (C); gamma-glutamyl transferase, GGT (D); alkaline phosphatase, ALP (E). Data are presented as mean ± 95% confidence interval (n=4-6; serum could not be obtained from some animals) and are analyzed with a two-way ANOVA followed by Bonferroni multiple comparison correction, if applicable, comparing strains at each dose. *, p < .05; **, p < .01; ***, p < .001; and ****, p < .0001.
Fig. 3.
Fig. 3.
Expression of key cytochromes 24 hours after single gavage with CRCE in three mouse strains: Cyp1a1 (A), Cyp1a2 (B), Cyp2b10 (C), Cyp2d22 (D), Cyp2e1 (E), Cyp3a11 (F). Data are presented as mean ± 95% confidence interval (n=3-6; not all genes were detectable for all animals) and are analyzed with a two-way ANOVA, followed by Bonferroni multiple comparison correction, if applicable, comparing strains at each dose. *, p < .05; **, p < .01; ***, p < .001; and ****, p < .0001.
Fig. 4.
Fig. 4.
Expression of key UDP- glucuronosyltransferases 24 hours after single gavage with CRCE in three mouse strains: Ugt1a1 (A), Ugt1a6 (B), Ugt1a9 (C), and Ugt2a3 (D). Data are presented as mean ± 95% confidence interval (n=3-6; not all genes were detectable for all animals) and are analyzed with a two-way ANOVA, followed by Bonferroni multiple comparison correction, if applicable, comparing strains at each dose. *, p < .05; **, p < .01; ***, p < .001; and ****, p < .0001.
Fig. 5.
Fig. 5.
Metabolite plasma concentrations 24 hours after single gavage with CRCE in three mouse strains: CBD (A), CBD acid (B), 7-OH-CBD (C), THC (D), THC acid (E), and 11-OH-THC (F). Data are presented as mean ± 95% confidence interval (n=1-6; not all metabolites were detectable for all animals) and are analyzed with a two-way ANOVA, if enough data points per group, followed by Bonferroni multiple comparison correction, if applicable, comparing strains at each dose. *, p < .05; **, p < .01; ***, p < .001; and ****, p < .0001.
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References

    1. Alugupalli KR, Kothari S, Cravens MP, Walker JA, Dougharty DT, Dickinson GS, Gatto LA, Bäumler AJ, Wangdi T, Miller DR, Pardo-Manuel de Villena F, Siracusa LD. Identification of collaborative cross mouse strains permissive to Salmonella enterica serovar Typhi infection. Sci Rep. 2023. Jan 9;13(1):393. doi: 10.1038/s41598-023-27400-1. - DOI - PMC - PubMed
    1. Aylor DL, Valdar W, Foulds-Mathes W, Buus RJ, Verdugo RA, Baric RS, Ferris MT, Frelinger JA, Heise M, Frieman MB, Gralinski LE, Bell TA, Didion JD, Hua K, Nehrenberg DL, Powell CL, Steigerwalt J, Xie Y, Kelada SN, Collins FS, Yang IV, Schwartz DA, Branstetter LA, Chesler EJ, Miller DR, Spence J, Liu EY, McMillan L, Sarkar A, Wang J, Wang W, Zhang Q, Broman KW, Korstanje R, Durrant C, Mott R, Iraqi FA, Pomp D, Threadgill D, de Villena FP, Churchill GA. Genetic analysis of complex traits in the emerging Collaborative Cross. Genome Res. 2011. Aug;21(8):1213–22. doi: 10.1101/gr.111310.110. Epub 2011 Mar 15.. - DOI - PMC - PubMed
    1. Chan P, Mahler J. NTP technical report on the toxicity studies of Glyphosate (CAS No. 1071-83-6) Administered In Dosed Feed To F344/N Rats And B6C3F1 Mice. Toxic Rep Ser. 1992. Jul;16:1–D3. - PubMed
    1. Chen S, Li Y, Li X, Wu Q, Puig M, Moulin F, Gingrich J, Guo L. Metabolism and liver toxicity of cannabidiol. J Environ Sci Health C Toxicol Carcinog. 2024;42(3):238–254. doi: 10.1080/26896583.2024.2366741. Epub 2024 Jun 21. - DOI - PMC - PubMed
    1. Chesler EJ, Miller DR, Branstetter LR, Galloway LD, Jackson BL, Philip VM, Voy BH, Culiat CT, Threadgill DW, Williams RW, Churchill GA, Johnson DK, Manly KF. The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics. Mamm Genome. 2008. Jun;19(6):382–9. doi: 10.1007/s00335-008-9135-8. Epub 2008 Aug 21. - DOI - PMC - PubMed

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