7-Hydroxycannabidiol and 7-carboxycannabidiol induced cytotoxicity via apoptosis and endoplasmic reticulum stress in human hepatic cells

Yuxi Li; Xilin Li; Qiangen Wu; Montserrat Puig; Frederic Moulin; Supratim Choudhuri; Jeremy Gingrich; Lei Guo; Si Chen

doi:10.1007/s00204-025-04001-7

7-Hydroxycannabidiol and 7-carboxycannabidiol induced cytotoxicity via apoptosis and endoplasmic reticulum stress in human hepatic cells

Arch Toxicol. 2025 Jun;99(6):2627-2638. doi: 10.1007/s00204-025-04001-7. Epub 2025 Mar 3.

Authors

Yuxi Li¹, Xilin Li², Qiangen Wu¹, Montserrat Puig³, Frederic Moulin⁴, Supratim Choudhuri⁵, Jeremy Gingrich⁵, Lei Guo¹, Si Chen⁶

Affiliations

¹ Division of Biochemical Toxicology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), 3900 NCTR Road, Jefferson, AR, 72079, USA.
² Division of Genetic and Molecular Toxicology, NCTR, U.S. FDA, Jefferson, AR, 72079, USA.
³ Division of Biotechnology Review and Research III, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. FDA, Silver Spring, MD, 20993, USA.
⁴ Division of Hepatology and Nutrition, Office of New Drugs, Center for Drug Evaluation and Research, U.S. FDA, Silver Spring, MD, 20993, USA.
⁵ Division of Food Ingredients, Office of Pre-Market and Additive Safety, Office of Food Chemical Safety, Dietary Supplements, and Innovation, Human Foods Program, U.S. FDA, College Park, MD, 20740, USA.
⁶ Division of Biochemical Toxicology, National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), 3900 NCTR Road, Jefferson, AR, 72079, USA. si.chen@fda.hhs.gov.

Abstract

Cannabidiol (CBD), a major component of extract from the plant Cannabis sativa L., has demonstrated efficacy in treating childhood-onset epilepsy; however, animal studies and clinical trials have reported elevated liver enzymes after CBD use, suggesting potential liver toxicity. In a previous study, we demonstrated that CBD caused cytotoxicity with apoptosis and endoplasmic reticulum (ER) stress in human hepatic cells. In the present study, we investigated the toxicity profile of the two main metabolites of CBD, 7-hydroxy-CBD and 7-carboxy-CBD, in primary human hepatocytes and HepG2 cells. Our findings indicated that both metabolites induced cellular damage similar to the parent drug in these cells. 7-Hydroxy-CBD and 7-carboxy-CBD also caused cell cycle disturbances, apoptosis, and ER stress in HepG2 cells. Additionally, we explored the role of cytochrome P450 (CYP) in the metabolism of 7-hydroxy-CBD and 7-carboxy-CBD using HepG2 cell lines expressing 14 individual CYPs. We determined that 7-hydroxy-CBD is metabolized by CYP2D6, and CYP2D6-mediated metabolism attenuated the cytotoxicity, apoptosis, and ER stress induced by 7-hydroxy-CBD. The CYPs did not metabolize 7-carboxy-CBD. In summary, our findings highlight the mechanisms underlying cytotoxicity induced by 7-hydroxy-CBD and 7-carboxy-CBD in hepatic cells.

Keywords: 7-Carboxy-CBD; 7-Hydroxy-CBD; Apoptosis; CYP-overexpressing cells; ER stress; HepG2; Primary human hepatocytes.

MeSH terms

Apoptosis* / drug effects
Cannabidiol* / analogs & derivatives
Cannabidiol* / metabolism
Cannabidiol* / toxicity
Cytochrome P-450 Enzyme System / metabolism
Endoplasmic Reticulum Stress* / drug effects
Hep G2 Cells
Hepatocytes* / drug effects
Hepatocytes* / metabolism
Hepatocytes* / pathology
Humans

Substances

Cannabidiol
Cytochrome P-450 Enzyme System
7-hydroxycannabidiol

Grants and funding

FD999999/ImFDA/Intramural FDA HHS/United States