How St. John's Wort Ingredients Harm Liver Cells

Greg Howard
15th January, 2024

How St. John's Wort Ingredients Harm Liver Cells

St. John's Worts

Photo adapted from: Marcin Zuwała / CC BY (Source)
St. John’s Wort is a herbal remedy commonly used to treat mild to moderate depression. While generally considered safe, there have been rare reports of liver damage (hepatotoxicity) in individuals taking it. The exact cause of this liver damage remains unclear, prompting research into the specific components of St. John’s Wort that might be responsible. A recent study conducted by researchers at the University of Basel[1] investigated the potential for liver cell damage caused by two of the main active ingredients in St. John’s Wort: hypericin and hyperforin, comparing their effects to those of citalopram, a commonly prescribed antidepressant. The study focused on how these substances affect mitochondria – often described as the ‘powerhouses’ of cells – and whether they induce oxidative stress, a process where harmful molecules damage cells. To perform this research, the team used two types of human liver cells in laboratory settings: HepG2 and HepaRG cells. HepaRG cells are particularly useful because, unlike many other liver cell lines, they closely resemble real liver cells in their function, including their ability to metabolize drugs[2]. The findings revealed a significant difference between hypericin, hyperforin, and citalopram. Hypericin proved toxic to cells at very low concentrations – starting to deplete ATP (the cell’s energy source) at just 5 micromolar in HepaRG cells and 20 micromolar in HepG2 cells. In contrast, hyperforin and citalopram showed no toxicity even at much higher concentrations (100 micromolar). This suggests that hypericin is the primary component of St. John’s Wort likely responsible for any potential liver damage. Further investigation showed that hypericin directly damages mitochondria. It reduced the rate at which mitochondria produce energy, specifically by interfering with several key parts of the electron transfer system (complexes I, II, and IV). This disruption led to an increase in the production of superoxide, a type of reactive oxygen species (ROS) that causes oxidative stress. The study also found that hypericin reduced levels of protective molecules within the mitochondria, such as superoxide dismutase 2 (SOD2) and thioredoxin 2 (TRX2), and decreased levels of glutathione, a crucial antioxidant[3]. These findings align with previous research showing that citalopram can also induce oxidative stress and mitochondrial dysfunction in the liver[4], although the mechanism appears to be different, with citalopram’s effects being less directly targeted at the mitochondria themselves. Interestingly, the damage caused by hypericin didn’t trigger apoptosis (programmed cell death), but instead led to necrosis – a more uncontrolled form of cell death. The study also observed a reduction in mitochondrial DNA copy number, indicating damage to the mitochondria’s genetic material. These results suggest that hypericin’s toxicity stems from its direct impact on mitochondrial function, leading to energy depletion, oxidative stress, and ultimately, cell death. This mechanism could explain the rare cases of liver toxicity observed in patients taking St. John’s Wort preparations. It’s important to note that the study did not investigate the potential for interactions between hypericin and other components of St. John’s Wort, or how individual susceptibility might influence the risk of liver damage. However, it provides a crucial step towards understanding the potential risks associated with this widely used herbal remedy. Furthermore, the study builds on previous work demonstrating that drug-induced liver damage can occur even without severe disruption of mitochondrial fatty acid oxidation[5], highlighting the complexity of the mechanisms involved in drug-induced liver injury. The focus on mitochondrial toxicity and oxidative stress provides a specific pathway to investigate and potentially mitigate the risks associated with St. John’s Wort use.

MedicineBiotechBiochem

References

Main Study

1) Mechanisms of hepatocellular toxicity associated with the components of St. John's Wort extract hypericin and hyperforin in HepG2 and HepaRG cells.

Published 12th January, 2024

https://doi.org/10.1016/j.toxlet.2024.01.008

Related Studies

2) Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells.

Journal: Drug metabolism and disposition: the biological fate of chemicals, Issue: Vol 34, Issue 1, Jan 2006

3) The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway.

https://doi.org/10.1128/MCB.00099-20

4) In vitro and in vivo evaluation of the mechanisms of citalopram-induced hepatotoxicity.

https://doi.org/10.1007/s12272-016-0766-0

5) Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity.

https://doi.org/10.1007/s10565-020-09537-1


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