Methyl eugenol (ME), a phenylpropanoid compound found in the essential oils of various aromatic plants, has recently garnered attention due to its significant antioxidant, anticancer, and neuroprotective properties. ME, commonly used in the fragrance and food industries, is also studied for its potential therapeutic effects, particularly in mitigating diseases associated with oxidative stress, such as Alzheimer’s disease, cancers, and ischemic brain injuries. However, despite its therapeutic promise, concerns regarding its toxicological effects, particularly hepatotoxicity and alterations in the gut microbiota, need to be addressed. This review explores the dual nature of ME as a potential therapeutic agent and its associated risks, underscoring the need for further research to balance its benefits and potential harm.
Occurrence and Biosynthesis
ME occurs naturally in a variety of plant species across several families, such as Apiaceae, Myrtaceae, and Lamiaceae. Its concentration varies significantly across species, with some plants, like Cinnamomum chordatum and Melaleuca species, containing high levels of ME in their essential oils. The biosynthesis of ME starts with phenylalanine, which is converted into eugenol through several enzymatic steps, culminating in the methylation of eugenol by eugenol O-methyltransferase to form ME. This biosynthetic pathway is key in understanding its natural occurrence and its potential for large-scale production in industrial applications.
Inhibition of Oxidative Stress
Oxidative stress results from an imbalance between reactive oxygen species (ROS) and antioxidant defenses, leading to cellular damage. ME has demonstrated notable antioxidant properties, primarily by modulating oxidative stress pathways. It activates nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response. ME facilitates Nrf2’s translocation to the nucleus, where it induces the expression of antioxidant genes, such as glutathione S-transferase A1, to protect cells from oxidative damage. ME also stabilizes Nrf2 by inhibiting its degradation, which results in reduced ROS levels and enhanced cellular protection in various models, including those of kidney damage and ischemic injury. The activation of the AMPK/GSK3β axis further contributes to the protective effects by enhancing Nrf2's nuclear retention, which underscores ME's potential as an antioxidant therapy.
Antiproliferative Effects
In addition to its antioxidant properties, ME has demonstrated antiproliferative and anticancer activity against various cancer types, including breast, colon, prostate, and skin cancers. ME induces autophagy and modulates key signaling pathways such as mTOR/PI3K/Akt, which are critical for tumor growth and survival. ME’s ability to trigger apoptosis and cell cycle arrest, particularly in cancer cells, makes it a promising candidate for cancer therapy. Furthermore, when combined with other compounds like myricetin, ME enhances the inhibition of cancer cell growth, showcasing its potential in synergistic cancer treatments.
Neuroprotective Properties
The neuroprotective effects of ME have been well-documented, especially in the context of neurodegenerative diseases like Alzheimer's and Parkinson's diseases. Oxidative stress plays a pivotal role in the progression of these diseases, and ME has shown promising results in mitigating neuronal damage. ME has been found to inhibit the formation of toxic protein aggregates in Alzheimer’s disease models and to reduce oxidative stress in brain tissue, improving neuronal survival. Additionally, ME has demonstrated neuroprotective potential in ischemic brain injury, reducing cerebral infarction and edema. These effects are attributed to ME’s ability to scavenge ROS, upregulate antioxidant enzymes, and modulate inflammatory responses, offering a multifaceted approach to neuroprotection.
Toxicological Effects of ME
Despite its therapeutic potential, ME also poses significant toxicological risks. In high concentrations, it has been shown to cause hepatotoxicity, as evidenced by increased liver enzymes and damage to liver tissues in animal studies. Prolonged exposure to ME can disrupt liver metabolism, including alterations in the TCA cycle and glutamate metabolism, which may lead to serious hepatic dysfunction. Additionally, ME has been linked to changes in the gut microbiota, further complicating its potential adverse effects. These findings underscore the importance of regulating ME use, particularly in agricultural and industrial applications, to prevent long-term health risks, especially among workers who may be chronically exposed to the compound.
Conclusions
Methyl eugenol has shown considerable promise as an antioxidant, anticancer, and neuroprotective agent, offering potential therapeutic benefits for diseases related to oxidative stress, such as Alzheimer’s disease and cancer. However, the toxicological risks, including hepatotoxicity and alterations in the gut microbiota, warrant caution in its application. More research is needed to explore the long-term effects of ME and its underlying molecular mechanisms to optimize its therapeutic potential while minimizing adverse effects. Clinical trials and studies focusing on safe dosages and formulations will be essential in determining the viability of ME in medical and industrial applications. Future studies should also focus on the development of ME derivatives or synergistic compounds that can maximize its benefits while mitigating toxicity.
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https://www.xiahepublishing.com/2835-6357/FIM-2024-00048
The study was recently published in the Future Integrative Medicine.
Future Integrative Medicine (FIM) publishes both basic and clinical research, including but not limited to randomized controlled trials, intervention studies, cohort studies, observational studies, qualitative and mixed method studies, animal studies, and systematic reviews.
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