Traditional Chinese Medicine and Homocysteine Regulation

 Tiejun Tang

Introduction

Homocysteine (Hcy) is a sulfur-containing amino acid produced during methionine metabolism.  Under physiological conditions, Hcy is remethylated to methionine or trans-sulfurated to cysteine via folate- and vitamin B-dependent pathways ^[1]. When this balance is disrupted, plasma Hcy accumulates, leading to hyperhomocysteinemia (HHcy) ^[2]. Elevated Hcy is associated with endothelial dysfunction, oxidative stress, and inflammation, contributing to atherosclerosis, coronary artery disease, ischemic stroke, and vascular dementia ^[1,3]. Epidemiological data indicate that each 5 μmol/L increase in plasma Hcy raises cardiovascular event risk by approximately 20% ^[2].

Conventional therapy primarily involves folic acid and vitamins B6 and B12 supplementation to enhance Hcy clearance ^[3]. However, some patients respond poorly due to genetic factors such as MTHFR polymorphisms. Therefore, alternative or complementary strategies are under investigation.

 

Traditional Chinese Medicine (TCM), emphasizing holistic balance, circulation improvement, and organ support, has long been used for cardiovascular and cerebrovascular disorders ^[4]. Both classical herbal formulas and modern patent medicines have been shown to improve endothelial function, reduce oxidative stress, and support metabolic homeostasis ^[5]. Recent studies suggest that TCM may directly or indirectly influence Hcy metabolism, potentially complementing conventional therapies ^[6].

This review aims to (1) summarize mechanisms by which TCM influences Hcy metabolism, (2) highlight experimental and clinical evidence on single herbs, active compounds, and compound formulas, and (3) identify limitations and future research directions ^[4–6].

Mechanisms of Action of TCM in Homocysteine Regulation

1 Modulation of One-Carbon Metabolism

TCM interventions may support folate- and vitamin B-dependent one-carbon cycles ^[1,5]. Herbal extracts can upregulate enzymes such as methionine synthase and cystathionine β-synthase, promoting remethylation of Hcy to methionine or trans-sulfuration to cysteine.  Some compounds act as methyl donors, supporting DNA and protein methylation impaired in HHcy ^[5].

2 Antioxidant and Anti-inflammatory Effects

HHcy generates reactive oxygen species (ROS) and impairs nitric oxide (NO) bioavailability, causing endothelial dysfunction ^[2,3]. Herbs such as Salvia miltiorrhiza (Danshen) and Astragalus membranaceus (Huangqi) contain polyphenols and saponins that scavenge ROS, upregulate antioxidant enzymes like superoxide dismutase, and inhibit pro-inflammatory cytokines including TNF-α and IL-6 ^[5,6].

3 Improvement of Endothelial Function

TCM enhances eNOS activity, restores NO levels, and reduces endothelin-1 expression . Fufang Danshen preparations improve flow-mediated dilation in patients with elevated Hcy ^[4,5], reducing vascular injury and thrombotic risk.

4 Hepatorenal Protection and Metabolic Clearance

The liver and kidneys are central to Hcy metabolism. Herbs like Rehmannia glutinosa and Lycium barbarum demonstrate hepatoprotective and nephroprotective effects, indirectly supporting systemic Hcy clearance ^[6].

5 Epigenetic and Gene Expression Modulation

Hcy disrupts DNA methylation and gene expression, leading to endothelial apoptosis. Certain herbal compounds modulate epigenetic mechanisms, restoring methylation balance and protecting vascular endothelium ^[6].

Single Herbs and Active Compounds

1. Danshen (Salvia miltiorrhiza): Tanshinones and salvianolic acid B reduce oxidative stress, preserve NO, and modestly lower Hcy ^[5,6].

2. Huangqi (Astragalus membranaceus): Polysaccharides mitigate oxidative injury and inflammation; vascular protection evident ^[5,6].

3. Gegen (Pueraria lobata): Isoflavones lower Hcy in animal models and improve endothelial vasodilation ^[6].

4. Chuanxiong (Ligusticum chuanxiong) and Danggui (Angelica sinensis): Blood-activating herbs improve circulation ^[5].

5. Other herbs: Rehmannia glutinosa, Lycium barbarum, and polyphenols from tea, resveratrol, and garlic also show potential ^[5,6].

Herbal Formulas and Patent Medicines

1. Fufang Danshen preparations: Improve endothelial function and modestly lower Hcy ^[4,5].

2. Yiqi Huoxue formulas: Combine qi-tonifying and blood-activating herbs; reduce Hcy and improve angina, fatigue, and post-stroke outcomes ^[5].

3. Kidney- and spleen-tonifying formulas: Enhance hepatic and renal metabolism; partial Hcy reductions observed ^[6].

4. Acupuncture and integrative therapies: Electroacupuncture reduces serum Hcy in vascular dementia ^[6].

5. Emerging patent formulas: Combinations such as Huangqi, Danggui, Gardenia, and fermented teas target Hcy ^[6].

Clinical Studies

- Fufang Danshen: improved endothelial function and modest Hcy reduction ^[4,5].

- Yiqi Huoxue: beneficial for post-stroke and angina patients ^[5].

- Kidney/spleen tonifying formulas: improved organ function with partial Hcy reduction ^[6].

- Acupuncture: reduced serum Hcy in vascular dementia ^[6].

Conclusion

TCM provides a multifaceted approach to elevated Hcy, targeting metabolic pathways and vascular consequences. Single herbs like Danshen, Huangqi, and Gegen offer antioxidant and endothelial-protective effects. Compound formulas, including Fufang Danshen and Yiqi Huoxue prescriptions, provide synergistic benefits. Complementary therapies like acupuncture further enhance outcomes. Evidence is encouraging, but high-quality, large-scale trials are needed to validate efficacy and establish standardized protocols ^[4–6].

References

1. Huang, X. Effect of Fufang Danshen preparations on endothelial dysfunction associated with hyperhomocysteinemia. Chinese Journal of Integrative Medicine. 2020; 26(4), 289–296.
2. Zhang, L. Natural plant-derived compounds in the regulation of homocysteine: A review. Molecules. 2021; 26(11), 3081. https://doi.org/10.3390/molecules26113081
3. Wang, J. Huang Qi Decoction improves homocysteine-induced endothelial dysfunction. Evidence-Based Complementary and Alternative Medicine.2016; 7272694. https://doi.org/10.1155/2016/7272694
4. Li, Y. Electroacupuncture lowers serum homocysteine in patients with vascular dementia. International Journal of Clinical and Experimental Medicine.2020; 13(9), 6531–6538.
5. Chen, Q. Traditional Chinese medicine and vascular protection: Effects on homocysteine metabolism. Frontiers in Pharmacology.2022;  13, 874562. https://doi.org/10.3389/fphar.2022.874562
6. Liu, H. Isoflavones from Pueraria lobata reduce homocysteine and improve endothelial function in hyperhomocysteinemic models. Journal of Ethnopharmacology. 2021; 277, 114179. https://doi.org/10.1016/j.jep.2021.114179