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The Fall and Rise of 黄连

Rhizoma Coptidis (RC), more commonly known as 黄连 is one of the coldest and most bitter herbs in Chinese Medicine. It’s strong properties of eliminating, drying and strengthening (苦泻、苦燥、苦坚) is used to clear heat, dry dampness and remove toxins (清热燥湿,泻火解毒). However, did you know that this herb was once banned by the Singapore government for 30 years? Why were we the only country to ban it? And what has happened since then?

Rhizoma Coptidis 黄连
Figure 1: Rhizoma Coptidis (黄连)

In 1965, RC was first brought into Singapore by Chinese immigrants. Given Singapore’s tropical climate, RC gained popularity as it was commonly used for ailments found here. At the same time, Singapore had begun mass screenings of G6PD deficiency in newborns[1].Through these screenings, it was found that RC increased the risk of complications for G6PD deficient newborns.


You may ask, what exactly is G6PD deficiency and how is it related to RC? Well, G6PD deficiency is a genetic disorder that causes red blood cells to break down (haemolysis), when exposed to certain foods, medicines or chemicals, which may lead to anaemia and jaundice[2]. Hence, babies with G6PD deficiency are more susceptible to these conditions. Concurrently, RC contains berberine, which is thought to promote haemolysis, especially in G6PD-deficient red blood cells[3]. Hence, it was thought that RC could potentially lead to more extensive haemolysis in G6PD-deficient infants, therefore resulting in higher risk of potentially fatal haemolytic anaemia and hypoxia (lack of oxygen).


Rhizoma Coptidis , Berberine, 黄连
Figure 2: Berberine (黄连素)

This was further evidenced through observations and case studies carried out to find the cause of G6PD Deficiency. In one such study, it was found that 22 out of 102 G6PD deficient neonates suffered from severe neonatal jaundice (NNJ) after exposure to TCM herbal medicines, particularly RC, in utero, as compared to 2 out of 34 for those without[1]. Hence, Chinese herbal medicine containing berberine (黄连素), specifically RC (黄连) was identified as one of the triggers of acute haemolysis in G6PD deficient babies. Due to this correlation, coupled with the rise in use of RC and number of G6PD cases, RC was subsequently banned under orders from the Department of Health (now MOH).


This ban sparked research projects throughout Hong Kong, Taiwan and China, to find out in detail the effects RC has on G6PD deficient individuals. After years of research, there was no clear association of RC with aggravation of anaemia or liver dysfunction, and that the rise of both RC and G6PD leaned towards a correlation without any specific analysis. Hence in 2012, the Berberine expert panel (taskforce created in Singapore) decided to progressively lift the ban, taking into account the sufficient safeguards available and the safety of berberine when used appropriately. In 2013, the local sale and use of Chinese Proprietary Medicines containing berberine was finally allowed. Consequently, in 2016, with the absence of major safety issues for 4 years, HSA further lifted the ban completely, to allow for the sale and import of herbs containing berberine[4].


The in-depth research on RC not only gave more clarity between its association with G6PD deficient individuals, but also shone light on its benefits and uses. For one, RC has shown to be effective against the infamous Helicobacter pylori (H.pylori) bacteria, which is a common cause of gastric inflammation, stomach ulcer or even stomach cancer[5]. RC contains protoberberine alkaloids, which include berberine, as well as other compounds such as coptisine, palmatine, epiberberine, jatrorrhizine (as shown in figure 3).


Figure 3: Structure of the 5 major alkaloids in RC

The 5 major alkaloids share the same isoquinoline parent structure characterized by quaternary nitrogen and aromaticity, contributing to their excellent anti-H.pylori and antimicrobial activity, allowing them to target and kill H.pylori effectively. Their effectiveness in decreasing order are: Coptisine, berberine, epiberberine, palmatine, jatrorrhizine[6].


Moreover, of these 5 alkaloids, coptisine is likely to be able to inhibit urease as well[6]. Urease is an enzyme that neutralizes the acidic environment of the human stomach, and this allows H.pylori to better survive, colonize and harm the stomach lining[7]. By inhibiting urease, the acidic conditions of the stomach would kill H.pylori, thus further helping to prevent/treat H.pylori infection, and prevent further complications.


RC has also been found to be a potential cardiovascular protective agent that is beneficial to the heart, with beneficial effects that can be used to significantly reduce the risk of cardiovascular diseases[8]. For one, it has been discovered to reduce blood lipid (fat) levels[9], such that it can slow down the onset of atherosclerosis, which is the thickening or hardening of the arteries caused by buildup of plaque containing fatty substances. As atherosclerosis can lead to coronary artery disease, heart attacks, strokes, or even death[10]. Through its anti-lipid and anti-atherosclerosis effect, RC can potentially reduce the risk of such cardiovascular diseases and its associated morbidities/mortalities. With potentially lower lipid levels, RC could reduce the risk of obesity, and potentially prevent related comorbidities such as hypertension, other cardiovascular diseases, and osteoarthritis etc[11].


Moreover, RC also showed to contain myocardial protective effect, meaning that it can help to protect the heart muscles (myocardium) from injuries such as myocardial ischemia-reperfusion injury[8], which involves inflammation, and possible damage of the heart tissues. This can help prevent or reduce further adverse heart complications, especially following loss of blood supply to the heart (myocardial ischemia), cardiac surgery or circulatory arrest (cardiac arrest/suspended blood flow)[12]. This safeguards and helps to retain heart function in such patients.


Other than its benefits in targeting H.pylori infections and cardiovascular diseases, RC and specifically berberine, has many other potential benefits. These include being able to reduce the risk of cancer through inhibiting proliferation of tumour cells, being able to treat diabetes by enhancing insulin sensitivity and even reducing inflammation for diseases such as infections and metabolic disorders. Moreover, it has also shown to contain neuroprotective effects[9] in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, cerebral ischemia, schizophrenia, and multiple sclerosis[13]. In Alzheimer’s disease, berberine was also found to significantly mitigate learning deficits[9]. But the most important question is: even with all these benefits of RC, is it still safe to use? Yes, it’s safe to use, provided it is under the supervision of a medically trained physician. After all, 黄连 is a medical herb, and just like any other medication, it is advisable not to self-medicate, but only do so under the instruction of a licensed physician. Should you have any doubts with regards to G6PD or 黄连 or any questions for that matter, feel free to approach any medically licensed physician.






References:


[1] Ho, C. E., Goh, Y. L., & Zhang, C. (2014, December 25). From prejudice to evidence: The case of Rhizoma Coptidis in Singapore. Evidence-Based Complementary and Alternative Medicine. https://www.hindawi.com/journals/ecam/2014/871720/


[2] Krans, B. (2018, September 17). G6PD test: Purpose, procedure, and follow-up. Healthline. https://www.healthline.com/health/glucose-6-phosphate-dehydrogenase#preparation


[3] Linn, Y. C. (2019, April). Did the herb cause this? - myths and facts about Chinese herbs. Singapore Medical Association - For Doctors, For Patients. https://www.sma.org.sg/news/2019/April/did-the-herb-cause-this---myths-and-facts-about-chinese-herbs


[4] HSA allows sale and import of Chinese herbs containing berberine from 1 April 2016. HSA. (2016, March 21). https://www.hsa.gov.sg/announcements/press-release/hsa-allows-sale-and-import-of-chinese-herbs-containing-berberine-from-1-april-2016#:~:text=The%20prohibition%20on%20the%20use,dehydrogenase%20(G6PD)%20deficient%20babies


[5] Mayo Foundation for Medical Education and Research. (2022, May 5). Helicobacter pylori (H. pylori) infection. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/h-pylori/symptoms-causes/syc-20356171


[6] Li, C., Huang, P., Wong, K., Xu, Y., Tan, L., Chen, H., Lu, Q., Luo, C., Tam, C., Zhu, L., Su, Z., & Xie, J. (2018, September 7). Coptisine-induced inhibition of helicobacter pylori: Elucidation of specific mechanisms by probing urease active site and its maturation process. Journal of enzyme inhibition and medicinal chemistry. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136390/#:~:text=Rhizoma%20Coptidis%20(the%20rhizoma%20of,pylori%2Drelated%20gastrointestinal%20diseases.


[7] Ansari, S., & Yamaoka, Y. (2017, April 12). Survival of helicobacter pylori in gastric acidic territory. Helicobacter. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851894/


[8] Tan, H.-L., Chan, K.-G., Pusparajah, P., Duangjai, A., Saokaew, S., Mehmood Khan, T., Lee, L.-H., & Goh, B.-H. (2016, October 7). Rhizoma Coptidis: A potential cardiovascular protective agent. Frontiers in pharmacology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054023/#:~:text=Rhizoma%20coptidis%20which%20contains%20alkaloids,obesity%20effect%20and%20anti%2Dhepatic


[9] Jin, Y., Khadka, D. B., & Cho, W.-J. (2015, December 4). Pharmacological effects of berberine and its derivatives: A patent update. Expert opinion on therapeutic patents. https://pubmed.ncbi.nlm.nih.gov/26610159/


[10] Martel, J. (2020, February 27). Atherosclerosis: Symptoms, causes, diagnosis, and treatment. Healthline. https://www.healthline.com/health/atherosclerosis#complications


[11] Nordisk, N. (2022, August 29). Complications/comorbidities of obesity. Discover the science to obesity for HCPs. https://www.rethinkobesity.global/global/en/weight-and-health/obesity-related-complications.html#:~:text=comorbidities%20of%20obesity-,Obesity%20related%20complications,Osteoarthritis


[12] Frank, A., Bonney, M., Bonney, S., Weitzel, L., Koeppen, M., & Eckle, T. (2012, February 23). Myocardial ischemia reperfusion injury: From basic science to clinical bedside. Seminars in cardiothoracic and vascular anesthesia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3457795/


[13] Imenshahidi , M., & Hosseinzadeh, H. (2020, July 10). Berberine neuroprotection and antioxidant activity. Oxidative Stress and Dietary Antioxidants in Neurological Diseases. https://www.sciencedirect.com/science/article/abs/pii/B9780128177808000141#:~:text=Berberine%20has%20the%20potential%20to,%2C%20schizophrenia%2C%20and%20multiple%20sclerosis.&text=%E2%96%AA-,The%20antioxidant%20capacity%20of%20berberine%20is%20the,mechanism%20in%20its%20neuroprotection%20properties.



Author: Edwin Chia & Jolene Oh

Video animation: Physician Eunice Aw

Chong Hoe Healthcare

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