含朱砂、雄黄的中成药，是药还是毒？

刘杰，陆远富，时京珍，张锋，吴芹（综述），康裕健（审校）

（1.University of Kansas Medical Center，Kansas City，KS，66160，USA；2.遵义医学院贵州省基础药理重点实验室，贵州 遵义 563003；3.贵阳中医学院中心实验室，贵州 贵阳 550004；4.University of Louisville，Louisville，KY，40292，USA，USA；5.四川大学华西医院再生医学中心，四川 成都 610041）

Introduction

Cinnabar（96%as HgS）and realgar（90%as As4S4）have been used in traditional Chinese medicines for thousands of years and are still used today［1］.However，both mercury（Hg）and arsenic（As）are highly toxic substances，and their safety and risk are of concern［2－4］.Approximate 150Chinese medicines are forbidden in the USA or European market because the contents of Hg and As are higher than the allowable limits in food and drugs.The Chinese Pharmacopeia Committee has reduced the allowable Hg and As contents in traditional Chinese medicines twice in recent years［5］，but Hg and As contents are still thousands fold over the health food standards，as Hg and As in traditional Chinese medicines comes mainly from intentional addition，presumably as an active ingredient in a given remedy.In 2007，Fu－Fang Lu－Hui Jiao Nang（复方芦荟胶囊）in England was found that mercury contents 117 000－fold over European Food Standards and was banned with serious punishments；in 2008，20%online－sold Ayurvedic medicines are found with heave metals over Food and Drug Administration Agency of the U.S.（FDA）limits and called for strict regulation［6］；in 2009，Wu－Bao－Wan（五 宝 丸 ）in Hong Kong market was found to have mercury over allowable limit and the residents were advised not to buy；in 2010，20%of traditional Chinese medicines in Dutch market were found with metals over the allowable limits and asked for rigorous regulation［7］，and in 2011，an editorial of“Southern China”（南方周末）called for removing of cinnabar and realgar from traditional Chinese medicines.Indeed，both Hg and As are toxic substances，but are cinnabar and realgar similar to well－known toxic Hg and As compounds？Are cinnabar and realgar remedies or poisons？This chapter summarizes recent progress of toxicological and pharmacological studies on this issue and discusses research perspectives.

Occurrence of cinnabar and realgar in traditional Chinese medicines

Cinnabar is the naturally occurring mineral with mercury in combination with sulfur，and is red in color，so called red mercury sulfide，or Zhu Sha（朱砂）.Cinnabar is insoluble and stable，and cinnabar powder has been used as an important ingredient in over 46traditional Chinese medicine recipes［1］.In general，the adverse effects at therapeutic doses of cinnabar－containing traditional Chinese medicines are rare and generally are tolerable and reversible［8，9］.An example of cinnabar－containing Zhu－Sha－An－Shen Wan（朱砂安神丸，20%cinnabar）and the chemical structures of cinnabar and toxic Hg compounds are given in Figure 1.

Realgar is also called red arsenic due to a deep red color，or Xionghuang（雄黄）.It contains＞90%tetra－arsenic tetra－sulfide and arsenic disulfide（As4S4，As2S2）and is widely used in combination with herbs and other traditional remedies for both external and internal uses［1］.The therapeutic uses of realgar－containing preparations range widely，from common colds，toothache and tonsillitis，asthma，abdominal pains，spasms，sedation， ulcers，heatstroke，coma，delirium，to malignancies［10］.In recent years，realgar is successfully used in combination with other traditional medicines such as Realgar－Indigo naturalis（俗称黄黛片）［11］or with western medicines such as Imatinib for hematologic malignancies［12］. An example of realgarcontaining Liu－Shen Wan（六 神 丸，13%realgar）and the chemical structures of realgar and toxic As compounds are illustrated in Figure 1.

Over hundreds of Chinese medicines contain cinnabar，realgar，or both as parts of active ingredients.Table 1lists examples of cinnabar（HgS）and realgar（As4S4）in traditional Chinese medicines，including well－known recipes containing cinnabar（e.g.，Zhu－Sha－An－Shen Wan），realgar（e.g.Liu－Shen Wan），or both（e.g.，An－Gong－Liu－Huang Wan，安宫牛黄丸）.The clinical uses of these patented Chinese medicines range widely，from brain disorders，inflammatory diseases，common cold，to malignancies.

These cinnabar－and realgar－containing Chinese medicines are sold in drug stores as non－prescription remedies in China，and they are also available in many Chinese grocery stories in the USA as“dietary supplements”.

Tab.1 Examples of traditional Chinese medicines containing cinnabar（HgS）and realgar（As4S4）.

Tig.1 Cinnabar and realgar in traditional Chinese medicines

Safety issues of cinnabar－and realgar－containing Chinese medicines

Although cinnabar－and realgar－containing traditional Chinese medicines have long history of clinical use，their efficacy，mechanisms of action，and toxicity are largely unknown.Both Hg and As are well－known for its acute and chronic toxicity［13］，and the toxicity of cinnabar－and realgarcontaining Chinese medicines has been reported from over dose，long－term use，and inappropriate preparations［8，14］.

Human toxicity reports from inappropriate use of cinnabar－and realgar－containing Chinese medicines are shown in Table 2based on available literature in PubMed.The toxicity from realgar and cinnabar has firstly been reported in 1990sfrom using traditional Chinese medicines［15］or Indian Ayurvedic medicines［16］.The main toxicity manifestations are liver injury and nephrotoxicity.Cinnabar also induces allergic responses in sensitive individuals，such as that in Tatto allergy response［17］.A lethal case was reported from inhalation of mercury vapor when cinnabar is heated［18］.Realgar－induced acute renal failure has been reported［19］，and chronic toxicities resulted from the long－term use of realgarcontaining Niu－Huang－Jie－Du Pian are reported［14］.The severe toxicity and lethal cases occurred when realgarcontaining Liu－Shen－Wan is given to infants in over dose［20］.

In animal studies，the toxicity potential of cinnabar and realgar－containing Chinese medicines varied according to the dose and duration of the exposure.Ototoxicity occurred after administration of cinnabar to mice［21］，rats［22］，and guinea pigs［23］，and the doses of cinnabar needed to produce ototoxicity are thousand－fold higher than MeHg［22，23］.In rats chronically dosed with cinnabar for months，liver and kidney injury occurred［24］，and the doses of cinnabar to produce toxicity are also hundred folds higher than HgCl2［25］.Longterm administration of cinnabar in mice also evoked immunotoxicity［26］，and the doses needed to produce chronic hepatotoxicity and nephrotoxicity in mice are hundred－fold higher than HgCl2and MeHg［27，28］.In general，at the clinically relevant doses，the toxicity responses of cinnabarand realgar－containing Chinese medicines are much less than Hg and As compounds，including acute toxicity studies of Liu－Shen－Wan［29］，Zhu－Sha－An－Shen Wan［30］，and An－Gong－Niu－Huang Wan［31］in mice and in cell cultures［32］，fortifying the note that the toxicity potential of cinnabar and realgar is quite different from toxic Hg and As compounds.

Cinnabar－and realgar－containing Chinese medicines are drugs，not food.However，these Chinese medicines are regulated as “dietary supplements”and available in some Chinese grocery stories.Taken Liu－Shen－Wan as an example，the oral dose for an adult is 30mg，but for food，if one takes 100g，there would be a 3000－fold over the therapeutic dose.Thus，the abuse of cinnabar－and realgar－containing Chinese medicines without doctor′s advice is a potential risk of toxicity，and the use of food standard to regulate Chinese medicines is inappropriate.

The reason for differential toxicity of cinnabar and realgar from Hg and As compounds relies on the chemical forms of the metal.For example，As－containing seafood are generally safe，as arsenic in the seafood is in the forms of arsenobetaine，arsenosugar，and arsenocholine，all are relatively non－toxic forms of organic arsenic［33］；in comparison，a small amount of arsenite or arsenic trioxide can be lethal［34］.Similarly，when discussing with mercurial，three major forms of mercurials should be distinguished［35］.MeHg and HgCl2are much more toxic than HgS［9］.Thus，the use of total mercury or total arsenic to evaluate the potential toxicity of cinnabar and realgar is inappropriate，as chemical forms of metals are major determinant factor for its disposition and toxicity.

Toxicokinetic mechanism of differential toxicity of cinnabar and realgar

The disposition of cinnbar and realgar is a major reason for the observed differential toxicities.A series of acute toxicity studies were performed to compare the differential toxicity and metal accumulation of cinnabar－and realgarcontaining Chinese medicines with Hg and As compounds.The investigated Chinese medicines include cinnabarcontaining Zhu－Sha－An－Shen Wan （20%cinnabar）［30］，realgar－containing Liu－Shen－Wan（13%）［29］，Niu－Huang－Jie－Du（6.4%）［36］，as well as Chinese medicines containing both cinnabar and realgar such as An－Gong－Niu－Huang Wan（10%cinnabar and 10%realgar）［31］，and Wan－Sheng－Hua－Feng Dan（10%cinnabar and 10%realgar）［37］.All these studies have clearly demonstrated that tissue accumulation of Hg and As from cinnabar and realgar are much less（20－100fold less）than common mercurial and arsenicals，indicating the pharmacokinetic mechanisms dominates the differential toxicity.

An explanation to this phenomenon would be differences in their solubility and bioavailability.Absorption of cinnabar（less than 0.2%）from the gastrointestinal tract is much less than HgCl2（7%－15%）and MeHg（95%）［9］（Table 3），resulting in much less tissue accumulation of Hg.Taken a chronic study in mice（6weeks）as an example，hepatic Hg accumulation from cinnabar was approximately 3600－fold lower than MeHg and 270－fold lower than HgCl2［28］.Absorption of realgar（2%－4%）is also much lower than arsenite（80%－90%）and arsenate（90%）［34］，corresponding to less tissue As accumulation.Taken realgar－containing Niuhuang Jiedu Pian as an example，only 1mg of intake（27 mg）As can reach blood［38］.Realgar has a low solubility in water，and only 4%is bioavailable in physiological gastric juice or intestinal fluids［38］.

Tab.2 Toxicity reports of cinnabar－and realgar－containing traditional Chinese medicines

Another reason for this differential Hg and As accumulation may be related to transporters.For example，renal uptake transporters（Oat1，Oatp4c1，and Oat3）were upregulated after HgCl2and MeHg，but not after cinnabar，similarly，the renal efflux transporters（MATE－2K，Mrp3）was increased much more after HgCl2and MeHg，but not after cinnabar（Lu et al.，manuscript in preparation）.Thus，differential regulation of transporters could be a mechanism for differential tissue uptake and efflux of Hg and As compounds.

It is generally assumed that the severity of poisoning is related to the total amount of poison ingested，and assessment of health risk associated with cinnabar（Hg）and realgar（As）exposure from human ingestion of traditional Chinese medicines has typically taken this tactic.In reality，the bioavailability is a critical determinant of efficacy and toxicity of Hg and As compounds.It is the amount of toxicants to the target organ，rather than the amount ingested or inhaled that makes a poison［39］.The bioaccessibility of cinnabar and realgar and the corresponding half－lethal dose（LD50）are listed in Table 3.

Tab.3 Disposition of cinnabar and realgar after in relation to their oral LD50

Solubility of cinnabar and realgar is the missing link that deserves more work in the future to resolve the differential properties of cinnabar and realgar as compared to common Hg and As compounds.

Cinnabar and realgar are active ingredients in Chinese medicines

Cinnabar and realgar are known toxic substances，should they be simply removed from Chinese medicines as suggested in an Editorial of Southern China（南方周末）in 2011？It is presumed that any intentional use of known toxic metals in medicine is an unacceptable risk，but an opposing opinion holds that cinnabar and realgar have a long history of clear pharmacological utility with tolerable side effects.To address this question，the pharmacological basis of using cinnabar and realgar in a given recipe needs to be elucidated，and the benefits and potential risk should be carefully considered and balanced.

It would be simple to remove cinnabar and realgar from a given recipe to avoid toxic effects.However，this is not easy.Taken Wan－Sheng－Hua－Feng Dan（万 胜 化 风 丹 ）as an example，which is used for brain diseases such as stock recovery.After reduction of cinnabar（60%）and realgar（65%）to meet Chinese allowable Hg and As limits，its efficacy is not as good as the original recipe，and the sale has been reduced more than 95%in recent years.It is found that the removal and reduction of cinnabar and realgar from Wan－Sheng－Hua－Feng Dan resulted in decreased efficacy towards lipopolysaccharide（LPS）－induced neuroinflamation in neuroglia cell cultures［40］.Thus，simply removal or reduction of cinnabar and realgar is not the way to solve the problem.

Cinnabar－and realgar－containing An－Gong－Niu－Huang Wan（安宫牛黄丸）is another example.Some reported that reduction or removal of cinnabar and realgar do not affect the effect against brain hemorrhage，some reported the effect of cinnabar and realgar in brain lactate dehydrogenase（LDH）isoenzymes are subtle，but many reported the removal of cinnabar and realgar resulted in decreased effects towards brain trauma，hemorrhage，inflammation［41］.It has been shown that in neuro－glia cell cultures，realgar is an active ingredient of An－Gong－Niu－Huang Wan to protect against LPS－induced proinflammatory factors production［42］.

Addition of cinnabar and realgar in Chinese medicines is aimed to achieve better therapeutic outcomes，not for decoration with their red color.Cinnabar is used for transquil in many Chinese medicines［1］.Pharmacological studies showed tranquil effects of cinnabar in mice and rats，and anticonvulsive effects against chemical－induced seizures in mice.Removal of cinnabar resulted in a decreased efficacy for cinnabar－containing Zhu－Sha－An－Shen－Wan in protecting against epinephrine and Wu－Tao（乌 头 ）induced cardiac arrhythmia in rabbits［43］.Pharmacological doses of cinnabar could affect brain 5－hydroxytryptamine（5－HT）metabolism，with reductions on brain 5－HT synthesis and release，which could be a mechanism for its sedative actions，but higher doses was ineffective［44］.

Realgar is well－known of its antitumor effects and acts as the main active ingredient in combination with other traditional medicines as Realgar－Indigo naturalis in the treatment of certain leukemia［11］.Realgar acts synergistically with Imatinib and other chemotherapeutic agents in the treatment of BCR／ABL－associated leukemia［12，45］， and synergistically with the PI3－K inhibitor PI－103to eradicate acute myeloid leukemia stem cells by inducing differentiation［46］.Some examples of the utility of cinnabar and realgar in Chinese medicines are listed in Table 4.Elucidation of pharmacological basis of realgar in antitumor effects is essential to justify its existence as an anticancer chemotherapy in a given Chinese medicine［10］.

The use of modern technology to dissect the pharmacological basis of using cinnabar and realgar in Chinese medicines remains a challenge to scientist.Herbogenomic approach［47］is a novel，clever concept that considers a given recipe as a“whole”and uses the modern technology to explore the molecular basis of a given recipe to define the molecular targets and mechanisms.Herbogenomic approach is a better strategy to study cinnabar and realgarcontaining Chinese medicines，leading to the discovery and development of novel therapeutics［8］.

Tab.4 Examples for cinnabar and realgar as active ingredients in Chinese medicines

Summary and perspectives

It is more and more clear that the use of the total metal content to evaluate the true risk and safety of Chinese medicines is inappropriate［5，28］.The chemical forms of metals in Chinese medicines underlie their absorption，distribution，biotransformation，and elimination，and will greatly affect their toxicology potentials.Well－designed studies are needed to evaluate the true risk of cinnabar－and realgar－containing traditional medicines［46］.

Traditional Chinese medicines are usually composed of several herbs and such mixtures represent challenges to pharmacologists and toxicologists.Herbogenomic approach［47］is a novel approach to solve the problem.After verifying the therapeutic effects of a given recipe，detailed dissecting of molecular targets and identifying active ingredients will be followed to find the right answer.Herbmetal interactions are very important in Chinese medicines to achieve desirable efficacy.Therefore，we should not only limit our focus on cinnabar and realgar，but also open the eyes on the whole preparations to understand any synergistic effects as in the case of relagar in the treatment of leukemias［11，12，45］.

It is important to keep in mind that the clinical efficacy and safety are very important.A large scale epidemiology survey would be preferred to evaluate the true risk and utility of cinnabar and realgar in Chinese medicines.The biomarkers of the exposure and speciation analysis of Hg and As are important aspects in human subject studies.Translational studies from bench－side to bed are important to support or reject the existence of cinnabar and realgar in Chinese medicines.

All substances are poisons and there are none that is not apoison.Only a right dose differentiates a remedy from a“poison”.It is important to balance the pharmacological effects and toxicity.Using apoison to attack another poison，especially for anticancer agents，is the philosophy of Chinese medicines.It is realgar′s toxic effects that are desired for therapeutic effects.To seek a balance between the efficacy and safety is very important in evaluation of metals in Chinese medicines.

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