Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 7, 2008; DOI: 10.1124/jpet.108.139543
0022-3565/08/3262-363-368$20.00
JPET 326:363-368, 2008
PERSPECTIVES IN PHARMACOLOGY
Mineral Arsenicals in Traditional Medicines: Orpiment, Realgar, and Arsenolite
Jie Liu,
Yuanfu Lu,
Qin Wu,
Robert A. Goyer, and
Michael P. Waalkes
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, Centers for Cancer Research, National Cancer Institute at National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina (J.L., R.A.G., M.P.W.); and Department of Pharmacology, Zunyi Medical College, China (Y.L., Q.W.)
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Abstract
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Mineral arsenicals have long been used in traditional medicines for various diseases, yet arsenic can be highly toxic and carcinogenic. Arsenic in traditional medicines typically comes from deliberate addition for therapeutic purposes, mainly in the form of mineral arsenicals, including orpiment (As2S3), realgar (As4S4), and arsenolite (contains arsenic trioxide, As2O3). Inorganic arsenic is now accepted in Western medicine as a first line chemotherapeutic agent against certain hematopoietic cancers. This perspective analyzes the pharmacology and toxicology of these arsenicals used in traditional medicines. Orpiment and realgar are less soluble and poorly absorbed from the gastrointestinal tract, whereas the bioavailability of arsenic trioxide is similar to inorganic arsenic salts such as sodium arsenite. Pharmacological studies show that arsenic trioxide and realgar are effective against certain malignancies. Orpiment and realgar are used externally for various skin diseases. Realgar is frequently included as an ingredient in oral traditional remedies for its antipyretic, anti-inflammatory, antiulcer, anti-convulsive, and anti-schistosomiasis actions, but the pharmacological basis for this inclusion still remains to be fully justified. Toxicological studies show that cardiovascular toxicity is the major concern for arsenic trioxide and that the gastrointestinal and dermal adverse effects may occur after prolonged use of mineral arsenicals. Little is known regarding the possible secondary cancers resulting from the long-term use of any of these arsenicals. Similar to the safety evaluation of seafood arsenicals, total arsenic content alone appears to be insufficient for mineral arsenical safety evaluation. Arsenic speciation, bioavailability, and toxicity/benefit should be considered in evaluation of mineral arsenical-containing traditional medicines.
Traditional medicines, mainly Chinese medicines and Indian Ayurvedic medicines, are becoming more and more popular as alternative and supplementary remedies over recent years (Kumar et al., 2006
; Efferth et al., 2007). Toxic metals or metalloids, such as lead, mercury, and arsenic, are frequently found in traditional medicines, raising justifiably escalating public concerns (Ernst, 2002; Cooper et al., 2007). Indeed, at least for arsenicals, many traditional medicines call for intentional addition of mineral arsenicals based on their presumed or defined therapeutic properties (Ernst, 2002; Miller et al., 2002; Evens et al., 2004; Chinese Pharmacopeia Committee, 2005; Efferth et al., 2007). However, arsenic is a known human carcinogen producing cancers of the skin, lung, urinary bladder, liver, kidney, and possibly other sites (National Research Council, 1999; IARC, 2004) and has many other profound toxic effects following short-term or long-term exposure (National Research Council, 1999; Agency for Toxic Substances and Disease Registry, 2005; Liu et al., 2007). The general perception is that intentional addition of a known carcinogen to any medicine is a preposterous risk. The conundrum is that arsenicals have a long and remarkable history of pharmacology utility. Nonetheless, arsenic used in traditional medicines alarms the public, and this perspective will first assess the available database on mineral arsenicals in traditional medicines and then attempt to analyze their risk in light of their potential benefit.
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Use of Mineral Arsenicals in Traditional Medicines
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Arsenic has been used as a poison and as a therapeutic since ancient times (Miller et al., 2002; Agency for Toxic Substances and Disease Registry, 2005; Liu et al., 2007). In ancient Chinese medicines, the use of arsenic can be traced back to 200 B.C. in Shen Nong Ban Cao Jing, the first traditional Chinese medicine book. Using a poison to attack another poison or to fight against malignant diseases is a common concept in traditional Chinese medicines (Evens et al., 2004; Chinese Pharmacopeia Committee, 2005). The use of mineral elixir made from the "essence of the five planets," including arsenic-containing minerals, was thought to give humans perpetual life in Indian Ayurvedic medicines (Kumar et al., 2006). Table 1 lists properties of the three major arsenic-containing minerals used in traditional medicines. These arsenicals include orpiment, which is also called yellow arsenic, Arsenikon (Greek) or Cihuang (China), and contains As2S3. Another is realgar, which is also called red arsenic due to a deep red color, or Xionghuang (China), and contains >90% arsenic disulfide (As2S2) or As4S4. Arsenolite, which is the third common mineral arsenical called white arsenic, contains largely As2O3. Physicians prescribed arsenicals for both external and internal use throughout the 19th century (Miller et al., 2002; Evens et al., 2004). Arsenic and arsenic salts were key ingredients in antiseptics, antispasmodics, hematinics, sedatives, ulcer, and cancer cures. Arsenical preparations, such as Fowler solution (1% potassium arsenite), were used by many physicians in the treatment of malignant diseases, such as leukemia, Hodgkin's disease, pernicious anemia, and nonmalignant diseases, such as psoriasis, pemphigus, eczema, and asthma for centuries (Miller et al., 2002; Evens et al., 2004). Arsphenamine was the standard therapy for syphilis for nearly 40 years before it was replaced by penicillin. Approximately 60 different arsenic preparations have been developed and used during the lengthy pharmacological history of arsenic until their uses were gradually replaced by more effective and less toxic modern agents (Miller et al., 2002; Evens et al., 2004; Efferth et al., 2007). Today, hundreds of traditional Chinese medicines still use orpiment, realgar, or arsenolite, and realgar alone is included in 22 oral remedies based on Chinese Pharmacopeia Committee (2005). In Indian Ayurvedic medicines, realgar is also a major component in bhasmas (Mitra et al., 2002; Kumar et al., 2006). Arsenic trioxide is now becoming a very promising chemotherapeutic agent in Western medicine to treat acute promyelocytic leukemia (APL) and possibly other malignancies (Miller et al., 2002; Evens et al., 2004; Hede, 2007).
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Arsenic Species and Their Short-Term Toxicity
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Arsenic exists in the trivalent and pentavalent forms and is widely distributed in nature. The most common toxic inorganic arsenic compounds are sodium arsenate (As5+) and sodium arsenite (As3+). In the body, arsenate can be reduced to arsenite, followed by conjugative methylation reaction to form monomethylarsononous acid (MMA), then dimethylarsinic acid (DMA), and finally trimethylarsonic acid (TMA), with these methylated species found in urine (Fig. 1A) (Liu et al., 2007). Arsenic toxicity is highly dependent on the chemical form, and where known, the acute oral LD50 values in rodents are also included under each arsenic compound in Fig. 1. In general, sodium arsenate (LD50 112–175 mg/kg) is four to five times less acutely toxic than sodium arsenite (LD50 15–44 mg/kg), and the pentavalent organic arsenicals, MMA (LD50 960 mg/kg), DMA (LD50 650 mg/kg), and TMA (LD50 10.6 g/kg), are 40 to 100 times less acutely toxic than arsenite (Kreppel et al., 1993; Agency for Toxic Substances and Disease Registry, 2005). Arsenicals in seafood mainly exist as organic forms (Fig. 1B), such as arsenobetaine (LD50 10 g/kg), arsenosugar (not available), and arsenocholine (LD50 6.5 g/kg) (Borak and Hosgood, 2007), with acute oral LD50 values 100 to 500-fold above arsenite or arsenate. In traditional medicines, natural arsenic-containing minerals are used as drugs, such as orpiment, realgar, and arsenolite (Fig. 1C). The oral LD50 for arsenic trioxide (i.e., arsenolite) in mice is 33 to 39 mg/kg (Carter et al., 2003), similar to sodium arsenite, but the LD50 for realgar is 3.2 g/kg, a difference of 100-fold compared with sodium arsenite (Zhang et al., 2004). The oral LD50 for orpiment is not available, possibly because orpiment is mainly for external use (Chinese Pharmacopeia Committee, 2005). The wide range of LD50 values among different arsenicals clearly indicates that mineral arsenical toxicity is highly dependent on the chemical form.
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Fig. 1. Acute oral toxicity (LD50) of arsenicals in rodents. A, common inorganic arsenicals and their organic arsenical metabolites. B, arsenic species in seafood. C, mineral arsenicals. N/A, LD50 data are not available.
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Bioavailability of Orpiment, Realgar, and Arsenolite/Arsenic Trioxide
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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 arsenic exposure from human ingestion of traditional medicines has typically taken this tactic (Ernst, 2002; Cooper et al., 2007). However, in many cases, a significant portion of some forms of mineral arsenicals are poorly absorbed into the body and would be unavailable to cause systemic damage. The disposition of these arsenicals in the body depends on various key factors, including solubility, absorption, distribution, and excretion. Table 2 lists the available data on disposition of these mineral arsenicals.
Orpiment has low solubility in water. Orpiment dissolution is kinetically slow and under anaerobic conditions; an increase in pH increases orpiment dissolution rate (Floroiu and Davis, 2004). For instance, in aqueous solution, more arsenic from orpiment is dissolved at pH 7 than at pH 4 (Marafante and Vahter, 1987). When orpiment is incubated in a cell culture media, 3% arsenic is released, which is actually decreased in the presence of pulmonary macrophages (Lantz et al., 1995). Macrophages engulf particles into phagosomes, which have an acidic milieu (Floroiu and Davis, 2004). Orally administrated orpiment is poorly absorbed, and over 82% is found in feces within 3 days, representing an unabsorbed portion of the dose compared to only 12% of an oral dose of sodium arsenate. Urinary arsenic metabolites from oral orpiment exposure are mainly DMA, suggesting that the bio-transformation of absorbed orpiment arsenicals occurs in the body (Marafante and Vahter, 1987).
Realgar in Niuhuang Jiedu Pian, a common preparation for a common cold, has a low solubility in water, and only 4% is bioavailable in physiological gastric juice or intestinal fluid (Koch et al., 2007). The average total arsenic concentration in a Niuhuang Jiedu Pian is approximately 7 ± 1% (i.e., 70,000 ppm), corresponding to 28 mg of arsenic per pill, of which only 1 mg of arsenic finds its way into the blood stream, and 40% of this absorbed arsenic (0.4 mg) is excreted in urine (Koch et al., 2007). Realgar exposure results in various arsenical metabolites in the urine, including MMA, DMA, arsenobetaine, and an unknown metabolite, the level of which peaked at approximately 14 h after ingestion (Koch et al., 2007). In healthy volunteers, <1% of total administered arsenic was found in the urine after repeated doses of Niuhuang Jiedu Pian (three tablets, twice a day) during a 7-day period (Tang and Wang, 2005). Oral administration of realgar in rats (150 mg/kg, daily for 5 weeks) showed that only a small portion of arsenic was absorbed and reached the blood (45 mg/ml), lung (5.4 mg/g), spleen (5.2 mg/g), or liver (2.9 mg/g) (Tang and Wang, 2005). To overcome the low solubility and poor bioavailability, realgar nanoparticles have been prepared by cryogrinding with polyvinylpyrrolidone and SDS, and arsenic solubility can greatly be increased compared to crude realgar powder (Wu and Ho, 2006). Realgar nanoparticles show remarkable increases in bioavailability both in vitro and in vivo. For example, urinary recovery of arsenic in rats after a single oral administration of realgar nanoparticles (50 mg/kg p.o.) was increased to 70% of the dose compared to 25% when realgar was given in crude powder (Wu and Ho, 2006).
Arsenic trioxide, purified from mineral arsenolite, is highly water-soluble and well absorbed after oral dose. Thus, the oral LD50 in mice for arsenic trioxide is very close to that of sodium arsenite (Carter et al., 2003). Pharmacokinetic studies in humans show that after arsenic trioxide infusion (10 mg/day i.v.) for 
90 days for cancer chemotherapy, blood arsenite levels reached steady state of 5.5 to 7.3 µM (Shen et al., 1997). In another study, patients received repeated administrations of arsenic trioxide at similar doses and duration, plasma concentration of arsenic reached a stead state after 4 weeks of treatment, and 60% arsenic dose was excreted in urine in the forms of arsenite (14%), arsenate (7%), MMA (19%), and DMA (21%) (Fujisawa et al., 2007). Compared to intravenous administration, orally given arsenic trioxide can achieve similar mean plasma levels (Kumana et al., 2002), an indication of its high level of absorption from the gastrointestinal tract.
It is clear that solubility and bioavailability of orpiment and realgar are poor compared to arsenic trioxide (i.e., arsenolite), but the preparation can have a major impact as seen with realgar (i.e., nanoparticles versus crude powder), and when realgar is included in traditional medicines, its bioavailability can be affected by other herbal components. For example, the individual herbs in Angong Niuhuang Wan can reduce arsenic release from realgar by 25 to 55% (Tang and Wang, 2005). Absorbed arsenic from orpiment or realgar does appear in the blood but with much less distribution to the tissues due to poor absorption. Arsenic from mineral arsenicals, once absorbed, can be acted upon to produce arsenical metabolites, including primarily DMA (Marafante and Vahter, 1987; Fujisawa et al., 2007; Koch et al., 2007). The bioavailability is a critical determinant of efficacy and toxicity of arsenical compounds. Thus, it is not surprising that realgar and orpiment have quite different toxicological profiles from arsenic trioxide.
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Pharmacology of Orpiment, Realgar, and Arsenolite/Arsenic Trioxide
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Mineral arsenicals have long history of therapeutic use in traditional medicines (Evens et al., 2004; Kumar et al., 2006; Efferth et al., 2007). Table 3 lists some examples of mineral arsenicals still used today in traditional remedies based on Chinese Pharmacopeia Committee (2005).
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TABLE 3 Examples of orpiment, realgar, and arsenolite/arsenic trioxide in traditional medicines
All of the recipes and uses are based on Chinese Pharmacopeia Committee (2005).
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Orpiment is mainly used externally as louse-killer, a cure for scabies, snake bites, insect stings, and skin diseases (Chinese Pharmacopeia Committee, 2005; Koch et al., 2007). Orpiment is included in Quingyi Piwen Dan, a preparation of detoxication and laxative use with other 74 herbs, but its use alone in oral remedies is not common. Nanoparticles of orpiment were prepared, and they were effective in killing leukemia K562 cells in vitro (Lin et al., 2007). Additional study is required with these orpiment nanoparticles because the absorption of arsenic from nanoparticle preparations are greatly enhanced.
Realgar is widely used in the combination with traditional medicines for both external and internal uses based on Chinese Pharmacopeia Committee (2005), and some examples are listed in Table 3. For example, the most common over-the-counter preparation Niuhuang Jiedu Pain contains 6.4% realgar, and the bioavailability of arsenic released from this preparation is very low (Koch et al., 2007). The therapeutic uses of these preparations range widely, for instance, for common colds, toothache, and tonsillitis, asthma, abdominal pains, spasms, sedation, ulcers, heat stroke, coma, and delirium. Few pharmacologic studies on these preparations are found in the English literature. The interactions of realgar with other herbs or minerals, such as cinnabar (HgS), in many cases are unknown. In this perspective, only the anticancer effects of realgar are briefly discussed. To enhance therapeutic efficacy and reduce adverse effects, physicians of traditional Chinese medicine prescribe the combination formulae of plant species/minerals based on clinical experience, and thousands of such formulae have been recorded (Wang et al., 2008). For example, Awei Huapi Gao, a preparation containing 4% realgar, appears effective against "lumps" or various malignancies in traditional therapies. Since the 1960s, realgar-containing preparations, such as Fufan Qingdai Pian, Kebai Dan, Manli Pian, etc., have been successfully used in the treatment of certain types of acute and chronic leukemia (Chen et al., 2000). When the realgar amount is doubled, as in Fufan Qingdai Pian, a better antitumor response is achieved (Chen et al., 2000). Realgar is less toxic compared to arsenic trioxide and is now used alone or in combination for hematologic malignancies (Lu et al., 2002; Shen et al., 2004). Recently, Realgar-Indigo naturalis formulae have been shown to be very effective against promyelocytic leukemia (Wang et al., 2008). Realgar acts as the principal component of the formula, whereas other plant active ingredients (such as indirubin and trashinone IIA) serve as adjuvant ingredients in inducing acute promyelocytic leukemia cell differentiation and the degradation/ubiquitination of promyelocytic leukemia-retinoic acid receptor-
oncoprotein, in enhancing G1/G0 arrest in APL cells through hitting multiple targets, and in intensifying aquaglyceroporin-9 expression and thus facilitating transportation of realgar into APL cells (Wang et al., 2008).
Arsenolite is traditionally used for removing lump or "scrofula" and is included in Ailin Yihao as a modification of Chinese Pharmacopeia Committee (2005) in the treatment of acute promyelocytic leukemia (Shen et al., 1997; Chen et al., 2000). Arsenic trioxide is an example of how an active ingredient is identified, purified, and successfully used to treat cancers with stunning efficacy (Miller et al., 2002; Hede, 2007). This is indeed a remarkable story of where traditional and modern medicines intersected to provide a cure for a once deadly disease. Arsenic trioxide is currently a first line chemotherapeutic in Western medicine for the treatment of certain leukemias, particularly in the treatment of drug-resistant and relapsed acute promyelocytic leukemia (Miller et al., 2002; Evens et al., 2004; Hede, 2007). In addition to the effective use for hematological malignancies, arsenic trioxide plus buthionine sulfoximine (a cellular GSH depleter) is also effective against solid tumor cells (Maeda et al., 2004). Arsenic trioxide is also effective against metastatic cervical cancers (Yu et al., 2007). New studies on chemotherapy with arsenic trioxide are underway (Hede, 2007).
In traditional medicine-based therapy, patient treatment commences without any experimental phase in the laboratory. The Western concept of "from bench to bedside" does not fit in the clinical practice of traditional remedies (Efferth et al., 2007). Nonetheless, the pharmacological basis for mineral arsenical inclusion in traditional medicine still remains to be fully justified.
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Toxicology of Orpiment, Realgar, and Arsenolite/Arsenic Trioxide
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Arsenicals have been known as Poisons of the King since ancient times, and it has a variety of short-term and long-term toxic effects, such as skin lesions, vascular toxicity, respiratory, renal, and liver toxicity, most importantly, the carcinogenic potential (IARC, 2004; Agency for Toxic Substances and Disease Registry, 2005). The wide range of LD50 among mineral arsenicals (Fig. 1) points toward the need to discuss the toxicology of mineral arsenicals individually (Table 4).
Intraperitoneal administration of orpiment was negative in mouse bone marrow cell micronucleus assay, despite the resultant of very high blood arsenic levels (900 ng/ml) (Tinwell et al., 1991). Intratracheal administration of orpiment (3.75 mg/kg, once a week for 15 weeks) in hamsters did not increase lung tumor incidence (Yamamoto et al., 1987). No toxicity reports in humans were identified from the literature, but the toxic potential of orpiment is generally thought to be greater than realgar (Chinese Pharmacopeia Committee, 2005).
Realgar is widely used externally and internally in combination with other traditional medicines. Many of these preparations are commercially available in drug stores without prescription, and in general, they are safe with very few reports on their toxicities or adverse effects. However, skin lesions and dermal adverse effects are reported from the long-term use of realgar-containing medicines, such as Niuhuang Jiedu Pian (Ernst, 2002; Wang, 2005). In humans chronically taking realgar-containing traditional medicines at higher doses, mild gastrointestinal discomfort may occur; however, no myelosuppression was observed (Lu et al., 2002). The major concern for high dose and long-term realgar treatment in humans is cardiac toxicity, manifested as prolonged QT wave, which is a dose-dependent finding. However, this side effect is tolerable and reversible (Shen et al., 2004). Liver is a major target organ of long-term arsenic toxicity, and the long-term use of realgar in humans may cause fatty liver; however, neither liver fibrosis nor dysfunction was observed (Qin et al., 2006). When realgar-containing Indian medicine Swarnabhasma (gold ash) was administered to mice for 8 weeks, no apparent long-term toxicity (as evidenced by serum aminotransferases, urea and creatine levels, and histopathology) was evident (Mitra et al., 2002). However, the well designed dose- and time-related toxicology studies are required to critically evaluate the toxicology profiles of realgar-containing traditional medicines.
Arsenic trioxide is highly toxic compared to orpiment and realgar. Short-term toxicity of arsenic trioxide is the major concern in the use of this agent to against malignancies, and at least three sudden deaths have been reported (Westervelt et al., 2001). Prompt chelation treatment is beneficial for short-term arsenic trioxide intoxication; for example, there was a potentially lethal case in which a patient ingested with 9000 mg of arsenic trioxide was rescued by prompt emergency care, forced diuresis, and chelation therapy with 2,3-dimercaptopropanol and meso-2.3-dimercaptopropanol (Vantroyen et al., 2004). The clinical doses of arsenic trioxide (5–10 mg i.v.) could induce cardiac injury, such as QT prolongation, arrhythmias, and, in extreme cases, cardiac arrest (Westervelt et al., 2001; Evens et al., 2004; Chou and Dang, 2005). Other adverse effects include skin lesions, gastrointestinal symptoms (Miller et al., 2002; Chou and Dang, 2005), neuropathy, and liver dysfunction are reported with long-term arsenic trioxide use (Miller et al., 2002; Evens et al., 2004; Chou and Dang, 2005) and are generally tolerable and reversible. In a long-term study in rabbits, arsenic trioxide at a dose of 0.2 mg/kg i.v. for 30 days produced cardiac injury, with alterations in cardiac function. These adverse effects are reversible after the termination of arsenic trioxide treatment (Wu et al., 2003). Possible secondary cancers have not been reported in patients receiving arsenic trioxide (Miller et al., 2002; Evens et al., 2004; Chou and Dang, 2005). However, arsenic-induced cancers may have a long latent period, and the longer time monitoring is needed to verify the carcinogenesis effects of arsenic trioxide or realgar used in traditional remedies.
"The dose makes a poison". In the evaluation of the toxic effects of mineral arsenicals, dose and duration of administration should be critically considered. Although mineral arsenicals in traditional medicines are beneficial and even curative of various diseases, it should be kept in mind that "the right dose differentiates a remedy from a poison". Another important consideration is to balance the benefit and risk. Arsenic trioxide is highly toxic, but to save a life from malignancies, the use of a poison like arsenic trioxide may be justified.
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Summary
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This perspective discussed mineral arsenicals used in traditional medicines. Orpiment and realgar have quite different chemical features and solubility from arsenolite/arsenic trioxide. The bioavailability of orpiment and realgar are low; however, arsenolite/arsenic oxide is high. Pharmacologic data indicate that the use of orpiment and realgar in traditional medicines may be desired in some cases; however, the therapeutic basis in most instances remains to be fully justified. Arsenolite/arsenic trioxide has been a major break-through as a cure for a subset of human leukemias, and its use as a mineral arsenical in traditional medicines prompted this finding. Cardiovascular toxicity is the major concern for arsenic trioxide, and realgar is much less acutely toxic than arsenic trioxide. Little is known about possible secondary cancers resulting from the long-term use of any of these arsenicals. Similar to the safety evaluation of seafood arsenicals, total arsenic content alone is insufficient for safety evaluation of mineral arsenical-containing traditional medicines, and arsenic speciation, bioavailability, and toxicity/benefit should be all considered in any such evaluation.
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Acknowledgements
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We thank Drs. Wei Qu, Yang Sun, and Larry Keefer for critical review of this perspective.
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Footnotes
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This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and NIEHS.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.108.139543.
ABBREVIATIONS: As2S3, orpiment; As4S4, realgar; As2O3, arsenolite (contains arsenic trioxide); APL, acute promyelocytic leukemia; MMA, monomethylarsononous acid; DMA, dimethylarsinic acid; TMA, trimethylarsonic acid.
Address correspondence to: Dr. Jie Liu, Inorganic Carcinogenesis Section, NCI at NIEHS, Mail Drop F0-09, Research Triangle Park, NC 27709. E-mail: liu6{at}niehs.nih.gov
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Abstract
Use of Mineral Arsenicals...
