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J Ethnopharmacol. 2018 Oct 29. pii: S0378-8741(17)34638-X. doi: 10.1016/j.jep.2018.10.037. [Epub ahead of print]

Study of the accumulation and distribution of arsenic species and association with arsenic toxicity in rats after 30 days of oral realgar administration.

Author information

1
Key laboratory of Beijing for identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medicial Sciences; 16 Nanxiaojie, Dongzhimen Nei, Beijing, 100700, China.
2
Shanghai Institute for Food and Drug Control; No. 1500 Shanghai Zhang Heng Road, Pudong New District, Shanghai, China 201203.
3
Key laboratory of Beijing for identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medicial Sciences; 16 Nanxiaojie, Dongzhimen Nei, Beijing, 100700, China. Electronic address: ahliang@icmm.ac.cn.
4
Shanghai Institute for Food and Drug Control; No. 1500 Shanghai Zhang Heng Road, Pudong New District, Shanghai, China 201203. Electronic address: jishen2013@163.com.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Realgar (As4S4) has been traditionally incorporated as a chief ingredient in traditional Chinese medicine formulations used to treat inflammation, poisoning, cancer, convulsion, and parasites. However, because of the toxicity of arsenic (As), the safety of realgar has been questioned.

AIM OF THE STUDY:

Because the toxicity and efficacy of As are closely related to its chemical species, we conducted examinations of As species accumulation and distribution in the rat body after one-time and 30-day realgar administration and then elucidated the probable roles of different As species in the short-term toxicity of realgar.

MATERIALS AND METHODS:

Realgar was administered to rats by gavage once or successively for 30 days, and then biological samples (plasma, urine, liver, kidney, and brain) were obtained from rats and analyzed using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) to determine As species accumulation and distribution. Additionally, the toxicity of realgar in rats was evaluated.

RESULTS:

The absorption, distribution and elimination half-life of total As species in realgar were 3.33h, 16.08h and 24.65h, respectively. After the administration of realgar for 30 days, no obvious drug-related toxicity occurred in rats, except that abnormal blood glucose (GLU), activated partial thromboplastin time (APTT) and potassium (K+) levels were observed. Dimethylarsenic acid (DMA) is the most abundant As species. According to the contents ordered from high to low, it was distributed in the urine>blood>liver>kidney>brain, similar to the DMA distribution after a single administration of realgar. The concentration of As species in vivo was DMA>monomethyl As (MMA)>As(Ⅲ)>As(Ⅴ)>AsB>AsC. The DMA contents in the liver and kidney of the treated group were approximately 40-fold and 50-fold higher than those in the corresponding tissues of the control group. As(III) was mainly detected in the liver, and its concentration was approximately 40-fold higher than that in the control group. MMA was mainly detected in rat kidneys, and its contents in the treated group were more than 2000-fold higher than those in the control group.

CONCLUSIONS:

After a single oral administration, the distribution and elimination of realgar in blood were slow, whereas it was rapidly absorbed and distributed in the liver, kidney and brain. Therefore, we recommend that realgar should not frequently used on a daily basis. Because the administration of a large dose of realgar did not display significant toxicity, we believe that the continuous administration of realgar for 30 days is safe in rats. In addition, hematology, biochemistry, and electrolyte levels and ECG should be monitored during realgar treatment. The accumulation and distribution of As species after 30 days of oral administration of realgar revealed that DMA and MMA are the main end products of As metabolism. Realgar-induced hepatotoxicity may be related to the accumulation of DMA and As(III). In addition, we speculate that nephrotoxicity and neurotoxicity may occur when DMA accumulates to a certain high level.

KEYWORDS:

3-phosphoinositide-dependent Kinase-I; ALB; ALT; APL; APTT; ASB; AST; As; As((III); As((V); AsC; BUN; CFDA; CHO; CMC; CMM; China Food and Drug Administration; Chinese materia medica; Crea; DMAIII; DMAV; ECG; GLU; GLUT-4; Glucose transporter type 4; HGB; HPLC-ICP-MS; JNK; K+; MMAIII; MMAV; Na(+); PDK-1; PT; RBC; ROS; Realgar; S-adenosylmethionine; SAM; TBIL; TCMs; TG; TP; URO; WBC; accumulation; activated partial thromboplastin time; acute promyelocytic leukemia; alanine aminotransferase; arsenate; arsenic; arsenic betaine; arsenic chrome; arsenic species; arsenite; aspartate aminotransferase; blood urea nitrogen; c-Jun N-terminal kinases; cholesterol; creatinine; dimethylarsinic acid; dimethylarsinous acid; distribution; electrocardiogram; glucose; haemoglobin; high performance liquid chromatography-inductively coupled plasma-mass spectrometry; monomethylarsonic acid; monomethylarsonous acid; potassium; prothrombin time; reactive oxygen species; red blood cell; sodium; sodium carboxyl methyl cellulose; total albumin; total bilirubin; total protein; toxicity; traditional Chinese medicines; triglycerides; urobilinogen; white blood cell

PMID:
30385423
DOI:
10.1016/j.jep.2018.10.037

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