Skip to main content
Log in

Changes in Copper, Zinc, Arsenic, Mercury, and Lead Concentrations in Rat Biofluids and Tissues Induced by the “Renqing Changjue” Pill, a Traditional Tibetan Medicine

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

The “Renqing Changjue” pill (RQCJ), as an effective prescription of Traditional Tibetan Medicine (TTM), has been widely used in treating advanced gastroenteropathy diseases for over a thousand years. However, the toxicity and adverse effects of TTM have attracted increasing attention because heavy metals may be added as active ingredients. In this work, we introduced a robust model based on endogenous metabolism enabling the study of changes in copper (Cu), zinc (Zn), arsenic (As), mercury (Hg), and lead (Pb) concentrations and the mechanism between biofluids (blood and urine) and tissue (liver, kidney, spleen) samples from rats treated with RQCJ, along with metabolic changes after different treatment time points. Inductively coupled plasma-mass spectrometry was used to monitor the heavy metals. Slightly different trends of heavy metals were observed in rat metabolites. The levels of Hg, As, and Pb were clearly dose-dependent in the tissue and biofluid samples. Basic recovery of Hg and Pb was found after stopping treatment with RQCJ. The accumulation of As was more obvious in the blood, liver, kidney, and spleen; however, Hg was deposited in the kidney. Pb accumulated the most in the spleen. The concentrations of Cu and Zn were constant or accumulated to a certain extent, which could cause the body to have Cu and Zn metabolism disorders in the administration period. Our findings highlight how metal changes and effects on the mechanisms might contribute to the progression of understanding of the toxicity information for RQCJ. Therefore, precautions should be taken in the clinic to monitor the potential toxicity of RQCJ with long-term administration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Zhao ZL, Dorje G, Wang ZT (2010) Identification of medicinal plants used as Tibetan Traditional Medicine jie-ji. J Ethnopharmacol 132(1):122–126

    Article  CAS  PubMed  Google Scholar 

  2. Ernst E (2002) Heavy metals in traditional Indian remedies. Eur J Clin Pharmacol 57(12):891–896

    Article  CAS  PubMed  Google Scholar 

  3. Saper RB, Kales SN, Paquin J, Burns MJ, Eisenberg DM, Davis RB, Phillips RS (2004) Heavy metal content of ayurvedic herbal medicine products. JAMA 292(23):2868–2873

    Article  CAS  PubMed  Google Scholar 

  4. Li CW, Duo J, Duo J, Chen X, Du Y, Yang H, Zheng Z, Yu M, Wei L (2014) Study on safety of Tibetan medicine of Zuotai and preliminary study on clinical safety and its compound Dangzuo. China J Chin Materia Medica 39(13):2573–2582

    Google Scholar 

  5. Ma JSX, Li B, Jia M (2013) Toxicological experimental studyof Tibetan medicine RQCJ. Asia-Pacific Traditional Med 9(2):15–17

    Google Scholar 

  6. Xu C, Wang Y, Rezeng C, Zhang L, Zhao B, Wang X, Wu X, Li Z, Chen J (2018) Tissue metabolomics study to reveal the toxicity of a traditional Tibetan medicine ‘Renqing Changjue’ in rats. RSC Adv 8(66):37652–37664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rezeng CZL, Limao C, Tong L, Li W, Wang Y (2016) Determination of the inorganic elements in Renqing Changjue by ICP-MS. J Qinghai Normal Univ (Natural Science Edition) 4:59–65

    Google Scholar 

  8. Chen BHN, Lue M, Le XC (2009) Metabolism, Toxicity, and biomonitoring of Arsenic Species. Progress Chemistry 21(2/3):474–482

    CAS  Google Scholar 

  9. Syversen T, Kaur P (2012) The toxicology of mercury and its compounds. J Trace Elem Med Biol 26(4):215–226

    Article  CAS  PubMed  Google Scholar 

  10. Dewanjee S, Sahu R, Karmakar S, Gangopadhyay M (2013) Toxic effects of lead exposure in Wistar rats: involvement of oxidative stress and the beneficial role of edible jute (Corchorus olitorius) leaves. Food Chem Toxicol 55:78–91

    Article  CAS  PubMed  Google Scholar 

  11. Wu H, Zhao J (2019) Disruption of the Golgi apparatus mediates zinc deficiency-induced impairment of cognitive function in mice. Metallomics 11(12):1984–1987

    Article  CAS  PubMed  Google Scholar 

  12. Nizamani P, Afridi HI, Kazi TG, Talpur FN, Baig JA (2019) Essential trace elemental levels (zinc, iron and copper) in the biological samples of smoker referent and pulmonary tuberculosis patients. Toxicol Rep 6:1230–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schleper B, Stuerenburg HJ (2001) Copper deficiency-associated myelopathy in a 46-year-old woman. J Neurol 248(8):705–706

    Article  CAS  PubMed  Google Scholar 

  14. Zietz BPDHH, Lakomek M, Schneider H, Keßler-Gaedtke B, Dunkelberg H (2003) Epidemiological investigation on chronic copper toxicity to children exposed via the public drinking water supply. Sci Total Environ 302(1):127–144

    Article  CAS  PubMed  Google Scholar 

  15. Tanaka YK, Ogra Y (2019) Evaluation of copper metabolism in neonatal rats by speciation analysis using liquid chromatography hyphenated to ICP mass spectrometry. Metallomics 11(10):1679–1686

    Article  CAS  PubMed  Google Scholar 

  16. Mohamed R, Zainudin BH, Yaakob AS (2020) Method validation and determination of heavy metals in cocoa beans and cocoa products by microwave assisted digestion technique with inductively coupled plasma mass spectrometry. Food Chem 303:125392

    Article  CAS  PubMed  Google Scholar 

  17. Khan S, Shah IA, Muhammad S, Malik RN, Shah MT (2014) Arsenic and heavy metal concentrations in drinking water in Pakistan and risk assessment: a case study. Human Ecol Risk Assessment 21(4):1020–1031

    Article  CAS  Google Scholar 

  18. Wang YLX, Rezeng C, Zhang L (2019) Study on the arsenic metabolites of Renqing Changjue in rat urine by HPLC-ICP-MS. Chin J Pharm Anal 39(2):263–271

    Google Scholar 

  19. Yang BJJ, Jiang Y, Tangka A, Zhongdeng L, Songji L, Xie B, Qiang W, Hao D, Gesang N, Pang W (2004) Study on the action and safety of mercury in Zuotai of Tibetan medicine. Tibetan Stud 1:73–80

    Google Scholar 

  20. Dong XHY (2001) Advances in zinc absorption and metabolism. China Feed 1:23–26

    Google Scholar 

  21. Smith KT, Cousins RJ, Silbon BL, Failla ML (1978) Zinc absorption and metabolism by isolated, vascularly perfused rat intestine. J Nutr 108(11):1849–1857

    Article  CAS  PubMed  Google Scholar 

  22. Byung EKNTTDJ (2008) Mechanisms for copper acquisition, distribution and regulation. Nat Chem Biol 4(3):176–185

    Article  CAS  Google Scholar 

  23. Zima T, Tesar V, Mestek O, Nemecek K (1999) Trace elements in end-stage renal disease. 1. Methodological aspects and the influence of water treatment and dialysis equipment. Blood Purif 17(4):182–186

    Article  CAS  PubMed  Google Scholar 

  24. Rayman MP, Infante HG, Sargent M (2008) Food-chain selenium and human health: spotlight on speciation. Br J Nutr 100(2):238–253

    Article  CAS  PubMed  Google Scholar 

  25. Brima EI, Haris PI, Jenkins RO, Polya DA, Gault AG, Harrington CF (2006) Understanding arsenic metabolism through a comparative study of arsenic levels in the urine, hair and fingernails of healthy volunteers from three unexposed ethnic groups in the United Kingdom. Toxicol Appl Pharmacol 216(1):122–130

    Article  CAS  PubMed  Google Scholar 

  26. Gochfeld M (2003) Cases of mercury exposure, bioavailability, and absorption. Ecotoxicol Environ Saf 56(1):174–179

    Article  CAS  PubMed  Google Scholar 

  27. Moreda-Piñeiro J, Moreda-Piñeiro A, Romarís-Hortas V, Moscoso-Pérez C, López-Mahía P, Muniategui-Lorenzo S, Bermejo-Barrera P, Prada-Rodríguez D (2011) In-vivo and in-vitro testing to assess the bioaccessibility and the bioavailability of arsenic, selenium and mercury species in food samples. TrAC Trends Anal Chem 30(2):324–345

    Article  CAS  Google Scholar 

  28. Sarkar A, Paul B (2016) The global menace of arsenic and its conventional remediation - a critical review. Chemosphere 158:37–49

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki Y, Ogra Y, Machida N, Watanabe I (2019) Changes in copper, zinc and cadmium distributions in the liver of Formosan squirrels with characteristic high copper accumulation. Metallomics 11(10):1753–1758

    Article  CAS  PubMed  Google Scholar 

  30. King JC, Shames DM, Woodhouse LR (2000) Zinc homeostasis in humans. J Nutr 130(5S Suppl):1360S–1366S

    Article  CAS  PubMed  Google Scholar 

  31. Jeong J, Eide DJ (2013) The SLC39 family of zinc transporters. Mol Asp Med 34(2–3):612–619

    Article  CAS  Google Scholar 

  32. Vasak M, Meloni G (2011) Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem 16(7):1067–1078

    Article  CAS  PubMed  Google Scholar 

  33. Huang L, Tepaamorndech S (2013) The SLC30 family of zinc transporters - a review of current understanding of their biological and pathophysiological roles. Mol Asp Med 34(2–3):548–560

    Article  CAS  Google Scholar 

  34. Liu QLJ (1999) Metabolism of copper in human body. Foreign Med Sci (Section of Medgeography) 20(1):16–21

    Google Scholar 

  35. Kim KB, Um SY, Chung MW, Jung SC, Oh JS, Kim SH, Na HS, Lee BM, Choi KH (2010) Toxicometabolomics approach to urinary biomarkers for mercuric chloride (HgCl(2))-induced nephrotoxicity using proton nuclear magnetic resonance ((1) H NMR) in rats. Toxicol Appl Pharmacol 249(2):114–126

    Article  CAS  PubMed  Google Scholar 

  36. Kumar GSA, Sharma SK, Gupta YK (2014) Safety evaluation of mercury based Ayurvedic formulation (SidhMakardhwaj) on brain, cerebrum, liver &kidney in rats. Indian J Med Res 4(139):610–618

    Google Scholar 

  37. States JC, Barchowsky A, Cartwright IL, Reichard JF, Futscher BW, Lantz RC (2011) Arsenic toxicology: translating between experimental models and human pathology. Environ Health Perspect 119(10):1356–1363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Guha Mazumder DN (2008) Chronic arsenic toxicity & human health. Indian J Med Res 128(4):436–447

    CAS  PubMed  Google Scholar 

  39. Ratnaike RN (2003) Acute and chronic arsenic toxicity. Postgrad Med J 79:391–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hughes MF (2002) Arsenic toxicity and potential mechanisms of action. Toxicol Lett 133:1–16

    Article  CAS  PubMed  Google Scholar 

  41. Loffredo CA, Aposhian HV, Cebrian ME, Yamauchi H, Silbergeld EK (2003) Variability in human metabolism of arsenic. Environ Res 92(2):85–91

    Article  CAS  PubMed  Google Scholar 

  42. Vahter M (2002) Mechanisms of arsenic biotransformation. Toxicology 181-182:211–217

    Article  CAS  PubMed  Google Scholar 

  43. Tseng CH (2007) Arsenic methylation, urinary arsenic metabolites and human diseases: current perspective. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 25(1):1–22

    Article  CAS  PubMed  Google Scholar 

  44. Sharma VK, Sohn M (2009) Aquatic arsenic: toxicity, speciation, transformations, and remediation. Environ Int 35(4):743–759

    Article  CAS  PubMed  Google Scholar 

  45. Pletz J, Sanchez-Bayo F, Tennekes HA (2016) Dose-response analysis indicating time-dependent neurotoxicity caused by organic and inorganic mercury-implications for toxic effects in the developing brain. Toxicology 347-349:1–5

    Article  CAS  PubMed  Google Scholar 

  46. Shi JF w, Wang M, Zhang F, Li B, Wang B, Zhu M, Chai Z (2007) Study on mecury-binding proteins in rats by hyphenated technique of high performance liquid chromatography - isotope dilution - inductively coupled plasma mass spectrometry. Chin J Anal Chem 35(6):803–808

  47. Lahti DW, Hoekman JD, Tokheim AM, Martin BL, Armitage IM (2005) Identification of mouse brain proteins associated with isoform 3 of metallothionein. Protein Sci 14(5):1151–1157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Peng CGY (2007) Studes of the physiological functions of carbonic anhydrase. J Peking Univ Health Sci 39(3):210–212

    CAS  Google Scholar 

  49. Zalups RK (1998) Intestinal handling of mercury in the rat: implications of intestinal secretion of inorganic mercury following biliary ligation or cannulation. J Toxicol Environ Health A 53(8):615–636

    Article  CAS  PubMed  Google Scholar 

  50. Zalups RK (1998) Basolateral uptake of inorganic mercury in the kidney. Toxicol Appl Pharmacol 151(1):192–199

    Article  CAS  PubMed  Google Scholar 

  51. Li SZJ (2002) Advances of mercury metabolism in the kidney. Chin Occup Med 29(2):47–48

    Google Scholar 

  52. Yang HZM, Geng L, Li C, Douzhou C, Zhi H, Wei L, Du Y (2019) Clinical safety evaluation of Tibetan medicine Renqingchangjue. China J Traditional Chin Medi Pharmacy 34(4):398–341

    Google Scholar 

  53. Jain RB (2019) Lead and kidney: concentrations, variabilities, and associations across the various stages of glomerular function. J Trace Elem Med Biol 54:36–43

    Article  CAS  PubMed  Google Scholar 

  54. Li ZZP (2008) The progress and prospect of fundamental research of the spleen. J Xi‘an Jiaotong Univ Med Sci 29(1):1–6

    Google Scholar 

  55. Gonick HC (2011) Lead-binding proteins: a review. J Toxicol 2011:686050

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This work is funded by the National Natural Science Foundation of China (81573832, 81773960, 82060648), Beijing Municipal Natural Science Foundation (8153036), and Qinghai Province Applied Fundamental Research (2018-ZJ-708).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zhongfeng Li.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOC 130 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, L., Rezeng, C., Wang, Y. et al. Changes in Copper, Zinc, Arsenic, Mercury, and Lead Concentrations in Rat Biofluids and Tissues Induced by the “Renqing Changjue” Pill, a Traditional Tibetan Medicine. Biol Trace Elem Res 199, 4646–4656 (2021). https://doi.org/10.1007/s12011-021-02586-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-021-02586-5

Keywords

Navigation