Browse > Article
http://dx.doi.org/10.3831/KPI.2016.19.022

General and Genetic Toxicology of Enzyme-Treated Ginseng Extract - Toxicology of Ginseng Rh2+ -  

Jeong, Mi-Kyung (East West Cancer Center, Dunsan Korean Medicine Hospital of Daejeon University)
Cho, Chong-Kwan (East West Cancer Center, Dunsan Korean Medicine Hospital of Daejeon University)
Yoo, Hwa-Seung (East West Cancer Center, Dunsan Korean Medicine Hospital of Daejeon University)
Publication Information
Journal of Pharmacopuncture / v.19, no.3, 2016 , pp. 213-224 More about this Journal
Abstract
Objectives: Ginseng Rh2+ is enzyme-treated ginseng extract containing high amounts of converted ginsenosides, such as compound k, Rh2, Rg3, which have potent anticancer activity. We conducted general and genetic toxicity tests to evaluate the safety of ginseng Rh2+. Methods: An acute oral toxicity test was performed at a high-level dose of 4,000 mg/kg/day in Sprague-Dawley (SD) rats. A 14-day range-finding study was also conducted to set dose levels for the 90-day study. A subchronic 90-day toxicity study was performed at dose levels of 1,000 and 2,000 mg/kg/day to investigate the no-observed-adverse-effect level (NOAEL) of ginseng Rh2+ and target organs. To identify the mutagenic potential of ginseng Rh2+, we conducted a bacterial reverse mutation test (Ames test) using amino-acid-requiring strains of Salmonella typhimurium and Escherichia coli (E. coli), a chromosome aberration test with Chinese hamster lung (CHL) cells, and an in vivo micronucleus test using ICR mice bone marrow as recommended by the Korean Ministry of Food and Drug Safety. Results: According to the results of the acute oral toxicity study, the approximate lethal dose (ALD) of ginseng Rh2+ was estimated to be higher than 4,000 mg/kg. For the 90-day study, no toxicological effect of ginseng Rh2+ was observed in body-weight changes, food consumption, clinical signs, organ weights, histopathology, ophthalmology, and clinical pathology. The NOAEL of ginseng Rh2+ was established to be 2,000 mg/kg/day, and no target organ was found in this test. In addition, no evidence of mutagenicity was found either on the in vitro genotoxicity tests, including the Ames test and the chromosome aberration test, or on the in vivo in mice bone marrow micronucleus test. Conclusion: On the basis of our findings, ginseng Rh2+ is a non-toxic material with no genotoxicity. We expect that ginseng Rh2+ may be used as a novel adjuvant anticancer agent that is safe for long-term administration.
Keywords
cancer; compound K; genotoxic; ginseng; ginsenoside; toxicity;
Citations & Related Records
Times Cited By KSCI : 3  (Citation Analysis)
연도 인용수 순위
1 Jena GB, Kaul CL, Poduri R. Genotoxicity testing, a regulatory requirement for drug discovery and development: impact of ICH guidelines. Indian J Pharm. 2002;34:86-99.
2 Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482-94.   DOI
3 Shumay DM, Maskarinec G, Kakai H, Gotay CC. Why some cancer patients choose complementary and alternative medicine instead of conventional treatment. J Fam Pract. 2001;50(12):1067.
4 Tian JH, Liu LS, Shi ZM, Zhou ZY, Wang L. A randomized controlled pilot trial of "Feiji Recipe" on quality of life of non-small cell lung cancer patients. Am J Chin Med. 2010;38(1):15-25.   DOI
5 Wang CZ, Calway T, Yuan CS. Herbal medicines as adjuvants for cancer therapeutics. Am J Chin Med. 2012;40(4):657-69.   DOI
6 Li Y, Zhou T, Ma C, Song W, Zhang J, Yu Z. Ginsenoside metabolite compound K enhances the efficacy of cisplatin in lung cancer cells. J Thorac Dis. 2015;7(3):400-6.   DOI
7 Zhang K, Li Y. Effects of ginsenoside compound K combined with cisplatin on the proliferation, apoptosis and epithelial mesenchymal transition in MCF-7 cells of human breast cancer. Pharm Biol. 2016;54(4):561-8.   DOI
8 Jia L, Zhao Y. Current evaluation of the millennium phytomedicine--ginseng (I): etymology, pharmacognosy, phytochemistry, market and regulations. Curr Med Chem. 2009;16(19):2475-84.   DOI
9 Christensen LP. Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv Food Nutr Res. 2009;55:1-99.
10 Qi LW, Wang CZ, Yuan CS. Isolation and analysis of ginseng: advances and challenges. Nat Prod Rep. 2011;28(3):467-95.   DOI
11 Shin BK, Kwon SW, Park JH. Chemical diversity of ginseng saponins from Panax ginseng. J Ginseng Res. 2015;39(4):287-98.   DOI
12 Jang SI, Lee YW, Cho CK, Yoo HS, Jang JH. Identification of target genes involved in the antiproliferative effect of enzyme-modified ginseng extract in HepG2 hepatocarcinoma cell. Evid Based Complement Alternat Med. 2013;2013:ID502568.
13 Wang W, Zhao Y, Rayburn ER, Hill DL, Wang H, Zhang R. In vitro anti-cancer activity and structure-activity relationships of natural products isolated from fruits of Panax ginseng. Cancer Chemother Pharmacol. 2007;59(5):589-601.   DOI
14 Wang CZ, Du GJ, Zhang Z, Wen XD, Calway T, Zhen Z, et al. Ginsenoside compound K, not Rb1, possesses potential chemopreventive activities in human colorectal cancer. Int J Oncol. 2012;40(6):1970-6.   DOI
15 Shibata S. Chemistry and cancer preventing activities of ginseng saponins and some related triterpenoid compounds. J Korean Med Sci. 2001;S16:S28-37.
16 Kim KH, Choi I, Lee YW, Cho CK, Yoo HS, Lee SB, et al. Target genes involved in antiproliferative effect of modified ginseng extracts in lung cancer A549 cells. Acta Biochim Biophys Sin (Shanghai). 2014;46(6):441-9.   DOI
17 Hwang JW, Baek YM, Jang IS, Yang KE, Lee DG, Yoon SJ, et al. An enzymatically fortified ginseng extract inhibits proliferation and induces apoptosis of KATO3 human gastric cancer cells via modulation of Bax, mTOR, PKB and $I{\kappa}B{\alpha}$. Mol Med Rep. 2015;11(1):670-6.   DOI
18 Chan PC, Peckham JC, Malarkey DE, Kissling GE, Travlos GS, Fu PP. Two-year toxicity and carcinogenicity studies of Panax ginseng in fischer 344 rats and B6C3F1 mice. Am J Chin Med. 2011;39(4):779-88.   DOI
19 Seely D, Dugoua JJ, Perri D, Mills E, Koren G. Safety and efficacy of Panax ginseng during pregnancy and lactation. Can J Clin Pharmacol. 2008;15(1):e87-94.
20 Park SJ, Lim KH, Noh JH, Jeong EJ, Kim YS, Han BC, et al. Subacute oral toxicity study of Korean red ginseng extract in sprague-dawley rats. Toxicol Res. 2013;29(4):285-92.   DOI
21 Schmid W. The micronucleus test. Mutat Res. 1975;31(1):9-15.   DOI
22 Tawab MA, Bahr U, Karas M, Wurglics M, Schubert- Zsilavecz M. Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos. 2003;31(8):1065-71.   DOI
23 Hasegawa H. Proof of the mysterious efficacy of ginseng: basic and clinical trials: metabolic activation of ginsenoside: deglycosylation by intestinal bacteria and esterification with fatty acid. J Pharmacol Sci. 2004;95(2):153-7.   DOI
24 Lee SJ, Kim YJ, Kim MG. Changes in the ginsenoside content during the fermentation process using microbial strains. J Ginseng Res. 2015;39(4):392-7.   DOI
25 Quan LH, Kim YJ, Li GH, Choi KT, Yang DC. Microbial transformation of ginsenoside Rb1 to compound K by Lactobacillus paralimentarius. World J Microbiol Biotechnol. 2013;29(6):1001-7.   DOI
26 Cho SH, Chung KS, Choi JH, Kim DH, Lee KT. Compound K, a metabolite of ginseng saponin, induces apoptosis via caspase-8-dependent pathway in HL-60 human leukemia cells. BMC Cancer. 2009;9:449.   DOI
27 Zheng ZZ, Ming YL, Chen LH, Zheng GH, Liu SS, Chen QX. Compound K-induced apoptosis of human hepatocellular carcinoma MHCC97-H cells in vitro. Oncol Rep. 2014;32(1):325-31.   DOI
28 Kim AD, Kang KA, Kim HS, Kim DH, Choi YH, Lee SJ, et al. A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells. Cell Death Dis. 2013;4:e750.   DOI
29 Kang KA, Piao MJ, Kim KC, Zheng J, Yao CW, Cha JW, et al. Compound K, a metabolite of ginseng saponin, inhibits colorectal cancer cell growth and induces apoptosis through inhibition of histone deacetylase activity. Int J Oncol. 2013;43(6):1907-14.   DOI
30 Hu C, Song G, Zhang B, Liu Z, Chen R, Zhang H, et al. Intestinal metabolite compound K of panaxoside inhibits the growth of gastric carcinoma by augmenting apoptosis via Bid-mediated mitochondrial pathway. J Cell Mol Med. 2012;16(1):96-106.   DOI
31 Zhang Z, Du GJ, Wang CZ, Wen XD, Calway T, Li Z, et al. Compound K, a ginsenoside metabolite, inhibits colon cancer growth via multiple pathways including p53-p21 interactions. Int J Mol Sci. 2013;14(2):2980-95.   DOI
32 Wang CZ, Cai Y, Anderson S, Yuan CS. Ginseng metabolites on cancer chemoprevention: an angiogenesis link?. Diseases. 2015;3(3):193-204.   DOI
33 Yang Z, Zhao T, Liu H, Zhang L. Ginsenoside Rh2 inhibits hepatocellular carcinoma through ${\beta}$-catenin and autophagy. Sci Rep. 2016;6:19383.   DOI
34 Tang XP, Tang GD, Fang CY, Liang ZH, Zhang LY. Effects of ginsenoside Rh2 on growth and migration of pancreatic cancer cells. World J Gastroenterol. 2013;19(10):1582-92.   DOI
35 Choi S, Kim TW, Singh SV. Ginsenoside Rh2-mediated G1 phase cell cycle arrest in human breast cancer cells is caused by p15 Ink4B and p27 Kip1-dependent inhibition of cyclin-dependent kinases. Pharm Res. 2009;26(10):2280-8.   DOI
36 Yoon JH, Choi YJ, Lee SG. Ginsenoside Rh1 suppresses matrix metalloproteinase-1 expression through inhibition of activator protein-1 and mitogen-activated protein kinase signaling pathway in human hepatocellular carcinoma cells. Eur J Pharmacol. 2012;679(1-3):24-33.   DOI
37 Scheutwinkel-Reich M, vd Hude W. Sister-chromatid exchange in Chinese hamster V79 cells exposed to quindoxin, carbadox and olaquindox. Mutat Res. 1984;139(4):199-202.   DOI
38 Jung JS, Ahn JH, Le TK, Kim DH, Kim HS. Protopanaxatriol ginsenoside Rh1 inhibits the expression of matrix metalloproteinases and the in vitro invasion/migration of human astroglioma cells. Neurochem Int. 2013;63(2):80-6.   DOI
39 Test No. 471: Bacterial Reverse Mutation Test [internet]. France: OECD; 1997. Available from: http://www.oecd-ilibrary.org/environment/test-no-471-bacterialreverse-mutation-test_9789264071247-en.
40 Chen Q, Tang S, Jin X, Zou J, Chen K, Zhang T, et al. Investigation of the genotoxicity of quinocetone, carbadox and olaquindox in vitro using Vero cells. Food Chem Toxicol. 2009;47(2):328-34.   DOI
41 Test No. 408: Repeated Dose 90-day Oral Toxicity Study in Rodents [internet]. France: OECD; 1998. Available from: http://www.oecd-ilibrary.org/environment/testno-408-repeated-dose-90-day-oral-toxicity-study-inrodents_9789264070707-en.