Liver Toxicity of Rare Ginsenosides in Rats after 13 Weeks of Oral Exposure

CAO Yuqing; TAO Feiyan; GAO Hui; CAI Yuqing; YU Yuan; SONG Linmeng; XUE Peng

doi:10.13386/j.issn1002-0306.2023020054

Volume 44 Issue 23

Nov. 2023

Turn off MathJax

Article Contents

Abstract

References

Science and Technology of Food Industry > 2023 > 44(23): 322-329. > DOI: 10.13386/j.issn1002-0306.2023020054

CAO Yuqing, TAO Feiyan, GAO Hui, et al. Liver Toxicity of Rare Ginsenosides in Rats after 13 Weeks of Oral Exposure[J]. Science and Technology of Food Industry, 2023, 44(23): 322−329. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2023020054.

Citation:

PDF (2726 KB)

Liver Toxicity of Rare Ginsenosides in Rats after 13 Weeks of Oral Exposure

School of Public Health, Weifang Medical University, Weifang 261200, China

More Information

Received Date: February 07, 2023
Available Online: October 03, 2023

Graphical Abstract

Abstract

Abstract

Objective: This study aims to evaluate the hepatotoxicity of rare ginsenosides in rats after 90 days of oral administration using heat-transformed rare ginsenosides as the primary material. Methods: A total of 48 male and female rats were randomly assigned into four groups: High-dose rare ginsenosides (600 mg/kg), medium-dose rare ginsenosides (200 mg/kg), low-dose rare ginsenosides (60 mg/kg), and a blank control group. After 90 days of oral gavage treatment, ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was employed for metabolomic analysis of rat serum and flow cytometry analysis of liver apoptosis to evaluate the potential liver damage comprehensively in rats. Results: A significant difference in hepatocyte apoptotic rate was observed between the high-dose group and the control group in both male and female rats (P<0.01). Metabolomic findings revealed no significant differences in metabolites between the low-dose and medium-dose groups compared to the control group (P>0.05). However, 23 differential metabolites, such as histidine, glutamate, proline and arginine were identified in the serum of female rats in the high-dose group, affecting the histidine and urea cycle metabolic pathways and causing hyperammonemia and liver damage. Ten differential metabolites affecting the alpha-linolenic acid and linoleic acid metabolic pathways were found in male rats, such as linoleic acid and arachidonic acid. High concentrations of arachidonic acid showed inflammatory and toxic effects, which could be absorbed into the portal vein system through blood and cause liver damage. Conclusion: High-dose rare ginsenosides mainly cause slight liver damage in male and female rats mainly due to the changes of histidine, α-linolenic acid and linoleic acid metabolic pathways. Hence, no adverse liver effects were observed at doses less than 200 mg/kg in both male and female rats.
- rare ginsenosides,
- Sprague Dawley rats,
- metabolomics,
- liver,
- flow cytometry analysis

FullText(HTML)

References (31)

References

[1]	SZCZUKA D, NOWAK A, ZAKŁOS-SZYDA M, et al. American ginseng ( Panax quinquefolium L.) as a source of bioactive phytochemicals with pro-health properties[J]. Nutrients,2019,11(5):1041. doi: 10.3390/nu11051041
[2]	JING J J, ZHANG R Y, WANG Y H, et al. Less polar ginsenosides have better protective effects on mice infected by Listeria monocytogenes[J]. Ecotoxicology and Environmental Safety,2021,213:112065. doi: 10.1016/j.ecoenv.2021.112065
[3]	LEE J W, CHOI B R, KIM Y C, et al. Comprehensive profiling and quantification of ginsenosides in the root, stem, leaf, and berry of Panax ginseng by UPLC-QTOF/MS[J]. Molecules,2017,22(12):2147. doi: 10.3390/molecules22122147
[4]	ZHANG F X, TANG S J, ZHAO L, et al. Stem-leaves of Panax as a rich and sustainable source of less-polar ginsenosides:Comparison of ginsenosides from Panax ginseng, American ginseng and Panax notoginseng prepared by heating and acid treatment[J]. Journal of Ginseng Research,2021,45(1):163−175. doi: 10.1016/j.jgr.2020.01.003
[5]	XUE P, YAO Y, YANG X S, et al. Improved antimicrobial effect of ginseng extract by heat transformation[J]. Journal of Ginseng Research,2017,41(2):180−187. doi: 10.1016/j.jgr.2016.03.002
[6]	ZHANG Y C, ZHANG J X, LIU C, et al. Extraction, isolation, and aromatase inhibitory evaluation of low-polar ginsenosides from Panax ginseng leaves[J]. Journal of Chromatography A,2017,1483:20−29. doi: 10.1016/j.chroma.2016.12.068
[7]	LU D, LIU J P, ZHAO W J, et al. Chronic toxicity of ginsenoside Re on Sprague-Dawley rats[J]. Journal of Ethnopharmacology,2012,144(3):656−663. doi: 10.1016/j.jep.2012.10.007
[8]	ZHAO Q, YANG M, DENG Y P, et al. The safety evaluation of salvianolic acid B and ginsenoside Rg1 combination on mice[J]. International Journal of Molecular Sciences,2015,16(12):29345−29356. doi: 10.3390/ijms161226176
[9]	LI C M, WANG Z Z, LI G S, et al. Acute and repeated dose 26-week oral toxicity study of 20 (S)-ginsenoside Rg3 in Kunming mice and Sprague-Dawley rats[J]. Journal of Ginseng Research,2020,44(2):222−228. doi: 10.1016/j.jgr.2018.10.001
[10]	GAO Y L, WANG T, WANG G F, et al. Preclinical safety of ginsenoside compound K:Acute, and 26-week oral toxicity studies in mice and rats[J]. Food and Chemical Toxicology,2019,131:110578. doi: 10.1016/j.fct.2019.110578
[11]	LIU J, LIU Y, WANG Y, et al. The integration of GC-MS and LC-MS to assay the metabolomics profiling in Panax ginseng and Panax quinquefolius reveals a tissue-and species-specific connectivity of primary metabolites and ginsenosides accumulation[J]. Journal of Pharmaceutical and Biomedical Analysis,2017,135:176−185. doi: 10.1016/j.jpba.2016.12.026
[12]	XUE P, YANG X S, ZHAO L, et al. Relationship between antimicrobial activity and amphipathic structure of ginsenosides[J]. Industrial Crops and Products,2020,143:111929. doi: 10.1016/j.indcrop.2019.111929
[13]	ZHANG Z H, WANG X Y, WANG J C, et al. Metabonomics approach to assessing the metabolism variation and endoexogenous metabolic interaction of ginsenosides in cold stress rats[J]. Journal of Proteome Research,2016,15(6):1842−1852. doi: 10.1021/acs.jproteome.6b00015
[14]	李媛媛, 张媛媛, 李俊霞, 等. 甲氨基阿维菌素苯甲酸盐和高效氯氰菊酯混配染毒致小鼠睾丸细胞遗传损伤研究[J]. 环境卫生学杂志,2020,10(4):363−366. [LI Y Y, ZHANG Y Y, LI J X, et al. Genetic damage of mouse testicular cells caused by mixed exposure to emamectin benzoate and beta-cypermethrin[J]. Journal of Environmental Hygiene,2020,10(4):363−366. doi: 10.13421/j.cnki.hjwsxzz.2020.04.006 LI Y Y, ZHANG Y Y, LI J X, et al. Genetic damage of mouse testicular cells caused by mixed exposure to emamectin benzoate and beta-cypermethrin[J]. Journal of Environmental Hygiene, 2020, 10（4）: 363−366. doi: 10.13421/j.cnki.hjwsxzz.2020.04.006
[15]	ZHANG R Y, ZHAI Q F, YU Y, et al. Safety assessment of crude saponins from Chenopodium quinoa Willd. husks:90-day oral toxicity and gut microbiota & metabonomics study in rats[J]. Food Chemistry,2022,375:131655. doi: 10.1016/j.foodchem.2021.131655
[16]	张若愚, 闫菲, 李雪宁, 等. 藜麦皂苷灌胃后大鼠尿液代谢及肠道菌变化[J]. 现代食品科技,2022,38(8):1−9. [ZHANG R Y, YAN F, LI X N, et al. Changes of urine metabolism and gut microbiome in rats after intragastric administration of quinoa saponins[J]. Modern Food Science and Technology,2022,38(8):1−9. doi: 10.13982/j.mfst.1673-9078.2022.8.0999 ZHANG R Y, YAN F, LI X N, et al. Changes of urine metabolism and gut microbiome in rats after intragastric administration of quinoa saponins[J]. Modern Food Science and Technology, 2022, 38（8）: 1−9. doi: 10.13982/j.mfst.1673-9078.2022.8.0999
[17]	LIU X X, MI X J, WANG Z, et al. Ginsenoside Rg3 promotes regression from hepatic fibrosis through reducing inflammation-mediated autophagy signaling pathway[J]. Cell Death & Disease,2020,11(6):454.
[18]	SHI Q Q, LI J, FENG Z Q, et al. Effect of ginsenoside Rh2 on the migratory ability of HepG2 liver carcinoma cells:Recruiting histone deacetylase and inhibiting activator protein 1 transcription factors[J]. Molecular Medicine Reports,2014,10(4):1779−1785. doi: 10.3892/mmr.2014.2392
[19]	刘佳, 孔嗣强, 张明, 等. 过量人参皂苷对小鼠原代培养肝细胞的毒性实验[J]. 中医药导报,2017,23(18):33−36. [LIU J, KONG S Q, ZHANG M, et al. Toxicity experiment of excess ginseng saponin on primitive cultured mouse liver cells[J]. Guiding Journal of Traditional Chinese Medicine and Pharmacy,2017,23(18):33−36. doi: 10.13862/j.cnki.cn43-1446/r.2017.18.009 LIU J, KONG S Q, ZHANG M, et al. Toxicity experiment of excess ginseng saponin on primitive cultured mouse liver cells[J]. Guiding Journal of Traditional Chinese Medicine and Pharmacy, 2017, 23（18）: 33−36. doi: 10.13862/j.cnki.cn43-1446/r.2017.18.009
[20]	HOLEČEK M. Histidine in health and disease:Metabolism, physiological importance, and use as a supplement[J].Nutrients,2020,12(3):848. doi: 10.3390/nu12030848
[21]	全敏, 杨松. 尿素循环障碍所致急慢性肝病的识别与治疗[J].中国实用儿科杂志,2021,36(10):758−762. [QUAN M, YANG S. Identification and treatment of acute and chronic liver diseases caused by urea cycle disorders[J]. Chinese Journal of Practical Pediatrics,2021,36(10):758−762. doi: 10.19538/j.ek2021100611 QUAN M, YANG S. Identification and treatment of acute and chronic liver diseases caused by urea cycle disorders[J]. Chinese Journal of Practical Pediatrics, 2021, 36（10）: 758−762. doi: 10.19538/j.ek2021100611
[22]	李敏, 陈哲晖, 周颖, 等. 尿素循环障碍的药物治疗[J]. 中国实用儿科杂志,2021,36(10):764−768. [LI M, CHEN Z H, ZHOU Y, et al. Drug treatment for urea cycle disorders[J]. Chinese Journal of Practical Pediatrics,2021,36(10):764−768. doi: 10.19538/j.ek2021100613 LI M, CHEN Z H, ZHOU Y, et al. Drug treatment for urea cycle disorders[J]. Chinese Journal of Practical Pediatrics, 2021, 36（10）: 764−768. doi: 10.19538/j.ek2021100613
[23]	蔡亚玮, 刘建宏, 马宁. 花生四烯酸靶向代谢组学在炎症中的研究现状[J]. 中国临床药理学杂志,2021,37(19):2721−2723,2728. [CAI Y W, LIU J H, MA N. Research status of arachidonic acid-targeted metabonomics in inflammation[J]. The Chinese Journal of Clinical Pharmacology,2021,37(19):2721−2723,2728. doi: 10.13699/j.cnki.1001-6821.2021.19.044 CAI Y W, LIU J H, MA N. Research status of arachidonic acid-targeted metabonomics in inflammation[J]. The Chinese Journal of Clinical Pharmacology, 2021, 37（19）: 2721−2723,2728. doi: 10.13699/j.cnki.1001-6821.2021.19.044
[24]	胡煜. 热应激通过miR-145-5p-花生四烯酸调节仔猪睾丸支持细胞自噬的分子机制[D]. 重庆:西南大学, 2021. [HU Yu. Animal genetics breeding and reproduction field:animal reproductive physiology and reproduction regulation[D]. Chongqing:Southwest University, 2021. HU Yu. Animal genetics breeding and reproduction field: animal reproductive physiology and reproduction regulation[D]. Chongqing: Southwest University, 2021.
[25]	INNES J K, CALDER P C. Omega-6 fatty acids and inflammation[J]. Prostaglandins, Leukotrienes and Essential Fatty Acids,2018,132:41−48. doi: 10.1016/j.plefa.2018.03.004
[26]	SIMOPOULOS A P. An increase in the omega-6/omega-3 fatty acid ratio increases the risk for obesity[J]. Nutrients,2016,8(3):128. doi: 10.3390/nu8030128
[27]	FARHANGFAR S D, FESAHAT F, ZARE-ZARDINI H, et al. In vivo study of anticancer activity of ginsenoside Rh2-containing arginine-reduced graphene in a mouse model of breast cancer[J]. Iranian Journal of Basic Medical Sciences,2022,25(12):1442−1451.
[28]	TAO T Z, CHEN F, BO L L, et al. Ginsenoside Rg1 protects mouse liver against ischemia-reperfusion injury through anti-inflammatory and anti-apoptosis properties[J]. Journal of Surgical Research,2014,191(1):231−238. doi: 10.1016/j.jss.2014.03.067
[29]	李大磊, 李延团, 韩兵, 等. 人参皂苷 CK 乳注射液对新西兰兔的长期毒性试验研究[J]. 中国中医药现代远程教育,2011,9(3):188−189. [LI D L, LI Y T, HAN B, et al. Long-term toxicity test of ginsenoside ck milk injection on new zealand rabbits[J]. Chinese Medicine Modern Distance Education of China,2011,9(3):188−189. doi: 10.3969/j.issn.1672-2779.2011.03.147 LI D L, LI Y T, HAN B, et al. Long-term toxicity test of ginsenoside ck milk injection on new zealand rabbits[J]. Chinese Medicine Modern Distance Education of China, 2011, 9（3）: 188−189. doi: 10.3969/j.issn.1672-2779.2011.03.147
[30]	浦滇, 李俊, 黄娜娜, 等. 人参皂苷CK对肝脏的药理作用研究概况[J]. 中国民族民间医药,2022,31(4):62−65. [PU D, LI J, HUANG N N, et al. Research progress on related effects of ginsenoside CK on liver[J]. Chinese Journal of Ethnomedicine and Ethnopharmacy,2022,31(4):62−65. PU D, LI J, HUANG N N, et al. Research progress on related effects of ginsenoside CK on liver[J]. Chinese Journal of Ethnomedicine and Ethnopharmacy, 2022, 31（4）: 62−65.
[31]	MANCUSO C, SANTANGELO R. Panax ginseng and Panax quinquefolius:From pharmacology to toxicology[J]. Food and Chemical Toxicology,2017,107:362−372. doi: 10.1016/j.fct.2017.07.019

Supplements (0)

Cited By

Cited by

Periodical cited type(2)

1.	李曼，刘立增，刘爱国，井琳，刘园，强锋，赵丽峥. 蛋白质对冰淇淋品质影响及其在冰淇淋中应用的研究进展. 食品工业科技. 2024(24): 416-426 . 本站查看
2.	贾世亮，刘永清，赵雅婷，尹宇浩，周绪霞，丁玉庭. 超低温深冷冻结对水产品冰晶生成及品质的影响研究进展. 食品与发酵工业. 2024(24): 362-372 .