Toxicology effects of Berberis vulgaris (barberry) and its active constituent, berberine: a review

Authors

1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Berberis vulgaris and berberine, its main component, traditionally have been used for treatment of various disorders. The pharmacological properties of them have been investigated using different in vivo and in vitro models. In spite of beneficial effects of B. vulgaris on different cell lines, there are documents have revealed negative impacts of it on animal and human. In this regards, the determination of its toxicity in a scientific view is necessary. In current report, we provide classified information about the toxicity of B. vulgaris and berberine in different conditions consist of acute, sub-acute, sub-chronic and chronic state. Besides, it discusses the cytotoxicity, genotoxicity, mutagenicity, and carcinogenicity of B. vulgaris and berberine as well as developmental toxicity and clinical studies. Data from the present study indicate that their toxicity is depending on the route and duration of administration. According to present study, they could induce GI upset and ulceration, immunotoxicity, phototoxicity, neurotoxicity, cardiotoxicity and jaundice in a dose dependent manner. They should be used with caution in pregnancy, neonatal and G6PD deficiency. Besides, consideration should be taken in co-administration of berberine with drugs that are metabolized with CYP enzymes due their inhibitory effects on these enzymes. Furthermore, they evoke cytotoxicity on both normal and cancer cell line which is time and concentration dependent.

Keywords


1. Rounsaville TJ, Ranney TG. Ploidy levels and genome sizes of Berberis L. and Mahonia Nutt. species, hybrids, and cultivars. HortScience 2010;45:1029-1033.

2. Bone K, Mills S. Materia medica.  Principles and practice of phytotherapy modern herbal medicine. 2st ed. USA: Churchill livingstone; 2013. p. 399-418.

3. Ahrendt LWA. Berberis and Mahonia: a taxonomic revision. Bot J Linn Soc 1961;57:1-410.

4. Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res 2008;22:999-1012.

5. Mokhber-Dezfuli N, Saeidnia S, Gohari A, Kurepaz-Mahmoodabadi M. Phytochemistry and pharmacology of Berberis species. Pharmacogn Rev 2014;8:8-15.

6. Singh IP, Mahajan S. Berberine and its derivatives: a patent review (2009 - 2012). Expert Opin Ther Pat 2013;23:215-231.

7. Smolinske SC. Herbal product contamination and toxicity. J Pharm Pract 2005;18:188-208.

8. Imenshahidi M, Hosseinzadeh H. Berberis Vulgaris and berberine: an update review. Phytother Res 2016;30:1745-1764.

9.   Abd El-Wahab AE, Ghareeb DA, Sarhan EE, Abu-Serie MM, El Demellawy MA. In vitro biological assessment of Berberis vulgaris and its active constituent, berberine: antioxidants, anti-acetylcholinesterase, anti-diabetic and anticancer effects. BMC Complement Altern Med 2013;13:218-229.

10. Lin K, Liu S, Shen Y, Li Q. Berberine attenuates cigarette smoke-induced acute lung inflammation. Inflammation 2013;36:1079-1086.

11. Yu FS, Yang JS, Lin HJ, Yu CS, Tan TW, Lin YT, et al. Berberine inhibits WEHI-3 leukemia cells in vivo. In Vivo 2007;21:407-412.

12. Cernakova M, Kost'alova D, Kettmann V, Plodova M, Toth J, Drimal J. Potential antimutagenic activity of berberine, a constituent of Mahonia aquifolium. BMC Complement Altern Med 2002;2:2.

13. Jiang Z, Liu F, Ong ES, Li SFY. Metabolic profile associated with glucose and cholesterol lowering effects of berberine in Sprague–Dawley rats. Metabolomics 2012;8:1052-1068.

14. Kulkarni SK, Dhir A. Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res 2010;24:317-324.

15. Domitrovic R, Jakovac H, Blagojevic G. Hepatoprotective activity of berberine is mediated by inhibition of TNF-a, COX-2, and iNOS expression in CCl(4)-intoxicated mice. Toxicology 2011;280:33-43.

16. Feng Y, Siu KY, Ye X, Wang N, Yuen MF, Leung CH, et al. Hepatoprotective effects of berberine on carbon tetrachloride-induced acute hepatotoxicity in rats. Chin Med 2010;5:33.

17. Hermenean A PC, Ardelean A, Stan M, Hadaruga N, Mihali CV, Costache M, Dinischiotu A. Hepatoprotective effects of Berberis vulgaris L. extract/β cyclodextrin on carbon tetrachloride–induced acute toxicity in mice. Int J Mol Sci 2012;13:9014-9034.

18. Imenshahidi M, Qaredashi R, Hashemzaei M, Hosseinzadeh H. Inhibitory effect of Berberis vulgaris aqueous extract on acquisition and reinstatement effects of morphine in conditioned place preferences (CPP) in mice. Jundishapur J Nat Pharm Prod 2014;9:e16145.

19. Mahmoudvand H, Sharififar F, Sharifi I, Ezatpour B, Fasihi Harandi M, Makki MS, et al. In vitro Inhibitory effect of Berberis vulgaris (berberidaceae) and its main component, berberine against different leishmania species. Iran J Parasitol 2014;9:28-36.

20. Mahmoudvand H, Ayatollahi Mousavi SA, Sepahvand A, Sharififar F, Ezatpour B, Gorohi F, et al. Antifungal, antileishmanial, and cytotoxicity activities of various extracts of Berberis vulgaris (berberidaceae) and its active principle berberine. ISRN Pharmacol 2014;2014.

21. Salehabadi A KM, Farzad MH, Namaei MH. Effect of root bark extract of Berberis vulgaris L. on leishmania major on BALB/c mice. Parasitol Res 2014;113:953-957.

22. Minaiyan M, Ghannadi A, Mahzouni P, Jaffari-Shirazi E. Comparative study of Berberis vulgaris fruit extract and berberine chloride effects on acetic acid-induced colitis in rats. Iran J Pharm Res 2011:97-104.

23. Liu CS, Zheng YR, Zhang YF, Long XY. Research progress on berberine with a special focus on its oral bioavailability. Fitoterapia 2016;109:274-282.

24. Feng R, Shou JW, Zhao ZX, He CY, Ma C, Huang M, et al. Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci Rep 2015;5:12155.

25. Tan XS, Ma JY, Feng R, Ma C, Chen WJ, Sun YP, et al. Tissue distribution of berberine and its metabolites after oral administration in rats. PloS One 2013;8.

26. Guo Y, Li F, Ma X, Cheng X, Zhou H, Klaassen CD. CYP2D plays a major role in berberine metabolism in liver of mice and humans. Xenobiotica 2011;41:996-1005.

27. Eaton DL, Gilbert SG. Principles of Toxicology. In: D.Kilassen C, editor. Casarett & Doull's Toxicology the basic science of poisons. 8st ed. New York: MC Grow Hi education; 2013. p. 34-37.

28. Peychev L. Pharmacological investigation on the cardiovascular effects of Berberis vulgaris on tested animals. Pharmacia 2005;52:118-121.

29. Morgan M, Bone K, Mills S, McMillan J. Safety monographs. In: Mills S, Bone K, editors. The Essential Guide to Herbal Safety. USA: Elsevier Health Sciences; 2005. p. 255-261.

30. Haginiwa J, Harada M. Pharmacological studies on crude drugs. V. Comparison of berberine type alkaloid-containing plants on their components and several pharmacological actions. Yakugaku Zasshi 1962;82:726-731.

31. Kulkarni SK, Dandiya PC, Varandani NL. Pharmacological investigations of berberine sulphate. Jpn J Pharmacol 1972;22:11-16.

32. Gardner Z, McGuffin M. American Herbal Products Association’s Botanical Safety Handbook. 2nd ed. New York: CRC Press; 2013.p. 130-132.

33. Lampe KF. Berberine. In: Smet PAGMD, K.Keller, R.Hansel, R.F.Chandler, editors. Adverse effects of herbal drugs. 1. New York: Springer-Verlag; 1992. p. 97-104.

34. Kheir MM, Wang Y, Hua L, Hu J, Li L, Lei F, et al. Acute toxicity of berberine and its correlation with the blood concentration in mice. Food Chem Toxicol 2010;48:1105-1110.

35. Yi J, Ye X, Wang D, He K, Yang Y, Liu X, et al. Safety evaluation of main alkaloids from rhizoma coptidis. J Ethnopharmacol 2013;145:303-310.

36. Ho CE, Goh YL, Zhang C. From prejudice to evidence: the case of rhizoma coptidis in singapore. Evid Based Complement Alternat Med 2014;871720:25.

37. Ning N, Wang YZ, Zou ZY, Zhang DZ, Wang DZ, Li XG. Pharmacological and safety evaluation of fibrous root of rhizoma coptidis. Environ Toxicol Pharmacol 2015;39:53-69.

38. Kupeli E, Kosar M, Yesilada E, Husnu K, Baser C. A comparative study on the anti-inflammatory, antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of turkish berberis species. Life Sci 2002;72:645-657.

39. Yesilada E, Kupeli E. Berberis crataegina DC. root exhibits potent anti-inflammatory, analgesic and febrifuge effects in mice and rats. J Ethnopharmacol 2002;79:237-248.

40. Mahmoudi M, Zamani Taghizadeh Rabe S, Balali-Mood M, Karimi G, Memar B, Rahnama M, et al. Immunotoxicity induced in mice by subacute exposure to berberine. J Immunotoxicol 2016;13:255-262.

41. Philogene BJ, Arnason JT, Towers GH, Abramowski Z, Campos F, Champagne D, et al. Berberine: a naturally occurring phototoxic alkaloid. J Chem Ecol 1984;10:115-123.

42. Zhou JY, Zhou SW, Zhang KB, Tang JL, Guang LX, Ying Y, et al. Chronic effects of berberine on blood, liver glucolipid metabolism and liver PPARs expression in diabetic hyperlipidemic rats. Biol Pharm Bull 2008;31:1169-1176.

43. Li K, Yao W, Zheng X, Liao K. Berberine promotes the development of atherosclerosis and foam cell formation by inducing scavenger receptor A expression in macrophage. Cell Res 2009;19:1006-1017.

44. Shouye Y, Xuhua W. A research on the erupted fetal diseases caused by traditional Chinese drugs—discussion from the issue that chinese goldthread rhizome is prohibited in Singapore. J Tradit Chin Med 2008;28:235-240.

45. Bone K. Berberine-containing herbs and pregnancy. Townsend Letter: The Examiner of Alternative Medicine 2007:59-61.

46. Jahnke GD, Price CJ, Marr MC, Myers CB, George JD. Developmental toxicity evaluation of berberine in rats and mice. Birth Defects Res B Dev Reprod Toxicol 2006;77:195-206.

47. Chan E. Displacement of bilirubin from albumin by berberine. Neonatology 1993;63:201-208.

48. Lin N, Gao X, Li J, Zhu J. Influence of huanglian and berberine on the erythrocytic osmotic fragilitas of experimental glucose-6-phosphate dehydrogenase deficiency in rats. Zhongguo Zhong Yao Za Zhi 1998;23:562-564.

49. Chen C YZ, Li Y, Fichna J, Storr M. Effects of berberine in the gastrointestinal tract—a review of actions and therapeutic implications. Am J Chin Med 2014;42:1053-1070.

50. Chopra RN IC. Indigenous Drugs of India. Calcutta: Academic Publishers; 1933. p. 294.

51. Pereira CV, Machado NG, Oliveira PJ. Mechanisms of berberine (natural yellow 18)-induced mitochondrial dysfunction: interaction with the adenine nucleotide translocator. Toxicol Sci 2008;105:408-417.

52. Dong D, Sun J, Luo D, Chen Q, Wang F, He S, et al. Effect of berberine on the cytosolic calcium concentration in the single ventricular cell of guinea pig. Chin J Pharm Toxicol 2000; 14: 128-130

53. Li BX, Yang BF, Zhou J, Xu CQ, Li YR. Inhibitory effects of berberine on IK1, IK, and HERG channels of cardiac myocytes. Acta Pharmacol Sin 2001;22:125-131.

54. Zhi D, Feng PF, Sun JL, Guo F, Zhang R, Zhao X, et al. The enhancement of cardiac toxicity by concomitant administration of berberine and macrolides. Eur J Pharm Sci 2015;76:149-155.

55. Rodriguez-Menchaca A, Ferrer-Villada T, Lara J, Fernandez D, Navarro-Polanco RA, Sanchez-Chapula JA. Block of HERG channels by berberine: mechanisms of voltage- and state-dependence probed with site-directed mutant channels. J Cardiovasc Pharmacol 2006;47:21-29.

56. Li CH, Wu DF, Ding H, Zhao Y, Zhou KY, Xu DF. Berberine hydrochloride impact on physiological processes and modulation of twist levels in nasopharyngeal carcinoma CNE-1 cells. Asian Pac J Cancer Prev 2014;15:1851-1857.

57. Yang X, Huang N. Berberine induces selective apoptosis through the AMPK‑mediated mitochondrial/caspase pathway in hepatocellular carcinoma. Mol Med Rep 2013;8:505-510.

58. Xie J, Xu Y, Huang X, Chen Y, Fu J, Xi M, et al. Berberine-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species generation and mitochondrial-related apoptotic pathway. Tumour Biol 2015;36:1279-1288.

59. Chu SC, Yu CC, Hsu LS, Chen KS, Su MY, Chen PN. Berberine reverses epithelial-to-mesenchymal transition and inhibits metastasis and tumor-induced angiogenesis in human cervical cancer cells. Mol Pharmacol 2014;86:609-623.

60. Kysenius K, Brunello CA, Huttunen HJ. Mitochondria and NMDA receptor-dependent toxicity of berberine sensitizes neurons to glutamate and rotenone injury. PloS One 2014;9:e107129.

61. Zhang LY, Wu YL, Gao XH, Guo F. Mitochondrial protein cyclophilin-D-mediated programmed necrosis attributes to berberine-induced cytotoxicity in cultured prostate cancer cells. Biochem Biophys Res Commun 2014;450:697-703.

62. Letasiova S, Jantova S, Miko M, Ovadekova R, Horvathova M. Effect of berberine on proliferation, biosynthesis of macromolecules, cell cycle and induction of intercalation with DNA, dsDNA damage and apoptosis in Ehrlich ascites carcinoma cells. J Pharm Pharmacol 2006;58:263-270.

63. Gu M, Xu J, Han C, Kang Y, Liu T, He Y, et al. Effects of berberine on cell cycle, DNA, reactive oxygen species, and apoptosis in l929 murine fibroblast cells. Evid Based Complement Alternat Med 2015;796306:13.

64. Chen TC, Lai KC, Yang JS, Liao CL, Hsia TC, Chen GW, et al. Involvement of reactive oxygen species and caspase-dependent pathway in berberine-induced cell cycle arrest and apoptosis in C6 rat glioma cells. Int J Oncol 2009;34:1681-1690.

65. Inoue K, Kulsum U, Chowdhury SA, Fujisawa S, Ishihara M, Yokoe I, et al. Tumor-specific cytotoxicity and apoptosis-inducing activity of berberines. Anticancer Res 2005;25:4053-4059.

66. Li W, Hua B, Saud SM, Lin H, Hou W, Matter MS, et al. Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice. Mol Carcinog 2015;54:1096-1109.

67. Choi MS, Oh JH, Kim SM, Jung HY, Yoo HS, Lee YM, et al. Berberine inhibits p53-dependent cell growth through induction of apoptosis of prostate cancer cells. Int J Oncol 2009;34:1221-1230.

68. Anis K, Kuttan G, Kuttan R. Role of berberine as an adjuvant response modifier during tumour therapy in mice. J Pharm Pharmacol 1999;5:697-700.

69. Peng PL, Kuo WH, Tseng HC, Chou FP. Synergistic tumor-killing effect of radiation and berberine combined treatment in lung cancer: the contribution of autophagic cell death. Int J Radiat Oncol Biol Phys 2008;70:529-542.

70. Iizuka N, Miyamoto K, Hazama S, Yoshino S, Yoshimura K, Okita K, et al. Anticachectic effects of coptidisrhizoma, an anti-inflammatory herb, on esophageal cancer cells that produce interleukin 6. Cancer Lett 2000;158:35-41.

71. Kuo CL, Chi CW, Liu TY. The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett 2004;203:127-137.

72. Pereira GC, Branco AF, Matos JA, Pereira SL, Parke D, Perkins EL, et al. Mitochondrially targeted effects of berberine [Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo(5,6-a) quinolizinium] on K1735-M2 mouse melanoma cells: comparison with direct effects on isolated mitochondrial fractions. J Pharmacol Exp Ther 2007;323:636-649.

73. Refaat A, Abdelhamed S, Yagita H, Inoue H, Yokoyama S, Hayakawa Y, et al. Berberine enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast cancer. Oncol Lett 2013;6:840-844.

74. Zhang L, Li J, Ma F, Yao S, Li N, Wang J, et al. Synthesis and cytotoxicity evaluation of 13-n-alkyl berberine and palmatine analogues as anticancer agents. Molecules 2012;17:11294-11302.

75. Pierpaoli E, Damiani E, Orlando F, Lucarini G, Bartozzi B, Lombardi P, et al. Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma. Carcinogenesis 2015;36:1169-1179.

76. Hu X, Wu X, Huang Y, Tong Q, Takeda S, Qing Y. Berberine induces double-strand DNA breaks in Rev3 deficient cells. Mol Med Rep 2014;9:1883-1888.

77. Jagetia GC, Rao. Isoquinoline alkaloid berberine exerts its antineoplastic activity by inducing molecular DNA damage in hela cells: a comet assay study. Biol Med 2015;7:223.

78. Chen S, Wan L, Couch L, Lin H, Li Y, Dobrovolsky VN, et al. Mechanism study of goldenseal-associated DNA damage. Toxicol Lett 2013;221:64-72.

79. Pasqual MS, Lauer CP, Moyna P, Henriques JAP. Genotoxicity of the isoquinoline alkaloid berberine in prokaryotic and eukaryotic organisms. Mutat Res 1993;286:243-252.

80. Xu C, Wang L, Hui X, Ma X, Ma F, Zhao Q, et al. DNA damage and effects on antioxidative enzymes in mouse marrow induced by berberine.  2013 International Conference on Human Health and Medical Engineering; China: WIT Transactions on Biomedicine and Health; 2014. p. 479-486.

81. Xu CB, Wang L, Hui XJ, Ma XP, Bi X, Zhao Q. Genetic toxicity of berberine on mouse heart.  2013 3rd International Conference on Biotechnology, Chemical and Materials Engineering; China: Adv Mat Res; 2014. p. 634-637.

82. Nozaka T, Watanabe F, Tadaki Si, Ishino M, Morimoto I, Kunitomo Ji, et al. Mutagenicity of isoquinoline alkaloids, especially of the aporphine type. Mutat Res 1990;240:267-279.

83. Fu PP, Xia Q, Zhao Y, Wang S, Yu H, Chiang H-M. Phototoxicity of herbal plants and herbal products. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2013;31:213-255.

84. Inbaraj JJ, Kukielczak B, Bilski P, Sandvik S, Chignell C. Photochemistry and photocytotoxicity of alkaloids from goldenseal (Hydrastis canadensis L.) 1. berberine. Chem Res Toxicol 2001;14:1529-1534.

85. Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism 2008;57:712-717.

86. Marin-Neto JA, Maciel BC, Secches AL, Gallo Junior L. Cardiovascular effects of berberine in patients with severe congestive heart failure. Clin Cardiol 1988;11:253-260.

87. Fung FY, Linn YC. Developing traditional chinese medicine in the era of evidence-based medicine: current evidences and challenges. Evid Based Complement Alternat Med 2015;425037:8.

88. Bateman J, Chapman RD, Simpson D. Possible toxicity of herbal remedies. Scott Med J 1998;43:7-15.

89. Linn YC, Lu J, Lim LC, Sun H, Sun J, Zhou Y, et al. Berberine-induced haemolysis revisited: safety of thizoma coptidis and cortex phellodendri in chronic haematological diseases. Phytother Res 2012;26:682-686.

90. Lo SN, Chang YP, Tsai KC, Chang CY, Wu TS, Ueng YF. Inhibition of CYP1 by berberine, palmatine, and jatrorrhizine: selectivity, kinetic characterization, and molecular modeling. Toxicol Appl Pharmacol 2013;272:671-680.

91. Vrzal R, Zdařilová A, Ulrichová J, Bláha L, Giesy JP, Dvořák Z. Activation of the aryl hydrocarbon receptor by berberine in HepG2 and H4IIE cells: biphasic effect on CYP1A1. Biochem Pharmacol 2005;70:925-936.

92. Chu CC, Pan KL, Yao HT, Hsu JT. Development of a whole-cell screening system for evaluation of the human CYP1A2-mediated metabolism. Biotechnol Bioeng 2011;108:2932-2940.

93. Han Y-L, Yu H-L, Li D, Meng X-L, Zhou Z-Y, Yu Q, et al. In vitro Inhibition of huanglian [rhizoma coptidis (L.)] and its six active alkaloids on six cytochrome P450 isoforms in human liver microsomes. Phytother Res 2011;25:1660-1665.

94. Zhao Y, Hellum BH, Liang A, Nilsen OG. The in vitro inhibition of human CYP1A2, CYP2D6 and CYP3A4 by tetrahydropalmatine, neferine and berberine. Phytother Res 2012;26:277-283.

95. Chatterjee P, Franklin MR. Human cytochrome P450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components. Drug Metab Dispos 2003;31:1391-1397.

96. Guo Y, Chen Y, Tan ZR, Klaassen CD, Zhou HH. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol 2012;68:213-217.

97. Wu X, Li Q, Xin H, Yu A, Zhong M. Effects of berberine on the blood concentration of cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic study. Eur J Clin Pharmacol 2005;61:567-572.