Iranian Journal of Basic Medical Sciences ijbms.mums.ac.ir Special issue Toxicology effects of Berberis vulgaris (barberry) and its active constituent, berberine: a review Seyede Zohre Kamrani Rad 1, Maryam Rameshrad 1, 2, Hossein Hosseinzadeh 1, 2* 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 A R T I C L E I N F O A B S T R A C T Article type: Berberis vulgaris and berberine, its main component, traditionally have been used for treatment of Reivew article 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 Article history: documents have revealed negative impacts of it on animal and human. In this regards, the Received: Dec 5, 2016 determination of its toxicity in a scientific view is necessary. In current report, we provide classified Accepted: Apr 13, 2017 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, Keywords: and carcinogenicity of B. vulgaris and berberine as well as developmental toxicity and clinical studies. Acute toxicity Data from the present study indicate that their toxicity is depending on the route and duration of Berberine administration. According to present study, they could induce GI upset and ulceration, immunotoxicity, Berberis vulgaris phototoxicity, neurotoxicity, cardiotoxicity and jaundice in a dose dependent manner. They should be Cancer cell used with caution in pregnancy, neonatal and G6PD deficiency. Besides, consideration should be taken Chronic toxicity in co-administration of berberine with drugs that are metabolized with CYP enzymes due their CYP enzyme inhibitory effects on these enzymes. Furthermore, they evoke cytotoxicity on both normal and cancer Developmental toxicity cell line which is time and concentration dependent. Pregnancy ►Please cite this article as: Kamrani Rad SZ, Rameshrad M, Hosseinzadeh H. Toxicology effects of Berberis vulgaris (barberry) and its active constituent, berberine: a review Iran J Basic Med Sci 2017; 20:516-529. doi: 10.22038/IJBMS.2017.8676 Introduction goldthread). Berberine widely consumed in Ayurvedic The genus Berberis with more than 500 species and Chinese medicine. (4, 6, 7). Berberine has been belongs to Berberidaceae family (1). Berberis vulgaris isolated from various parts of these species such as which is known as barberry, common or European root, stem, bark, fruit and rhizome (6). barberry (2) is an evergreen shrub which possesses Traditional use of root, bark, leaf and fruits yellow, spiny, angled or sulcated bark, oblong, obovate, of barberry as an immunemodulator and anti-microbial or elliptic leaves, yellow flowers and red, oblong agent as well as a treatment for central nervous system, fruits (3). It grows in Asia and Europe and is a cardiovascular, gastrointestinal, endocrine, and well-known herb in Iran (4). The main isolated renal problems have been proved with so many compounds from B. vulgaris are tannins, phenolic pharmacological studies (4, 8). Recently published compounds, triterpenes (lupeol, oleanolic acid), sterols articles demonstrated that barberry and berberine (its (stigmasterol, stigmasterol glucoside) and alkaloids main constituents) have anti-oxidant (9), anti- (berberamine, palmatine, berberine, oxyberberine, inflammatory (10), anti-tumor (11), anti-mutagenic (12) columbamine, isocorydine,Archive lambertinea and magniflo- and antiof-diabetic (9)SID effects. Their hypoglycemic and rine). Besides, bisbenzlisoquinolines (oxycanthine), cholesterol lowering properties (13), neuroprotective N-(p-trans- coumaroyl) tyramine, cannabisin G and (14), and hepatoprotective (15-17), effects have (±)-lyoniresinol have been isolated from this plant (5). scientifically been proved by numerous studies. B. Berberine, an isoquinoline alkaloid, is a member of vulgaris may possesses preventive effects in relapse of naturally occurring protoberberines class (Figure 1). morphine consumption in addicted individuals (18). It This alkaloid is present in plants of Berberidaceae, has been demonstrated that B. vulgaris and berberine Papaveraceae and Ranunculaceae families including induces inhibitory effects on Leishmania species (19-21). Arcangelisia flava (menispermaceae), B. vulgaris Also, it has been reported as an anti-fungal compound (barberry), B. aristata (tree turmeric), B. aquifolium (20). There are evidences in vivo and in vitro that (Oregon prape), B. lyceum, B. crataegina, Hydrastis berberine hydrochloride has beneficial effects on colitis (22). canadensis (goldenseal) and Coptis chinensis (Chinese *Corresponding author: Hossein Hosseinzadeh. Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Tel: +98-51-38819042; Fax: +98-51-38823251; email: [email protected] www.SID.ir Toxicology of barberry and berberine Kamrani Rad et al Berberine Oral administration Absorption Poor oral bioavailability and low plasma level Distribution Extensive tissue cocentration more than plasma Metabolism Intestine Liver Excretion Feces, urine and bile Figure 1. Chemical structure of berberine and its metabolites Berberine could be absorbed from the gastrointes- Figure 2. Schematic diagram of berberine pharmacokinetic tinal (GI) however; its oral bioavailability and its plasma level are very low. It should be noticed that derivative, in terms of acute, sub-acute, sub-chronic, berberine converted to ionized form in the physiolo- chronic toxicity with a mention on their develop- gical conditions and self-aggregated in low pH mental and mutagenic toxicity as evidenced from the conditions. Self-aggregation decreases its solubility in scientific literature in animal and human assays. the GI track and its permeability. The other barriers of berberine oral bioavailability are P-glycoprotein (P- Methods gp) mediated efflux, hepatobiliary re-extraction and A literature search was conducted and the available metabolization by CYP2D6 and CYP3A4 in the intestine information on toxicology and pharmacological proper- (23). It has been shown that berberine is converted to ties of B. vulgaris and berberine was collected via dihydroberberine form by gut flora, which has higher relevant keywords including B. vulgaris, barberry, intestine-absorbable rate in comparison berberine berberine, acute toxicity, sub-acute toxicity, sub-chronic (24). Berberine is distributed in the liver, kidneys, toxicity, chronic toxicity, mutagenic, developmental, muscle, lungs, brain, heart, pancreas and fat. Strikingly, miscarriage, cancer, and clinical trial in the following tissue concentration of berberine and its metabolites is databases: PubMed, Scopus, Google Scholar and Web of higher than plasma concentration (25). Berberine is Science. All kinds of relevant articles, abstracts or books metabolized in the liver by oxidative demethylation and were included. Furthermore, the reference lists of key glucuronidation to berberrubine (M1), thalifendine papers for further leads were searched. No time (M2), demethyleneberberine (M3), and jatrorrhizine limitation was considered in this review. Besides, no (M4) and their glucoronide forms (Figure 1). CYP2D6, constraint was accounted about including all kinds of 1A2, 3A4, 2E1 and CYP2C19 are the main CYPs in berberine containing herbs. Both in vivo and in vitro berberine metabolisms Archive(26). Finally, berberine studies ofwere included SID to this investigation. The toxic metabolites are excreted through feces, urine, and bile effects of barberry and berberine were categorized in (Figure 2). It is important to notice that there are some following main headings: toxicological findings, pharmacokinetic interactions in co-adminstration of developmental toxicity, cytotoxicity, genotoxicity, berberine with metformin, ketoconazole, digoxin and mutagenicity, carcinogenicity and clinical toxicity cyclosporine A (8). (Figure 3). In spite of the panoramic use of barberry in different folklores as an herbal medicine, there is Toxicol ogical findings no comprehensive study which categorized the toxic Acute toxicity effects of barberry in animal models and human Acute toxicity test is the first toxicity assessment studies. Hence, this review discusses on the which is examined during 14 days and determined from the administration of a single exposure. It toxic effects of barberry and berberine, as its main Iran J Basic Med Sci, Vol. 20, No. 5, May 2017 517 www.SID.ir Kamrani Rad et al Toxicology of barberry and berberine Figure 3. Number of published articles which are cited in each field estimates approximate lethal dose or concentration The oral LD50 of isolated berberine from Rhizoma (e.g., LD50 or LC50) as an intrinsic toxicity of coptidis is 713.58 mg/kg in mice that is classified in substance. The most often used species are mouse slight toxicity rank (35, 36). The comparison of and rat (27). fibrous root of Rhizoma coptidis (FRC) with Rhizoma B. vulgaris is moderately toxic. The oral LD50 value coptidis (RC) revealed LD50 value of FRC and RC were for powdered root of B. vulgaris in mice is 2600 mg/kg greater than 7 and 4.89 g/kg in mice, respectively. (28). In “The Essential