sign in sign up
<<
Home , Scutellaria, Scutellaria baicalensis, Scutellaria lateriflora

Medical Hypotheses 133 (2019) 109402

Contents lists available at ScienceDirect

Medical Hypotheses

journal homepage: www.elsevier.com/locate/mehy

The effect of supplementation with baicalensis on hepatic function T ⁎ Basant K. Puria,b, , Nikita Whitec, Jean A. Monroc a C.A.R., Cambridge, UK b Hammersmith Hospital, London, UK c Breakspear Medical Group, Hemel Hempstead, Hertfordshire, UK

ABSTRACT

The dried root of the angiosperm , also known as Chinese skullcap or Baikal skullcap, is widely used in traditional Chinese medicine, Korean traditional medicine and as a nutritional supplement; several studies have indicated that both the supplement and some of its ingredients may have clinically beneficial actions. However, the National Institutes of Health official guidance states that the use of Scutellaria “has been implicated in rare instances of clinically apparent liver injury” and that “the onset of symptoms and jaundice occurred within 6–24 weeks of starting skullcap, and the serum enzyme pattern was typically hepatocellular”, with marked increases in serum alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin levels. Careful perusal of all such published case reports showed that in each case the patient was concurrently taking at least one other supplement which had an established association with hepatic dysfunction. The authors hypothesised that long-term supplementation with Scutellaria baicalensis does not lead to hepatic dysfunction. The aim of this study was to test this hypothesis by assessing liver function before and after starting supplementation with Scutellaria baicalensis. Pre- and post-supplementation serum assays of alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin were carried out in 17 patients (16 female) of average age 38.6 (standard error 4.4) years who had each taken 1335 mg dried root daily for an average of 444 (71) days. The mean baseline versus follow-up values for each liver function test were: alanine transaminase: 25.7 (2.6) IU/L v. 25.1 (1.7) IU/L; aspartate transaminase: 22.1 (1.1) IU/L v. 23.5 (1.3) IU/L; alkaline phosphatase: 63.7 (4.6) IU/L v. 63.3 (3.9) IU/L; and bilirubin: 6.1 (0.6) μM v. 6.0 (0.7) μM. None of these changes was statistically significant; indeed, three of the four parameters showed a non-significant decrease over time. Furthermore, none manifested clinical symptoms or signs of hepatic dysfunction during Scutellaria supplementation. These results suggest that daily intake of a relatively high level of Scutellaria baicalensis for over a year is not associated with any biochemical or clinical evidence of hepatic dysfunction. Indeed, Scutellaria baicalensis has been shown in murine experiments to have hepatoprotective actions.

Introduction and background in the dried root extract of Scutellaria baicalensis including (5,6,7-trihydroxyflavone), (5,7-dihydroxy-8-methoxyflavone), Over 350 species have been identified in the genus Scutellaria of the (5,7,8-trihydroxyflavone), and (5,7- family, of the order of Angiospermae; while many dihydroxy-6-methoxy-2-phenylchromen-4-one) [26,36,43,11]. of these species appear to have medicinally useful properties, one The United States National Institutes of Health (NIH) has reported species in particular, namely Scutellaria baicalensis, is widely used in that the use of Scutellaria “has been implicated in rare instances of traditional Chinese medicine, Korean traditional medicine and as a clinically apparent liver injury” and that “the onset of symptoms and nutritional supplement [13,42]. This species is particularly found in jaundice occurred within 6 to 24 weeks of starting skullcap, and the , the Korean peninsula, and parts of Russia serum enzyme pattern was typically hepatocellular” (https://livertox. [45,22,40,17]. Dried extracts of the root of Scutellaria baicalensis, also nih.gov/Skullcap.htm). The NIH web-site quotes in detail a case report known as Chinese skullcap or Baikal skullcap, have been found to en- published in 1994 in which a 53-year-old woman, with no previous hance functioning of the immune system [20,38]; have anti-androgenic history of hepatic disease and no history of abuse or viral he- and growth-inhibitory actions in prostate cancer [5]; have anti-pro- patitis risk factors, developed insomnia, and jaundice four liferative and apoptotic activity in acute lymphocytic leukaemia, lym- weeks after starting to take an herbal sleep preparation which con- phoma and myeloma cell lines [27]; induce cell cycle arrest and tained Scutellaria [7]. Her serum liver function tests were markedly apoptosis in human lung cancer cells [19]; reduce gingivitis and dental elevated, as follows. Serum alanine transaminase (ALT): 1208 IU/L plaque [3]; reduce body mass and blood triglycerides in diabetic mice (normally should be below 65 IU/L); alkaline phosphatase: 298 IU/L [39]; and have been used for many other conditions, such as the (normally should be below 136 IU/L); and bilirubin: 9.0 mg/dL (normal treatment of diarrhoea, dysentery, hypertension, insomnia and re- range < 1.2 mg/dL). Within four weeks of stopping the herbal sup- spiratory infections [46]. Many active flavonoids have been discovered plementation, the jaundice had resolved and the serum bilirubin was in

⁎ Corresponding author at: Hammersmith Hospital, Du Cane Road, London W12 0HS, England, UK. E-mail address: [email protected] (B.K. Puri). https://doi.org/10.1016/j.mehy.2019.109402 Received 2 August 2019; Received in revised form 5 September 2019; Accepted 16 September 2019 0306-9877/ © 2019 Elsevier Ltd. All rights reserved. B.K. Puri, et al. Medical Hypotheses 133 (2019) 109402 the normal range and by 12 weeks her serum ALT and alkaline phos- supplementation with acute liver injury apply here also. phatase concentrations were also in their respective normal ranges. Finally, the preparation taken by the patient described by There have been several more recent similar case reports. A 78-year- Papafragkakis et al. [32] also contained black catechu, which is derived old woman presented with acute painless jaundice three weeks after from Acacia catechu. Therefore the above comments relating to ca- starting a supplement containing Scutellaria baicalensis, and her liver techins also apply here. function tests were also markedly elevated: serum ALT 1626 IU/L; as- partate transaminase (AST) 1053 IU/L (normal range 15–59 IU/L); al- The hypothesis kaline phosphatase: 354 IU/L; and bilirubin: 7.2 mg/dL [44]. Liver biopsy findings were consistent with acute drug-induced . Four In light of the above evidence, the authors hypothesised that long- weeks after stopping the supplement her liver function tests had im- term supplementation with Scutellaria baicalensis does not lead to he- proved, with the serum alkaline phosphatase and bilirubin levels al- patic dysfunction. ready normalised [44]. Chalasani and colleagues reported a series of four female patients, Evaluation of the hypothesis average age 61 years, who developed acute hepatic injury which was thought to be caused by taking flavocoxid, a proprietary blend of bio- This hypothesis was tested by assessing liver function tests in pa- flavonoids, including baicalin, for osteoarthritis. The mean time to tients before and after starting supplementation with Scutellaria baica- onset after starting flavocoxid was 11.2 weeks, and the mean liver lensis, in line with the above case reports. It should be noted that the function test findings were: ALT 1268 IU/L; alkaline phosphatase: above-mentioned liver function tests are sensitive indicators of hepatic 510 IU/L; and bilirubin: 9.4 mg/dL [10]. Between three and 12 weeks dysfunction, with ALT and AST indexing hepatic necroinflammation, after stopping flavocoxid their liver function test results had normalised alkaline phosphatase indexing cholestatic biliary tract dysfunction and and none of the patients showed evidence of chronic hepatic injury bilirubin measuring hepatic excretory function Martin et al. [30]. The [10]. A similar case report has been published in respect of the over- above NIH web-site mentions an onset up to 24 weeks after commen- the-counter arthritis supplement Move Free®, which contains Scutellaria cing supplementation, and therefore it was important to carry out the baicalensis [15], and regarding a supplement containing Scutellaria present study over a period of well over 24 weeks. baicalensis taken for joint pain [32]. An audit was carried out of 17 consecutive patients attending the Each of these cases was perused in detail by the one of authors Breakspear Medical Group who had started long-term supplementation (BKP). In the case reported by Caldwell et al. [7], the patient had taken with Scutellaria baicalensis in 2016–2018. The study had research ethics an herbal preparation containing both Scutellaria and root committee approval and was carried out in accordance with the (Valeriana officianalis) to help alleviate her worsening insomnia. An in Declaration of Helsinki. Each patient took three capsules of Scutellariae vitro study on human hepatic microsomes has shown that valerian and Vegetable (Scutellaria baicalensis) (Solgar, Leonia, NJ, USA) daily. Each valerian-containing products inhibit glucuronidation and so are likely capsule provided 370 mg raw Scutellaria root powder and 75 mg to interfere with the metabolism of xeno- and endobiotics [2]. A case of Scutellaria baicalensis root extract; the other ingredients were hydro- valerian-associated hepatotoxicity has been described [12], as has a xypropyl methylcellulose (or hypromellose) for the vegetable capsule case of valerian-associated hepatitis which responded to steroids [25]. shell and magnesium stearate as an anti-caking agent. Interestingly, in the original case report by Caldwell et al. [7], the pa- The age and sex of each subject, as well as any symptoms or signs of tient also regularly drank herbal tea containing chaparral (Larrea hepatic dysfunction, were recorded. From venous blood samples taken tridentate); this , too, has been associated with liver toxicity in prior to starting the supplement and again at least 24 weeks after many published case reports [23,8,37,1,4,21,35,24]. starting, pre- and post-supplementation serum assays of ALT, AST, al- Regarding the case described by Yang et al. [44], the Chinese kaline phosphatase and bilirubin were carried out at the The Doctors skullcap-containing supplement taken by the patient, namely Move Laboratory (London, UK). Free Advanced®, also contained glucosamine and chondroitin. Supple- After checking the data distributions for normality using the mentation with the combination of glucosamine and chondroitin is Shapiro-Wilk test, the changes in liver function tests (post-supple- associated with acute liver injury [9,41]. Indeed, in their study of 151 mentation versus pre-supplementation) were assessed using the two- patients with chronic liver disease, Cerda et al. [9] concluded that “The tailed paired t-test. The software package used for the statistical ana- consumption of products containing glucosamine and/or chondroitin lyses was R version 3.4.2, running on an x86_64-w64-mingw32/x64 sulfate is frequent among patients with chronic liver diseases and (64-bit) platform [34]. should be taken into account on the appearance of alterations in liver The study sample of 17 patients consisted of one male and 16 female function tests not explained by the underlying disease.” subjects, with a mean (standard error) age of 38.6 (4.4) years. Each In the case series described by Chalasani et al. [10], the acute he- took 1335 mg dried root supplementation daily for an average of 444 patic injury was attributed to flavocoxid. In addition to baicalin, this (71) days. None of the patients manifested clinical symptoms or signs of also contains the flavan flavonoid derived from Acacia catechu. hepatic dysfunction during Scutellaria supplementation. As Chalasani et al. [10] pointed out, “The hepatotoxic potential of the The pre- and post-supplementation mean values of each of the liver green tea extracts that contain in humans is well recognized… function tests, together with their associated t-test statistics, are shown Two catechins contained within the green tea are epigallocatechin in Table 1 and Figs. 1–4. None of the corresponding Shapiro-Wilk tests gallate (EGCG) and epicatechin gallate (ECG), and it is generally be- showed any evidence of deviation from normality. It should be noted lieved that EGCG is responsible for the hepatotoxicity due to green tea that the units for bilirubin concentrations are given as μM, which is the extracts. It is interesting that epicatechin is the flavonoid in that is unit most commonly used in the UK for this assay, in contrast to mg/dL, common to both green tea and flavocoxid, raising the suspicion if it is which is the unit of choice in the USA. The laboratory normal ranges for the culprit ingredient for causing liver injury.” It is also possible that these four assays were as follows: ALT 10–35 IU/L; AST < 31 IU/L; hypersensitivity may have contributed since “immunoallergic features alkaline phosphatase 35–104 IU/L; and bilirubin < 20 μM (equivalent occurred in some patients and flavocoxid is also associated with a hy- to approximately 1.17 mg/dL). persensitivity pneumonitis” [29,10]. The patient described by Dhanasekaran et al. [15] had been taking Discussion the supplement Move Free® which, like Move Free Advanced® (see above), also contained glucosamine and chondroitin. Thus the above In the present study, all the baseline values of the four liver function comments relating to the association of glucosamine and chondroitin tests were within their respective normal ranges. They all remained

2 B.K. Puri, et al. Medical Hypotheses 133 (2019) 109402

Table 1 Pre- and post-supplementation liver function test results. Standard errors are given in parentheses. The corresponding Shapiro-Wilk tests showed no evidence of deviation from normality.

Serum assay Mean pre-supplementationconcentration Mean post-supplementationconcentration Paired t-test

tdfp

ALT (IU/L) 25.76 (2.62) 25.06 (1.75) 0.30599 16 0.7636 AST (IU/L) 22.06 (1.09) 23.50 (1.25) 1.0790 15 0.2976 Alkaline phosphatase (IU/L) 63.71 (4.56) 63.29 (3.93) 0.14666 16 0.8852 Bilirubin (μM) 6.12 (0.59) 6.00 (0.66) 0.2120 16 0.8348

Fig. 1. Boxplots showing pre- and post-supplementation ALT concentrations. Fig. 3. Boxplots showing pre- and post-supplementation alkaline phosphatase concentrations.

Fig. 2. Boxplots showing pre- and post-supplementation AST concentrations. Fig. 4. Boxplots showing pre- and post-supplementation bilirubin concentra- tions. normal following an average of 444 days’ supplementation with a re- latively high daily intake of 1335 mg dried Scutellaria baicalensis root. Not only was none of the changes in each of these four tests statistically In attempting to reconcile the present results with the case report fi significant, but three of the four assays showed a non-significant de- ndings detailed above, it is noteworthy that, in all the case reports, the crease over time, corresponding to a non-significant improvement in patients had taken a combination of supplements rather than a sup- hepatic function while taking this supplement. plement consisting of just Scutellaria baicalensis (as in the present

3 B.K. Puri, et al. Medical Hypotheses 133 (2019) 109402 study). As mentioned above, in each case at least one of these other for 15 out of the 17 patients and showed a non-significant decrease. The supplement ingredients is known to cause liver damage. mean pre-supplementation GGT level was 15.13 (2.75) IU/L, while the Thus, it possible that one or more non-Scutellaria ingredients might mean post-supplementation level was 13.80 (1.30) IU/L (normal range have been responsible for the acute liver injury described in the above 6–42 IU/L; t = 0.4987, df = 14, p = 0.6258; LibreOffice Calc v. 6.0.7.3, case reports. Furthermore, far from a mechanism of hepatotoxicity build ID: 1:6.0.7-0ubuntu0.18.04.9, OS: Linux 4.15). Again, these having been found, Scutellaria baicalensis has actually been shown to findings are in line with our hypothesis. have hepatoprotective actions. For example, in a rat model, Scutellaria baicalensis has been reported to inhibit hepatic fibrosis induced by Grant support carbon tetrachloride or bile duct ligation [31]. In another rat experi- ment, Scutellaria baicalensis was found to protect against aflatoxin-B1- Nil. induced hepatic mutagenesis [14]. Again, a study in mice has shown that Scutellaria baicalensis protects against alcohol-induced acute liver Declaration of Competing Interest injury, possibly by downregulating a marker of endoplasmic reticulum stress [16]. Indeed, skullcapflavone I derived from Scutellaria baicalensis The authors declare that they have no known competing financial may potentially be able to reverse liver fibrosis [33]. It has also been interests or personal relationships that could have appeared to influ- found that baicalein, baicalin and wogonin, derived from Scutellaria ence the work reported in this paper. baicalensis, inhibit hemin-nitrite-hydrogen peroxide-induced hepatic injury; this appears to be dose-dependent and mediated by the inhibi- References tion of certain nitro-oxidative reactions [47]. Low-dose baicalin has been shown to upregulate the expression of multiple angiogenic genes [1] Alderman S, Kailas S, Goldfarb S, Singaram C, Malone DG. Cholestatic hepatitis after to increase cell proliferation in developing blood vessels, while high- ingestion of chaparral leaf: confirmation by endoscopic retrograde cholangiopan- creatography and liver biopsy. J Clin Gastroenterol 1994;19:242–7. dose baicalin inhibits angiogenesis by inducing cell death, suggesting [2] Alkharfy KM, Frye RF. Effect of valerian, valerian/hops extracts, and dose-dependent dual effects; the compound baicalein has been found to on glucuronidation in vitro. Xenobiotica 2007;37:113–23. exhibit only inhibitory effects [48]. [3] Arweiler NB, Pergola G, Kuenz J, Hellwig E, Sculean A, Auschill TM. Clinical and antibacterial effect of an anti-inflammatory toothpaste formulation with Scutellaria It is germane to draw attention to the detailed review of herbal and baicalensis extract on experimental gingivitis. Clin Oral Investig 2011;15:909–13. dietary supplement hepatotoxicity by Bunchorntavakul and Reddy [6], [4] Batchelor WB, Heathcote J, Wanless IR. Chaparral-induced hepatic injury. Am J who point out that ‘Currently, there is no gold standard, even with a Gastroenterol 1995;90:831–3. liver biopsy, for the diagnosis of herbal hepatotoxicity. The diagnosis, [5] Bonham M, Posakony J, Coleman I, Montgomery B, Simon J, Nelson PS. Characterization of chemical constituents in Scutellaria baicalensis with anti- therefore, depends greatly on the exclusion of other causes of liver androgenic and growth-inhibitory activities toward prostate carcinoma. Clin Cancer disease by a thorough clinical assessment, as well as laboratory testing. Res 2005;11:3905–14. The possibility of herbal hepatotoxicity superimposed on pre-existing [6] Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement he- patotoxicity. Aliment Pharmacol Ther 2013;37:3–17. liver disease should also be considered, especially because many herbal [7] Caldwell SH, Feeley JW, Wieboldt TF, Featherston PL, Dickson RC. Acute hepatitis remedies are used by patients with chronic liver diseases, and in this with use of over-the-counter herbal remedies. Va Med Q 1994;121:31–3. – situation, it is more challenging to make a clear-cut diagnosis.’ They [8] Centers for Disease, C. Chaparral-induced toxic hepatitis California and Texas, 1992. Morb. Mortal. Wkly. Rep. 41: pp. 812–814, 1992. point out, for example, that acute hepatitis E has been found to be re- [9] Cerda C, Bruguera M, Pares A. Hepatotoxicity associated with glucosamine and sponsible for some suspected cases of drug-induced hepatic injury. chondroitin sulfate in patients with chronic liver disease. World J Gastroenterol Therefore, in cases of elevated liver function test results in patients 2013;19:5381–4. [10] Chalasani N, Vuppalanchi R, Navarro V, Fontana R, Bonkovsky H, Barnhart H, et al. taking supplements, it is important to check for other causes including Acute liver injury due to flavocoxid (Limbrel), a medical food for osteoarthritis: a various types of infectious hepatitis, α1-antitrypsin deficiency, chemi- case series. Ann Intern Med 2012;156(857–860):w297–300. cally induced hepatitis, haemochromatosis, Wilson’s disease, non-al- [11] Cheng CS, Chen J, Tan HY, Wang N, Chen Z, Feng Y. Scutellaria baicalensis and cancer treatment: recent progress and perspectives in biomedical and clinical stu- coholic steatohepatitis and tick-borne illnesses such as chronic Q-fever. dies. Am J Chin Med 2018;46:25–54. Indeed, it is noteworthy that not all the above case reports pointing to a [12] Cohen DL, Del Toro Y. A case of valerian-associated hepatotoxicity. J Clin possible association between Scutellaria supplementation and hepato- Gastroenterol 2008;42:961–2. toxicity involved a comprehensive search for other causes of liver [13] Cole IB, Cao J, Alan AR, Saxena PK, Murch SJ. Comparisons of Scutellaria baica- lensis, Scutellaria lateriflora and Scutellaria racemosa: genome size, antioxidant toxicity. potential and phytochemistry. Planta Med 2008;74:474–81. In sum, the present study provides no evidence that Scutellaria [14] de Boer JG, Quiney B, Walter PB, Thomas C, Hodgson K, Murch SJ, et al. Protection fl baicalensis supplementation is associated with liver damage. In clinical against a atoxin-B1-induced liver mutagenesis by Scutellaria baicalensis. Mutat Res 2005;578:15–22. practice it should be noted that baicalin may increase the risk of [15] Dhanasekaran R, Owens V, Sanchez W. Chinese skullcap in move free arthritis bruising and bleeding, especially if a patient is taking anticoagulant supplement causes drug induced liver injury and pulmonary infiltrates. Case medication [28]. It may also decrease statin levels; it is metabolised by Reports Hepatol 2013;2013:965092. [16] Dong Q, Chu F, Wu C, Huo Q, Gan H, Li X, et al. Scutellaria baicalensis Georgi the cytochrome P450 system and so may potentially lead to increased extract protects against alcoholinduced acute liver injury in mice and affects the side-effects of other prescribed drugs [18]. Sixteen of the 17 partici- mechanism of ER stress. Mol Med Rep 2016;13:3052–62. pants in the present study were female, and the average age of all the [17] Elkin YN, Kulesh NI, Stepanova AY, Solovieva AI, Kargin VM, Manyakhin AY. Methylated flavones of the hairy root culture Scutellaria baicalensis. J Physiol participants was in the 30s; therefore, without further testing of more 2018;231:277–80. male participants or of those of more advanced age, caution must be [18] Fan L, Zhang W, Guo D, Tan ZR, Xu P, Li Q, et al. The effect of exercised in concluding that Scutellaria will not lead to hepatic dys- baicalin on pharmacokinetics of rosuvastatin, substrate of organic anion-trans- porting polypeptide 1B1. Clin Pharmacol Ther 2008;83:471–6. function in patients. [19] Gao J, Morgan WA, Sanchez-Medina A, Corcoran O. The ethanol extract of Finally, it is noteworthy that, in general, γ-glutamyl transpeptidase Scutellaria baicalensis and the active compounds induce cell cycle arrest and (GGT) levels were not reported in the studies mentioned above. This is apoptosis including upregulation of p53 and Bax in human lung cancer cells. – in spite of the fact that the GGT level is a highly sensitive and non- Toxicol Appl Pharmacol 2011;254:221 8. [20] Gol'dberg VE, Ryzhakov VM, Matiash MG, Stepovaia EA, Boldyshev DA, Litvinenko specific test of hepatic function; its level usually rises before the levels VI, et al. Dry extract of Scutellaria baicalensis as a hemostimulant in antineoplastic of other liver function test enzymes when the bile ducts become ob- chemotherapy in patents with lung cancer. Eksp Klin Farmakol 1997;60:28–30. structed and it is a particularly sensitive liver enzyme for detecting bile [21] Gordon DW, Rosenthal G, Hart J, Sirota R, Baker AL. Chaparral ingestion. The broadening spectrum of liver injury caused by herbal medications. JAMA duct problems. It is therefore recommended that the GGT level be in- 1995;273:489–90. cluded in future studies of this herb. In the cohort described in the [22] Guo L, Wang S, Zhang J, Yang G, Zhao M, Ma W, et al. Effects of ecological factors present study, pre- and post-supplementation GGT levels were available on secondary metabolites and inorganic elements of Scutellaria baicalensis and

4 B.K. Puri, et al. Medical Hypotheses 133 (2019) 109402

analysis of geoherblism. Sci China Life Sci 2013;56:1047–56. Molecules 2014;19:2536–45. [23] Katz M, Saibil F. Herbal hepatitis: subacute hepatic necrosis secondary to chaparral [37] Smith BC, Desmond PV. Acute hepatitis induced by ingestion of the herbal medi- leaf. J Clin Gastroenterol 1990;12:203–6. cation chaparral. Aust N Z J Med 1993;23:526. [24] Kauma H, Koskela R, Makisalo H, Autio-Harmainen H, Lehtola J, Hockerstedt K. [38] Smol'ianinov ES, Gol'dberg VE, Matiash MG, Ryzhakov VM, Boldyshev DA, Toxic acute hepatitis and hepatic fibrosis after consumption of chaparral tablets. Litvinenko VI, et al. Effect of Scutellaria baicalensis extract on the immunologic Scand J Gastroenterol 2004;39:1168–71. status of patients with lung cancer receiving antineoplastic chemotherapy. Eksp [25] Kia YH, Alexander S, Dowling D, Standish R. A case of steroid-responsive valerian- Klin Farmakol 1997;60:49–51. associated hepatitis. Intern Med J 2016;46:118–9. [39] Song KH, Lee SH, Kim BY, Park AY, Kim JY. Extracts of Scutellaria baicalensis [26] Kim AR, Kim SN, Jung IK, Kim HH, Park YH, Park WS. The inhibitory effect of reduced body weight and blood triglyceride in db/db Mice. Phytother Res Scutellaria baicalensis extract and its active compound, baicalin, on the transloca- 2013;27:244–50. tion of the androgen receptor with implications for preventing androgenetic alo- [40] Venkatarame Gowda Saralamma V, Lee HJ, Hong GE, Park HS, Yumnam S, Raha S, pecia. Planta Med 2014;80:153–8. Lee WS, Kim EH, Sung NJ, Lee SJ, Heo JD, Kim GS. Korean Scutellaria baicalensis [27] Kumagai T, Muller CI, Desmond JC, Imai Y, Heber D, Koeffler HP. Scutellaria Georgi flavonoid extract induces mitochondrially mediated apoptosis in human baicalensis, a herbal medicine: anti-proliferative and apoptotic activity against gastric cancer AGS cells. Oncol Lett 2017;14:607–14. acute lymphocytic leukemia, lymphoma and myeloma cell lines. Leuk Res [41] von Felden J, Montani M, Kessebohm K, Stickel F. Drug-induced acute liver injury 2007;31:523–30. mimicking autoimmune hepatitis after intake of dietary supplements containing [28] Lee W, Ku SK, Bae JS. Antiplatelet, anticoagulant, and profibrinolytic activities of glucosamine and chondroitin sulfate. Int J Clin Pharmacol Ther 2013;51:219–23. baicalin. Arch Pharm Res 2015;38:893–903. [42] Wang L, Shen X, Mi L, Jing J, Gai S, Liu X, et al. Simultaneous determinations of [29] Levy RM. Flavocoxid and hypersensitivity pneumonitis. Chest 2011;140:827–8. four major bioactive components in Acacia catechu (L.f.) Willd and Scutellaria [30] Martin P. Approach to the patient with liver disease. In: Goldman L, Schafer AI, baicalensis Georgi extracts by LC-MS/MS: Application to its herb-herb interactions editors. Goldman-Cecil Medicine. 25th ed.Philadelphia, PA: Elsevier; 2016. p. based on pharmacokinetic, tissue distribution and excretion studies in rats. 976–83. Phytomedicine 2018;56:64–73. [31] Nan JX, Park EJ, Kim YC, Ko G, Sohn DH. Scutellaria baicalensis inhibits liver fi- [43] Wang MH, Li LZ, Sun JB, Wu FH, Liang JY. A new antioxidant flavone glycoside brosis induced by bile duct ligation or carbon tetrachloride in rats. J Pharm from Scutellaria baicalensis Georgi. Nat Prod Res 2014;28:1772–6. Pharmacol 2002;54:555–63. [44] Yang L, Aronsohn A, Hart J, Jensen D. Herbal hepatoxicity from Chinese skullcap: a [32] Papafragkakis C, Ona MA, Reddy M, Anand S. Acute Hepatitis after ingestion of a case report. World J Hepatol 2012;4:231–3. preparation of chinese skullcap and black catechu for joint pain. Case Reports [45] Yuan QJ, Zhang ZY, Hu J, Guo LP, Shao AJ, Huang LQ. Impacts of recent cultivation Hepatol 2016;2016:4356749. on genetic diversity pattern of a medicinal plant, Scutellaria baicalensis [33] Park EJ, Zhao YZ, Lian L, Kim YC, Sohn DH. Skullcapflavone I from Scutellaria (Lamiaceae). BMC Genet 2010;11:29. baicalensis induces apoptosis in activated rat hepatic stellate cells. Planta Med [46] Zhao Q, Chen XY, Martin C. Scutellaria baicalensis, the golden herb from the garden 2005;71:885–7. of Chinese medicinal . Sci Bull (Beijing) 2016;61:1391–8. [34] Core R, Team R. A language and environment for statistical computing. Vienna, [47] Zhao Y, Li H, Gao Z, Gong Y, Xu H. Effects of flavonoids extracted from Scutellaria Austria: R Foundation for Statistical Computing; 2017. baicalensis Georgi on hemin-nitrite-H2O2 induced liver injury. Eur J Pharmacol [35] Sheikh NM, Philen RM, Love LA. Chaparral-associated hepatotoxicity. Arch Intern 2006;536:192–9. Med 1997;157:913–9. [48] Zhu D, Wang S, Lawless J, He J, Zheng Z. Dose dependent dual effect of baicalin and [36] Shin HS, Bae MJ, Choi DW, Shon DH. Skullcap (Scutellaria baicalensis) extract and herb Huang Qin extract on angiogenesis. PLoS One 2016;11(11):e0167125. its active compound, wogonin, inhibit ovalbumin-induced Th2-mediated response.

5