PHCOG RES.

ORIGINAL ARTICLE

Hepatoprotective effect of commercial herbal extracts on

carbon tetrachloride-induced liver damage in Wistar rats
Paula Cordero-Pérez, Liliana Torres-González, Marcelino Aguirre-Garza, Carlos Camara-Lemarroy1,
Francisco Guzmán-de la Garza1, Gabriela Alarcón-Galván2, Homero Zapata-Chavira3, Ma. de Jesús
Sotelo-Gallegos, Cipactli Nadjedja Torres-Esquivel, Ethel Sánchez-Fresno, Daniel Cantú-Sepúlveda,
Gerardo González-Saldivar, Judith Bernal-Ramirez, Linda E. Muñoz-Espinosa

Liver Unit, Gastroenterology Service from Department of Internal Medicine, 1Department of Physiology, 2Department of Pathology,
3
Transplant Service, School of Medicine and University Hospital, Universidad Autónoma de Nuevo León, Av. Gonzalitos S/N Col. Mitras Centro
C.P., Monterrey, Nuevo León, México

Submitted: 10-05-2012 Revised: 08-08-2012 Published: 22-05-2013

ABSTRACT
Background: Various hepatoprotective herbal products from plants are available in Mexico, Access this article online
where up to 85% of patients with liver disease use some form of complementary and Website:
www.phcogres.com
alternative medicine. However, only few studies have reported on the biological evaluation of
DOI: 10.4103/0974-8490.112417
these products. Objective: Using a model of carbon tetrachloride (CCl4)-induced hepatotoxicity
Quick Response Code:
in rats, we evaluated the effects of commercial herbal extracts used most commonly in the
metropolitan area of Monterrey, Mexico. Materials and Methods: The commercial products
were identified through surveys in public areas. The effect of these products given with or
without CCl4 in rats was evaluated by measuring the serum concentrations of aspartate
amino transferase (AST) and alanine amino transferase (ALT), and histopathological analysis.
Legalon® was used as the standard drug. Results: The most commonly used herbal products
were Hepatisan® capsules, Boldo capsules, Hepavida® capsules, Boldo infusion, and milk thistle
herbal supplement (80% silymarin). None of the products tested was hepatotoxic according
to transaminase and histological analyses. AST and ALT activities were significantly lower
in the Hepavida+CCl4-treated group as compared with the CCl4-only group. AST and ALT
activities in the silymarin, Hepatisan, and Boldo tea groups were similar to those in the CCl4
group. The CCl4 group displayed submassive confluent necrosis and mixed inflammatory
infiltration. Both the Hepatisan+CCl4 and Boldo tea+CCl4 groups exhibited ballooning
degeneration, inflammatory infiltration, and lytic necrosis. The silymarin+CCl4 group exhibited
microvesicular steatosis. The Hepavida+CCl4- and Legalon+CCL4-treated groups had lower
percentages of necrotic cells as compared with the CCl4-treated group; this treatment was
hepatoprotective against necrosis. Conclusion: Only Hepavida had a hepatoprotective effect.
Key words: Alanine transferase, aspartate transferase, hepatoprotection, liver injury,
natural products

INTRODUCTION used scientific methods to evaluate the effects of plants used

in traditional CAM for the treatment of liver ailments.[7-10] In
Interest in complementary and alternative medicine (CAM) many cases, the mechanisms and modes of action of these
is increasing throughout the world probably because there plants as well as their therapeutic effectiveness have been
are only few universally effective and available options for the confirmed in clinical studies. Several hundred plants have
treatment of common liver diseases such as cirrhosis, fatty been examined so far, but only a handful have been studied
liver, and chronic hepatitis.[1-6] In recent years, researchers have thoroughly. Among these are Silybum marianum (milk thistle),
Picrorhiza kurroa (kutki), Curcuma longa (turmeric), Camellia
sinensis (green tea), and Glycyrrhiza glabra (licorice).[11,12]
Address for correspondence:
Dr. Sc. Paula Cordero-Pérez, Department of Internal Medicine,
Liver Unit, Gastroenterology Service, Av. Gonzalitos #235 Col. The increasing use of herbal medicines reflects their
Mitras Centro C.P. 64460, Monterrey, Nuevo León, México. perceived effectiveness in the treatment and prevention of
E-mail: [email protected]
disease, and the belief that these treatments are safe because

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 Cordero-Pérez, et al.: Hepatoprotecitve effect of commercial herbal extracts

they are “natural.” In addition, most countries do not impose Mexico). Boldo infusion (1 g) was obtained from Therbal
strict regulations on herbal preparations, and, therefore, (Mexico City, Mexico). Milk thistle herbal supplement (80%
access to these kinds of therapies is almost unrestricted.[13,14] silymarin) was obtained from GNC Herbal Plus (Pittsburg,
PA, USA). Pentobarbital sodium was purchased from
The use of CAM in the treatment of liver disease varies among Holland S.A. de C.V. (Jiutepec, Mor, Mexico).
different geographic regions. It is estimated that 20–65% of
the population in Europe, 39% in the United States, and 85% Animal procedures
in Mexico have used CAM for this purpose.[15,16] Several recent Animal procedures were performed in accordance with
surveys from Europe and the United States have demonstrated the Guiding Principles for the Production, Care, and Use
sharp increases in the use of botanical drugs.[15,17] For example, of Laboratory Animals of the Mexican Official Norm
21% of patients attending an outpatient liver clinic took herbal NOM-062-Z00-1999 published in the Federal Official
preparations and 13% used herbs to treat liver diseases as per Diary on August 22, 2001. All protocols used in this study
a previous study.[15] were approved by the ethics committee of our institution.
Experiments were performed on male Wistar rats weighing
The risks of toxicity associated with several commercially 200–300 g. The animals were maintained under standard
available herbal preparations have surfaced recently, conditions, such as stable room temperature (24 ± 3°C), a
challenging the notion that these therapies are innocuous.[18,19] 12 h light/dark cycle, and access to commercial rat pellets
This association between herbal remedies and hepatotoxicity and water ad libitum.
is not a novel finding. It is well known that some plants,
particularly the species containing pyrrolizidine derivatives, Assessment of toxicity in vivo
may be hepatotoxic.[13,20] The risks are particularly high The rats were divided into eight groups (n = 5). One group
when the therapeutic preparation contains a combination received physiological saline (1 ml/kg, p.o.) and served as
of numerous plants. the normal control (NC). One group received a CCl4/oil
preparation (1:1, 1 ml/kg, i.p.) and served as the acute
The present study was undertaken to evaluate the effects toxicity control; this group was sacrificed after 24 h to
of commercial herbal extracts in the normal liver and in obtain liver and blood samples. One group received Legalon
a rat model of acute carbon tetrachloride (CCl4)-induced (70 mg/kg, p.o.), a silymarin preparation that was used as the
hepatotoxicity. CCl4 is a chemical used widely to induce hepatoprotective standard drug. The other groups received
liver damage in experimental studies, and its toxicity has one of the following: Hepatisan (800 mg/kg, p.o.), Boldo
been studied extensively. CCl4-induced hepatic injury capsules (1500 mg/kg, p.o.), Hepavida (1200 mg/kg, p.o.),
is characterized by leakage of cellular enzymes into the Boldo tea (0.1 ml/kg, p.o.), or silymarin (200 mg/kg, p.o.).
bloodstream and by centrilobular necrosis.[21,22] The dose of each product was established based on the
dose stated for human consumption in the product insert.

MATERIALS AND METHODS To evaluate the potential hepatotoxicity, the six commercial
products mentioned above were administered daily for
Identification of commercial herb products 1 week.[23] This duration of treatment was selected to confirm
To identify the five most commonly used commercial that the dose to be tested for hepatoprotection was not toxic.
herbal products employed in the treatment of liver diseases At the end of the week, blood and liver samples were collected,
in the region, we administered surveys in various public and the serum activities of aspartate amino transferase (AST)
areas around the metropolitan area of Monterrey, Nuevo and alanine amino transferase (ALT) were measured, and
León, Mexico. The survey asked the respondents to list all liver samples were analyzed histopathologically. Rats were
the commercial herbal products of which they were aware. anesthetized with pentobarbital sodium (35 mg/kg, i.p.), and
3 ml of blood was obtained from the abdominal aorta of each
Chemicals rat. Serum was obtained after centrifugation at 3500 rpm for
Sodium chloride solution (0.9%) was obtained from PISA 10 min and was stored at −20°C until enzyme analysis. The
(Guadalajara, Jal, Mexico), and olive oil was obtained from livers were dissected carefully and transferred immediately
Ybarra SA (Seville, Spain). CCl4 (99.9%) was purchased to a 10% formalin solution for fixation. Histopathological
from Sigma-Aldrich Chemical Co. (St. Louis, MO, USA). analysis was performed on the fixed tissue.[24,25]
Legalon® 70 mg silymarin) was obtained from Nycomed
(Naucalpan de Juárez, Edo. México, Mexico). Hepatisan Assessment of hepatoprotection in vivo
capsules (400 mg) were obtained from Herbital (Puebla, Pue, To evaluate the possible hepatoprotective effect, an
Mexico). Boldo capsules (500 mg) and Hepavida® capsules additional six groups (n = 5 each) were included:
(400 mg) were obtained from Botnatura (Irapuato, Gto, Legalon+CCl4, Hepatisan+CCl4, Boldo capsules+CCl4,

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 Cordero-Pérez, et al.: Hepatoprotecitve effect of commercial herbal extracts

Hepavida+CCl4, Boldo tea+CCl4, and silymarin+CCl4. RESULTS

To study the effect of the commercial products on CCl4-
induced toxicity, each product was administered at the dose The five most commonly used herbal products for the
described above for 3 consecutive days, and then CCl4/oil treatment of liver diseases in the Monterrey metropolitan
(1:1, 1 ml/kg, i.p.) was administered.[26,27] The rats were area are listed in Table 1. Four products were manufactured
sacrificed 24 h after injection of CCl4, and the samples were in Mexico and one in the United States. There was a wide
obtained as described above. diversity in the constituents of these products. However,
four contained Boldo, two of which contained almost
Measurement of serum transaminases exactly the same ingredients [Table 1].
The activities of AST and ALT were measured using
an automatic biochemical detection system (DTII Vitro Assessment of in vivo toxicity
Systems Chemistry; module DTSCII, Johnson and After 7 days of administration, none of the products tested
Johnson Ortho-Clinical Diagnostics, New Brunswick, increased ALT and AST activities significantly as compared
NJ, USA). In the AST assay (21CFR 862.1100), the amino with the NC group. The ALT and AST activities were
group of l-aspartate is transferred to a-ketoglutarate significantly lower in the Legalon group than in the NC group
in the presence of pyridoxal-5-phosphate to produce (P = 0.0251 and P = 0.0006, respectively) [Table 2]. This
glutamate and oxaloacetate. The oxaloacetate formed in
the deamination of the l-aspartate is converted to malate Table 1: Constituents and sources of
by malate dehydrogenase in the presence of reduced commercial products
nicotinamide adenine dinucleotide (NADH), which is Commercial Ingredients Country
Product
oxidized to NAD+. The rate of oxidation of NADH is
monitored by reflectance spectrophotometry at 37°C. The Hepavida Rhamnus purshiana, Brickellia Mexico
grandiflora, Tagetes floridas,
rate of change is then used to calculate enzyme activity.[28] Arctostaphylos pungens,
In the ALT assay (21 CFR 862.1030), the amino group of Amphipterygium adstringens,
l-alanine is transferred to a-ketoglutarate in the presence of Selaginella spp., Peumus boldus,
Cynara scolymus, Taraxacum
pyridoxal-5-phosphate to produce glutamate and pyruvate. officinale, Foeniculum vulgare,
The pyruvate formed in the deamination of l-alanine Solidago virgaurea, Lantana trifolia,
is converted to lactate by lactate dehydrogenase in the Kohleria deppeana
Boldo capsules Peumus boldus Mexico
presence of NADH, which is oxidized to NAD+. The Hepatisan Rhamnus purshiana, Brickellia Mexico
rate of oxidation of NADH is monitored by reflectance grandiflora, Miconia argentea,
spectrophotometry at 37°C. The rate of change is then Tagetes floridas, Arctostaphylos
pungens, Amphipterygium
used to calculate enzyme activity.[29] adstringens, Selaginella spp.,
Peumus boldus, Cynara scolymus,
Histology Taraxacum officinale, Foeniculum
Liver tissues were embedded in paraffin blocks using vulgare, Solidago virgaurea,
Lantana trifolia, Kohleria deppeana.
conventional methods. The blocks were sectioned Boldo tea 100% (Peumus boldus) Mexico
at 5 µm and stained with hematoxylin–eosin. The Silymarin 80% silymarin USA
slides were obser ved under light microscopy to
identify histopathological changes including ballooning Table 2: AST (IU/L) and ALT (IU/L) activities in
degeneration, lytic necrosis, confluent necrosis, submassive commercial herbal products compared with the
necrosis, microvesicular steatosis, macrovesicular steatosis, normal control
and lymphocytic or mixed inflammatory infiltration. We Treatment AST (IU/L) ALT (IU/L)
also calculated the percentage of necrotic cells from the Mean Standard Mean Standard
number of necrotic or apoptotic cells observed at three error error
different high power fields (X400); from zones 1–3, 50 Normal control 285 31.9 69 10.4
cells were counted in each zone. Legalon 98* 41.2 59 13.4
Hepavida 187 41.2 92 13.4
Boldo capsules 307 41.2 108 13.4
Statistical analysis
Hepatisan 397 41.2 111 13.4
The data are expressed as mean and standard error. The Boldo tea 344 41.2 104 13.4
data were analyzed using the Mann–Whitney–Wilcoxon Silymarin 163 35.7 59 11.6
test, Dunnett’s test, and Pearson correlation where Significance 0.0006** 0.0251**
appropriate. The SPSS statistical software package (v. 16.0; n = 5 rats in each group. The data are expressed as mean and standard error.
AST, aspartate aminotransferase; ALT, alanine aminotransferase. *: Significantly
SPSS Inc., Chicago, IL, USA) was used for all analyses. different from the normal control, Dunnett’s test, P < 0.05. **: Significant,
P < 0.05 was considered significant. Dunnett’s test of the equality of effects for all treatments.

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 Cordero-Pérez, et al.: Hepatoprotecitve effect of commercial herbal extracts

suggests that none of the products tested was hepatotoxic, All animals exhibited hepatocyte ballooning degeneration
at least when given subacutely. independent of the treatment received. The CCl4 group
showed submassive and confluent necrosis with mixed
The livers of the CCl4 group showed severe inflammatory inflammatory infiltration. The Legalon+CCl4 group exhibited
infiltration and necrosis. No other group showed microvesicular steatosis without necrosis, particularly in the
abnormalities in the liver architecture, necrosis, or steatosis. perivenular region. Both the Hepatisan+CCl4 and Boldo
These results indicate that none of the products studied tea+CCl 4 groups exhibited ballooning degeneration,
produced hepatotoxicity. Thus, they were all considered for
lymphocytic or mixed inflammatory infiltration, and
further evaluation of their possible hepatoprotective effects.
lytic necrosis [Figure 1]. The silymarin group exhibited
Assessment of hepatoprotection in vivo microvesicular steatosis irrespective of CCl4 administration.
AST and ALT activities were significantly lower in the
Hepavida+CCl4 and Legalon+CCl4 groups as compared The total percentages of necrotic cells differed significantly
with the CCl4-only group, and these levels were comparable between the treatments. The percentages were significantly
to those of the NC. The enzyme activities were significantly higher in the Hepatisan, Boldo tea, and silymarin groups
higher in the groups treated with silymarin, Hepatisan, and than in the NC. The percentages of necrotic cells were
Boldo tea than in the NC group; the enzyme activities in significantly lower in the Legalon and Hepavida groups
the silymarin, Hepatisan, and Boldo tea groups did not than in the CCl4 group, indicating a hepatoprotective effect
differ significantly from those in the CCl4 group [Table 3]. against necrosis [Table 4].
Table 3: Comparison of AST (IU/L) and ALT (IU/L) activities between treatments with different
commercial herbal products as compared with the normal control and CCl4
Treatment AST (IU/L) ALT (IU/L)
Mean Standard error Mean Standard error
Normal control 285 1920 69 22
CCl4 8421 2479 1439 329
Legalon+CCl4 399 2147 B 102 285 B
Hepavida+CCl4 858 2147 B 246 285 B
Boldo capsules+CCl4 1318 2147 525 285
Hepatisan+CCl4 1485 2147 A,B 478 285 A
Boldo tea+CCl4 12757 2147 A 1459 285 A
Silymarin+CCl4 7577 2147 A 1309 285 A
Significance 0.0015* 0.0034*
n = 5 rats in each group. Results given as mean and standard error. AST, aspartate aminotransferase; ALT, alanine aminotransferase; CCl4, carbon tetrachloride.
*:Significant, Mann–Whitney–Wilcoxon test of the equality of effects for all treatments. A, significantly different from the normal control. B, significantly different from the
toxicity control (CCl4). Mann–Whitney–Wilcoxon test, P < 0.05

Table 4: Comparison of the percentages of

necrotic cells between different commercial
herbal products and controls
Percentage of necrotic cells
Treatment Median Mean Median
range
a b c
Normal control 6 0 0
CCl4 22 47 50
Legalon+CCl4 22 47 50
Hepavida+CCl4 9 B 10 0
Boldo capsule+CCl4 11 B 15 10
Hepatisan+CCl4 12 12 9
d d Boldo tea+CCl4 25 A 55 55
Figure 1: Hematoxylin and eosin staining, X40. (a) Normal control, Silymarin+CCl4 26 A 60 65
normal histological findings in the liver parenchyma. (b) CCl 4, Significance 0.0012*
submassive confluent necrosis and mixed inflammatory infiltration. (c) n = 5 rats in each group. The mean, median, and median range are shown. CCl4,
Legalon+CCl4, perivenular microvesicular steatosis without necrosis. carbon tetrachloride.
(d) Hepatisan+CCl4, ballooning inflammatory infiltration and lytic *:Significant, Mann–Whitney–Wilcoxon test of the equality of effects for all
necrosis. (e) Boldo tea+CCl4, ballooning degeneration, inflammatory treatments. A, significantly different from the normal control. B, significantly
different from the toxicity control (CCl4). Mann–Whitney–Wilcoxon test, P < 0.05
infiltration, and lytic necrosis

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For treatments given without CCl4, the histological changes silymarin stated on the label and how these differ from the
correlated significantly only with AST and ALT activities amount contained in Legalon.
(Pearson correlation = 0.739, P < 0.0001). For treatments
given with CCl4, ALT and AST activities were positively Strenghts and weaknesses of the study
associated with the presence of confluent necrosis We used a well-studied model of hepatotoxicity (CCl4)
(P = 0.0019 and P = 0.0033, respectively) [Table 5]. AST and used both biochemical and histological markers of
activity was also positively associated with submassive liver injury. In addition, we compared the effects of the
necrosis (P = 0.030) [Table 5]. commercial products against the reference drug Legalon,
a drug with established hepatoprotective properties.
DISCUSSION There are some weaknesses in our study. Our sample size
was small (5 animals per group), a fact that could account
Principal findings for the large standard errors we obtained in our data. We
We tested the hepatoprotective effects of five commercial also did not objectively test the commercial products in
herbal products using a rat model of CCl 4-induced order to confirm that they possessed the contents that
hepatotoxicity, comparing them to the reference drug were reported in the label by the manufacturer. There are
Legalon. We found that none showed hepatotoxic also inherent complications in identifying which of the
effects in our experimental model and that only Boldo many components in a commercial mixture of herbs are
tea caused slight histological inflammation after 7 days responsible for its biological effects, if any, are found.
of administration. However, only one of these products
(Hepavida) showed consistent hepatoprotective effects Relation to other studies
against CCl4-induced damage. The reference drug Legalon We know of no other studies that have analyzed the
was also hepatoprotective. hepatoprotective effects of these commercial products. As
mentioned above, Legalon is of established efficacy. Several
Boldo, which comes from a tree in the Monimiaceae family, studies have reported that the major histopathological
is believed to be a regulator of hepatic function and an parameters altered with CCl4-induced damage are
antispasmodic, digestive stimulant, and sedative.[30,31] Four degeneration in hepatocytes, the presence of necrosis
of the products tested contained Boldo, and, of these, and inflammatory infiltration, and elevated ALT and AST
only one had a beneficial effect, suggesting that Boldo has activities.[37,38] Our histology analyses showed a positive
poor hepatoprotective properties. Silymarin, a mixture association between elevated ALT and AST activities and
of flavonolignans extracted from seeds of S. marianum, is the presence of confluent necrosis and submassive necrosis
composed primarily of silibinin, silidianin, and silychristin.[9,32] in the groups that received commercial products, which
A survey in patients in a hepatology clinic found that 31% were ineffective in attenuating the increase in enzyme
were using over-the-counter “alternative agents” for their liver activities caused by CCl4 treatment.
diseases, the most common being milk thistle (silymarin).[33]
In our study, the silymarin extract did not show toxicity at the Implications
doses administered, but it failed to show a hepatoprotective A wide variety of herbal products are available in Mexico,
effect against CCl4-induced damage in rats. Legalon, a many without the official approval of the Secretary of Health.
standardized extract of silymarin, which we used as a positive It has been reported that 60–80% of the general population
control for hepatoprotection,[34-36] showed no toxicity and uses these products, and up to 85% of patients with liver
attenuated the increase in liver enzyme activities in our CCl4 disease use some form of CAM.[39] There are reported cases
toxicity model. Although the silymarin concentrations in both of acute liver disease, at times severe, associated with the
preparations differed, this suggests that the extract should be consumption of herbal products, and some products have
analyzed to determine whether it contains the amounts of been withdrawn from the market based on recommendations

Table 5: Associations between biochemical and histological variables

Variable Factor Level Median Level Median Significant
ALT (UI/L) Confluent necrosis NO 64 Yes 836 0.0019
AST (UI/L) Dominant hitologic image Global degeneration 659 Confluent necrosis 3684 0.0229
AST (UI/L) Confluent necrosis NO 245 Yes 3278 0.0033
AST (UI/L) Submassive necrosis NO 988 Yes 10464 0.0304
n = 5 rats in each group. AST, aspartate aminotransferase; ALT, alanine aminotransferase. Significant: Pearson correlation, P < 0.05

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 Cordero-Pérez, et al.: Hepatoprotecitve effect of commercial herbal extracts

made by national pharmacovigilance agencies.[13,40] However, 2. Kashi MR, Torres DM, Harrison SA. Current and emerging
therapies in nonalcoholic fatty liver disease. Semin Liver Dis
consumption of these products is increasing. 2008;28:396–406.
3. Lam BP, Younossi ZM. Treatment regimens for non-alcoholic
In this paper, we studied five herbal products used fatty liver disease. Ann Hepatol 2009;8:S51–9.
commonly in the region. 4. Cubero FJ, Urtasun R, Nieto N. Alcohol and liver fibrosis. Semin
Liver Dis 2009;29:211–21.
Consistency in biological activity and composition are 5. Ghany MG, Doo EC. Antiviral resistance and hepatitis B therapy.
essential to ensuring the safety of therapeutic agents. Hepatology 2009;49:S174–84.
However, botanical preparations rarely meet this standard 6. Chevaliez S, Pawlotsky JM. How to use virological tools
for optimal management of chronic hepatitis C. Liver Int
because of problems identifying plants, variable growing 2009;29:S9–14.
conditions, differences in the processing of extracts, and 7. Azzam HS, Goertz C, Fritts M, Jonas WB. Natural products and
lack of information about the pharmacologically active chronic hepatitis C virus. Liver Int 2007;27:17–25.
ingredients. The use of marker compounds to standardize 8. Luk JM, Wang X, Liu P, Wong KF, Chan KL, Tong Y, et al.
herbal preparations promotes batch-to-batch consistency Traditional Chinese herbal medicines for treatment of liver
but does not ensure consistent pharmacological activity. fibrosis and cancer: From laboratory discovery to clinical
evaluation. Liver Int 2007;27:879–90.
Moreover, analyses of purportedly standardized herbal
9. Ball KR, Kowdley KV. A review of Silybum marianum (milk thistle)
preparations show that botanical products often do not as a treatment for alcoholic liver disease. J Clin Gastroenterol
contain the amounts of the compounds stated on the 2005;39:520–8.
label.[41] It is possible that some of these factors contributed 10. Mayer KE, Myers RP, Lee SS. Silymarin treatment of viral
to the results obtained in this study. For example, both hepatitis: A systematic review. J Viral Hepat 2005;12:559–67.
Hepavida and Hepatisan supposedly contain the same 11. Luper S. A review of plants used in the treatment of liver disease:
Part 1. Altern Med Rev 1998;3:410–21.
compounds, yet only Hepavida was hepatoprotective. A
12. Luper S. A review of plants used in the treatment of liver disease:
similar finding was obtained with products that contain Part 2. Altern Med Rev 1999;4:178–88.
Boldo; only one was hepatoprotective in our model. This 13. Larrey D. Hepatotoxicity of herbal remedies. J Hepatol
suggests that the presence of the active ingredient (boldine) 1997;26:47–51.
in this plant should be confirmed in the commercial 14. De Smet PA. Herbal remedies. N Engl J Med 2002;347:2046–56.
products, given the variability of the effects of the different 15. Strader DB, Bacon BR, Lindsay KL, La Brecque DR, Morgan T,
preparations. Wright EC, et al. Use of complementary and alternative medicine
in patients with liver disease. Am J Gastroenterol 2002;97:2391–7.

As suggested above, there is a need for quality control 16. Taddei-Bringas GA, Santillana-Macedo MA, Romero-Cancio
JA, Romero-Tellez MB. Acceptance and use of medicinal plants
in laboratories that produce botanical products used in in family medicine [Article in Spanish]. Salud Publica Mex
the treatment of diseases, and the presence of active 1999;41:216–20.
pharmacological components should be confirmed. Reporting 17. Kessler RC, Davis RB, Foster DF, Van Rompay MI, Walters EE,
and regulatory systems should be created to monitor adverse Wilkey SA, et al. Long-term trends in the use of complementary
and alternative medical therapies in the United States. Ann
effects of herbal products, and care should be taken in Intern Med 2001;135:262–8.
the identification of compounds and in the evaluation of 18. Larrey D, Vial T, Pauwels A, Castot A, Biour M, David M, et al.
the potential benefits of phytotherapy. In conclusion, only Hepatitis after germander (Teucrium chamaedrys) administration:
Hepavida had a hepatoprotective effect in our model. Another instance of herbal medicine hepatotoxicity. Ann Intern
Med 1992;117:129–32.
For future research 19. MacGregor FB, Abernethy VE, Dahabra S, Cobden I, Hayes PC.
Hepatotoxicity of herbal remedies. BMJ 1989;299:1156–7.
Simple methods could be used to test commercial products
20. Valla D, Benhamou JP. Drug-induced vascular and sinusoidal
for their advertised hepatoprotective effects, given that lesions of the liver. Baillieres Clin Gastroenterol 1988;2:
they are usually poorly regulated. However, our results only 481–500.
apply to relatively short periods of administration. Further 21. Recknagel RO, Glende EA Jr, Dolak JA, Waller RL. Mechanisms
research is needed to establish if the products tested of carbon tetrachloride toxicity. Pharmacol Ther 1989;43:
139–54.
here might have hepatoprotective effects after chronic
22. Janakat S, Al-Merie H. Optimization of the dose and route of
use (months to years) or if they have liver regenerative injection, and characterisation of the time course of carbon
properties. Evidently, their clinical value could only be tetrachloride-induced hepatotoxicity in the rat. J Pharmacol
established with human studies. Toxicol Methods 2002;48:41–4.
23. Morita M, Akai S, Hosomi H, Tsuneyama K, Nakajima M, Yokoi T.
Drug-induced hepatotoxicity test using gamma-glutamylcysteine
REFERENCES synthetase knockdown rat. Toxicol Lett 2009;189:159–65.
24. Cámara-Lemarroy CR, Guzmán-de la Garza FJ, Cordero-Pérez
1. Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic P, Alarcón-Galván G, Torres-Gonzalez L, Muñoz-Espinosa LE,
steatohepatitis. Gastroenterology 2008;134:1682–98. et al. Comparative effects of triflusal, S-adenosylmethionine,

Pharmacognosy Research | July-September 2013 | Vol 5 | Issue 3 155

 Cordero-Pérez, et al.: Hepatoprotecitve effect of commercial herbal extracts

and dextromethorphan over intestinal ischemia/reperfusion 35. Fernandez J, Lagos P, Rivera P, Zamorano-Ponce E. Effect of
injury. Scientific World Journal 2011;11:1886–92. boldo (Peumus boldus Molina) infusion on lipoperoxidation
25. Guzmán-de la Garza FJ, Cámara-Lemarroy CR, Alarcón-Galván induced by cisplatin in mice liver. Phytother Res 2009;23:1024–7.
G, Cordero-Pérez P, Muñoz-Espinosa LE, Fernández-Garza NE. 36. Lanhers MC, Joyeux M, Soulimani R, Fleurentin J, Sayag M,
Different patterns of intestinal response to injury after arterial, Mortier F, et al. Hepatoprotective and anti-inflammatory effects
venous or arteriovenous occlusion in rats. World J Gastroenterol of a traditional medicinal plant of Chile, Peumus boldus. Planta
2009;15:3901–7. Med 1991;57:110–5.
26. Nencini C, Giorgi G, Micheli L. Protective effect of silymarin on 37. Morazzoni P, Bombardelli E. Silybum marianum (Carduus
oxidative stress in rat brain. Phytomedicine 2007;14:129–35. marianus). Fitoterapia 1995;66:3–42.
27. Tiwari P, Kumar A, Ali M, Mishra KP. Radioprotection of plasmid 38. Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybum
and cellular DNA and Swiss mice by silibinin. Mutat Res marianum) for the therapy of liver disease. Am J Gastroenterol
2010;695:55–60. 1998;93:139–43.
28. Reference Method for AST. Manual Reference Method: 21 CFR 39. Orhan DD, Orhan N, Ergun E, Ergun F. Hepatoprotective effect
Part 862. Section 1110. of Vitis vinifera L. leaves on carbon tetrachloride-induced acute
29. Reference Method for ALT. Manual Reference Method: 21 CFR liver damage in rats. J Ethnopharmacol 2007;112:145–51.
Part 862. Section 1030. 40. Blumenthal M, Golberg A, Brinckmann J. The complete German
30. Tsai JH, Liu JY, Wu TT, Ho PC, Huang CY, Shyu JC, et al. Effects Commission E monographs. Therapeutic Guide to Herbal
of silymarin on the resolution of liver fibrosis induced by carbon Medicine;2000;1:38–40.
tetrachloride in rats. J Viral Hepat 2008; 15:508–14. 41. Gyamfi MA, Yonamine M, Aniya Y. Free-radical scavenging
31. Orhan DD, Aslan M, Aktay G, Ergun E, Yesilada E, Ergun F. action of medicinal herbs from Ghana: Thonningia sanguinea
Evaluation of hepatoprotective effect of Gentiana olivieri herbs on experimentally induced liver injuries. Gen Pharmacol
on subacute administration and isolation of active principle. Life 1999;32:661–7.
Sci 2003;72:2273–83.
32. World Health Organization. WHO Traditional Medicine Strategy
2002–2005, Geneva. WHO 2002;1:1–61. Cite this article as: Cordero-Pérez P, Torres-González L, Aguirre-Garza M,
33. Stedman C. Herbal hepatotoxicity. Semin Liver Dis 2002;22: Camara-Lemarroy C, Guzmán-de la Garza F, Alarcón-Galván G, Zapata-
195–206. Chavira H, et al. Hepatoprotective effect of commercial herbal extracts
on carbon tetrachloride-induced liver damage in Wistar rats. Phcog Res
34. Muñoz O, Montes M, Wilkomirsky T. Plantas Medicinales de 2013;5:150-6.
uso en Chile. In: Química Y Farmacología. Santiago: Editorial
Universitaria; 2001. p. 223–6. Source of Support: Nil, Conflict of Interest: None declared.

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