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Research Article

Protective Role of Achillea biebersteinii Pretreatment on Dimethoate Induced Oxidative Stress in Guinea Pigs Liver

Yahya Saleh Al-Awthan, Mohamed Ali Al-Duais, Amany Abdulfatah Hazeb and Waleed Ahmed Alril
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Objective: The present study investigated the influence of Achillea biebersteinii (Ab), a medicinal herb used widely in Yemeni’s folk medicine as analgesic, antipyretic, against diarrhea and flatulence and for liver diseases, on the liver antioxidant potential of guinea pigs acutely intoxicated with dimethoate pesticide (DM). Materials and Methods: Animals were administered with Ab aqueous extract (50 and 100 mg kg–1 b.wt., orally) or silymarin (100 mg kg–1 b.wt., orally) for 2 weeks followed by single acute DM administration (80 mg kg–1 b.wt., 1/4 of the LD50 orally). Data were analyzed by one-way ANOVA using SPSS. Results: The results showed that the treatment with Ab extract significantly lowered the DM induced serum levels of hepatic marker enzymes (AST, ALT and ALP). Liver histopathology also showed that Ab extract reduced the incidence of lesions including the swelling of cells, lymphocytes infiltration, nucleus fragmentation and condensation and necrosis induced by DM treatment in guinea pigs. Conclusion: The results of this study suggest that Ab aqueous extract could protect the liver against DM-induced oxidative damage.

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Yahya Saleh Al-Awthan, Mohamed Ali Al-Duais, Amany Abdulfatah Hazeb and Waleed Ahmed Alril, 2017. Protective Role of Achillea biebersteinii Pretreatment on Dimethoate Induced Oxidative Stress in Guinea Pigs Liver. Pakistan Journal of Biological Sciences, 20: 403-409.

DOI: 10.3923/pjbs.2017.403.409

Received: August 07, 2017; Accepted: September 22, 2017; Published: October 03, 2017

Copyright: © 2017. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.


Organophosphate (OP) compounds are used worldwide in agriculture for crop protection and pest control and include the most toxic chemical agents. Thousands of different OP compounds have been synthesized and are used in agriculture for crop protection and pest control1. Some have also been used in the medical treatment as ectoparasiticides, in public health programs as insecticides, acaricides and nematicides and in commerce as lubricants, plasticizers and flame-retardants2,3. Exposure to low level of these OP pesticides is known to produce a variety of adverse biological effects reported in human and experimental studies which can be used as markers of exposure or effect1. The inhibition of acetylcholinesterase (AChE) activity is one of the primary effects of OP pesticides which accumulates acetylcholine and prevents the normal transmission of nerve impulses leading to continuous stimulation of the muscles, glands and the central nervous system which finally cause death4. Previous report indicated that the toxicity of OP insecticides caused devastating effects on many organs and systems4,5. Dimethoate (DM), which is considered as one of the most important OP insecticide, is frequently used in agriculture against a wide range of insects especially in qat farms in Yemen. Recent study showed that DM was one of the more contamination sources6 and was detected at high concentration in water samples in Saudi Arabia7. Main groups at risk of high rates of DM exposure are pesticide producers, pesticide workers and farm owners8. Previous studies showed that DM intoxication cause oxidative stress by generation of free radicals and induce hepatic lipid peroxidation in rat9, guinea pig10, rabbit11 and mice12. The DM, similar to other OPs, inhibits AChE which is present in mammals, fish, birds and insects. The inhibition creates a buildup of acetylcholine at the nerve synapses which results in continuous stimulation of the muscles eventually leading to seizures, exhaustion and possibly death13. In addition, previous reports showed that OP pesticides caused oxidative stress involved by generation of free radicals and lipid peroxidation14. The liver is the primary organ involved in xenobiotic metabolism and is a major target organ for chemicals and drugs. Therefore, the toxicity of liver is an important endpoint in the evaluation of a particular xenobiotic effect. Natural antioxidants from plants origin are reported to provide a good protection that slows down the process of oxidative damage caused by reactive oxygen species (ROS) that involved in the toxicity of various OP pesticides15. Achillea L. (Asteraceae) is represented by 140 species in the world16. Achillea biebersteinii (Ab), one of the medicinal plants of Yemen, is an erect herbaceous perennial plant upto 1 m high. The leaves are densely hairy with 2-3 pinnatisect and contain golden yellow flowers which are ray-florets 4-517. There are different Achillea species used worldwide for their pharmaceutical properties. Their extracts exhibit pharmacological activities such as anti-inflammatory, analgesic, antipyretic, diuretic, in wound healing, against diarrhea, hypoglycemic, anthelmintic and anti-bacterial remedies18-21. Antioxidant activity of different species of Achillea including Achillea distans22, Achillea ligustica23, Achillea wilhelmsii24, Achillea millefolium25 and Ab26,27 have been previously investigated. These studies reported that infusions prepared from Achillea species had antioxidant capacity and protective effect, which is consistent with their total flavonoid and phenol contents. In addition, three Achillea species extract showed protective effects against lipid peroxidation and DNA damage in vitro28. Recently, Mais et al.29 reported that Ab showed hypolipidemic effect. Also, Abd-Alla et al.30 reported that Ab showed antiulcer agent with hyperglycaemia lowering effect. More recently, Varasteh-Kojourian et al.31 showed that two Achillea extracts including Ab possess remarkable antioxidant activity. Accordingly, it is more interested to study the influence of plant extracts on oxidative stress induced by pesticide intoxication. This has encouraged us to investigate the effect of acute DM exposure on oxidative stress by assessing liver marker enzymes and other histological parameters, as well as the protective action of Ab aqueous extract on DM-intoxicated guinea pigs. So, the aim of the present study was to investigate some of the biochemical and histological alterations which might occur as a result of DM intoxication in guinea pigs. In addition, to study the protective effects of the aqueous extract of Ab against DM -induced acute liver injury in guinea pigs.


Plant material: The whole plant of Ab was collected in Feb-March, 2010 from Ibb, Yemen. The plant was authenticated by Mr. Esam Aqlan, Biology Department, Ibb University, Yemen. Voucher specimens were kept in the herbarium for future references.

Preparation of the aqueous extracts: The plants were washed, cut into small pieces, shade dried for 5 days and then dried overnight in an oven. The dried plants (200 g) were boiled for 30 min with distilled water (2000 mL). The resulting water extract was filtered and subsequently concentrated with a water bath (90°C) until it became creamy and was then dried in an oven (60°C) that finally gave 20 g (10% of initial amount) of powder. The dried extracts were dissolved in saline and administrated orally when experiments were performed.

Chemicals: Dimethoate 40 EC was applied as a commercial emulsifiable concentrate formulation containing 40% active ingredient. It was diluted in corn oil for the final concentration.

Animals and treatments: Adult male guinea pigs (350±50 g) were obtained from the animal house of Biology department, Faculty of Science, Ibb University, Yemen and kept for 1 week on a commercial diet in environmentally controlled conditions with free access to diet and water ad libitum. Animals were divided into 5 groups of 5 each. Animals of group I received oral administration of corn oil 24 h prior to decapitation. The animals of group II were given single administration of DM (80 mg kg–1) orally dissolved in corn oil 24 h prior to decapitation. The animals of group III and IV were given the pretreatment of aqueous extracts of Ab (50 and 100 mg kg–1, respectively) orally dissolved in normal saline once daily for 2 weeks in succession followed by single administration of DM (80 mg kg–1, 1/4 of the LD50) orally. The animals of group V were given silymarin pretreatment (100 mg kg–1 p.o.) suspended in normal saline once daily for 2 weeks followed by single administration of DM (80 mg kg–1, 1/4 of the LD50) orally. Twenty four hours after the toxin administration, the animals of each group were anaesthetized with ether and blood was collected directly from the portal vein. The blood sample of each animal was divided in two tubes, one of them mixed with heparin to prevent coagulation and the other was allowed to clot at room temperature for 1 h and then centrifuged (Beckman, UK) at 3000 rpm and 4°C for 15 min to obtain sera. The separated serum was sampled into clean tubes and kept in a deep-freezer (Labotech, India) at -24°C for further analysis.

Biochemical indicators of liver function: Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) were determined using Medichem Middle East Diagnostics kits (Syria) according to the method of Tietz32. The activity of serum alkaline phosphatase (ALP) was determined using Reactivos GPL Diagnostics kits (Spain) according to the method of King33. The enzyme activity was expressed as U L–1.

Histopathological examination: Control and experimental animals were put under light ether anaesthesia, dissected as quickly as possible and then livers were removed. Small pieces were fixed in 10% neutral formalin for 24 h, then washed by the running tap water and stored in 70% ethyl alcohol (Analytical grade) until further processing. Blocks of about 5×5 mm size were dehydrated, cleared and embedded in paraffin wax. Paraffin sections of 5 microns thickness were cut using rotary microtome (Leica, Germany) and stained with haematoxylin and eosin.

Statistical analysis: Data were analyzed using IBM SPSS statistics 20 software and the results of the biochemical estimations were reported as mean±standard deviation (SD). Total variation, present in a set of data was estimated by one-way analysis of variance (ANOVA) and follow up test (LSD). Differences with a p<0.05 were considered as statistically significant.


Results of liver enzymes (AST, ALT, ALP): Single acute DM treatment (80 mg kg–1) for 24 h in guinea pigs caused a statistically significant increase (p<0.001) in the level of AST, ALT, ALP in serum when compared to control animals, whereas, Ab (100 mg kg–1) and silymarin (100 mg kg–1) pre-treatment to the DM-intoxicated animals resulted in a significant normalization (p<0.001) of the enzymes activities (Table 1).

Results of liver morphological changes: The liver sections of the guinea pigs treated with DM showed many histological changes. The parenchymatous cells showed cytoplasmic vacuolization and degeneration in nuclei. Moreover, an increase in the number of Kupffer cells in the liver parenchyma was observed. Severe congestion, leucocytes infiltration in the parenchymatous tissue and portal area, enlargement of the hepatic sinusoids and enlargement of the central and the portal veins, clear size of hemorrhage, remarkable dilated veins and disruption of hepatic architecture.

Table 1: Effects of Achillea biebersteinii (Ab) on serum marker enzymes in DM-intoxicated guinea pigs
Values are expressed as Mean±SD, n= 5 for each treatment group. Means assigned with the same letter show insignificant differences between these values. aSignificantly different from controls. b,cSignificantly different from DM-treated animals. Significance *p<0.05, high significance **p<0.01 and very high significance ***p<0.001 compared with control respectively. Significant differences between groups were calculated by ANOVA and follow up test (LSD)

Fig. 1(a-f):
Hepatoprotective effect of Achillea biebersteinii (Ab) against DM-induced hepatotoxicity in guinea pigs. Liver sections were stained with H and E: (a) Normal, (b, c) DM-treated animals, (d) Ab (50 mg kg–1 b.wt.)+DM, (e) Ab (100 mg kg–1 b.wt.)+DM and (f) Silymarin (100 mg kg–1 b.wt.)+DM, magnification 400X
H: Hepatocytes, CV: Central vein, N: Nucleus, S: Sinusoidal space, BH: Ballooning hepatocytes, V: Dialated vessel, h: Hemorrhage, NC: Necrosis, FN: Fragmented nucleus, CN: Condensed nucleus, *Hepatic degeneration

Changes in the nucleus appeared in the form of condensed chromatin, binucleated cells and fragmented nuclei. The protective effect of 50 and 100 mg kg–1 p.o., of aqueous extracts of Ab extract produced 30 and 60% inhibition in inflammatory changes against 80% inhibition observed in silymarin treated group (Fig. 1).


For several decades, the extensive use of pesticides in most developing countries is becoming an increasingly serious environmental problem due to factors such as water contamination, ecosystem disruption and habitat contamination34. It is an established fact that pesticides and some of their metabolites can cause harm to human and the environment35. The current study was performed to investigate the hepatotoxicity of a commonly used OP insecticide, DM, in guinea pigs following single acute exposure. In the present study, single acute DM treatment (80 mg kg–1) for 24 h in guinea pigs caused a statistically significant increase in the level of AST, ALT and ALP in serum when compared to control animals. In fact, available data on the hepatotoxicity action of DM were limited for adult mice12,36, rat37-39 and rabbit11 but there is little data available on the effect of DM on guinea pigs performed previously in our lab10. DM also caused a significant hepatic damage, as observed from the elevation of hepatospecific enzyme activities, as well as severe alterations in different liver parameters. The liver seemed to be mostly affected by DM treatment alone, as the liver is the most active mammalian organ in xenobiotic metabolism and contains a larger variety of enzymes for this action. Accordingly, its role in metabolic conversions is its susceptibility to the toxicity from these agents40. The co-administration of Ab extract and silymarin with DM to guinea pigs resulted in marked improvement of the liver enzymes activities when compared to that which received DM alone. One of the possible explanations for the observed recovery of various enzyme activities involved in the detoxification following Ab or silymarin treatment could be because these materials exert their hepatoprotective influence by acting as antioxidants which mediated by its free radical scavenging and modulation of the xenobiotic detoxification process41. These findings were in agreement with the results reported by Al-Said et al.42. There is no information concerning the protective action of Achillea species on oxidative injury induced by DM. However, there are several reports concerning with the protective effects of different Achillea species against chemical intoxication. For example, Konyalioglu and Karamenderes, (2005) demonstrated that 15 Achillea L. species showed protective effects against H2O2-induced oxidative damage in human erythrocytes and leucocytes43. Also, Yaeesh et al.44 reported that the aqueous-methanol extract of Achillea millefolium exhibeted a hepatoprotective, antispasmodic and calcium antagonist activities44. In addition, three Achillea species extracts showed protective activity against lipid peroxidation, protein oxidation and DNA damage in vitro28. Whereas, other results obtained by Baris et al.45 showed that the methanol extract of Ab showed weaker antioxidative capacity.

Recently, Babelly et al.29 reported that Ab showed hypolipidemic effect suggesting the potential protective role in coronary heart disease. Finally, Varasteh-Kojourian et al.31. showed that two Achillea extracts including Ab possess remarkable antioxidant activity and could be good natural alternatives to synthetic antioxidants in pharmaceutical and food industries31. The increases in plasma transaminase (AST and ALT) were observed in all doses of Ab extract on carbon tetrachloride-induced liver damage in rats46. The co-administration of Ab extract and silymarin with DM to guinea pigs resulted in marked improvement of the liver histology when compared to that which received DM alone. There are several reports supported the role of antioxidant in attenuating the histopathology of some pesticides and toxins in experimental animals. For example, Sutcu et al.47. revealed a histopathological changes in liver tissue of rats treated with methidathion and the severity of these lesions was reduced by administration of a combination of vitamin C and E. Also, Zama et al.48 concluded that chlorpyrifos can lead to an increase in LPO production in adult and fetal tissues of rat, while treatment with the Paronychia argentea extract leads to protection against chlorpyrifos toxicity. In addition, recent published articles demonstrated the hepatoprotective role of vitamins (C and E) and Withania somnifera aqueous extract in attenuating DM-induced histopathology in liver of guinea pigs10,49 were in consistence with the results of the present study. Therefore, a study of some commonly used plant products as antioxidants against xenobiotic-induced oxidative stress, appeared to be of interest. The present study demonstrated that administration of Ab extract to guinea pigs modulates the oxidative stress induced by DM insecticide and suggests a possible adaptive mechanism to counteract oxidative stress situation. Hence, such studies on oxidative/antioxidant status during a free radical exposure can be used as an index of protection against xenobiotic challenges. Finally, the exact chemical ingredient that could introduce the protective effect in this study, should be separated and characterized from the plant extract and studied alone. Therefore, these steps were difficult to be done in our lab. So, it is of importance to recommend such study research in the future.


The extensive use of pesticides in developing countries by farmers without consideration to their harmful effects and the increasing use of medicinal plants encourage us to design the research. The presented study concluded that guinea pigs administered with Ab aqueous extract protect the hepatocytes against an acute dose of DM insecticide, but further studies are required to explain the exact mode of protection. In addition, the characterization of the chemical ingredients that are responsible for the hepatoprotective effect is highly recommended.


This study discovers the positive effect of Achillea biebersteinii aqueous extract against dimethoate induced oxidative stress in the liver of guinea pigs. Oral administration of plant extract in different concentration provided protective effect when compared to silymarin group suggesting the antioxidant capacity of Achillea biebersteinii. This study will help the researcher to reveal the critical areas of antioxidants-oxidative stress relationship especially in pesticide toxicity. Thus, a new idea on the use of Achillea plant extract to manage pesticide toxicity may be achieved.


The authors are grateful to Afaf A. Obad, Hend Y. Alqade, Salah M. Aboesba, Esam M. Aqlan and Samira Hezabr, Department of Biology, Faculty of Science, Ibb University, Yemen, for their assistance in this study.

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