Hepatoprotective Effect of Aqueous Extract of Solanum macrocarpon Leaves against Carbon tetrachloride-induced Liver Damage in Rats

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1 Journl of Applied Phrmceuticl Science Vol. 5 (Suppl 2), pp , 2015 Aville online t DOI: /JAPS S13 ISSN Heptoprotective Effect of Aqueous Extrct of Solnum mcrocrpon Leves ginst Cron tetrchloride-induced Liver Dmge in Rts Olusol Bolji Adewle 1*, Omotde Iidun Oloyede 2, Amos Onsny 1, Isrel Idowu Olyide 1, Scholstic Onyeuchi Andozie, Adewle Oluwseun Fdk 1 1 Deprtment of Chemicl Sciences, Biochemistry Unit, Afe Blol University, P.M.B. 5454, Ado-Ekiti, Nigeri. 2 Deprtment of Biochemistry, Ekiti Stte University, P.M.B 5354, Ado-Ekiti, Nigeri. ARTICLE INFO Article history: Received on: 15/06/2015 Revised on: 30/06/2015 Accepted on: 17/07/2015 Aville online: 04/09/2015 Key words: Cron tetrchloride; Chemoprotective; Heptoprotective; Phytochemicl; Solnum mcrocrpon. ABSTRACT Liver dmge is growing concern of tody s modern society. The incresing incidence of exposure to toxic gents hs contriuted to liver diseses. There is therefore need for heptoprotective gents. This study ws imed t investigting the protective effect of queous extrct of the leves of Solnum mcrocrpon ginst CCl 4-induced liver dmge in rts. Six groups of four nimls ech were used for the investigtion. Group 1 served s control, groups 2, 3 nd 4 nimls were pre-treted with lef extrct of Solnum mcrocrpon t 250mg/kg, 500mg/kg nd 750mg/kg ody weight respectively for 14 dys prior to single intrperitonel dministrtion of CCl 4. Animls in groups 5 nd 6 received only the extrct t dose of 750mg/kg ody weight nd CCl 4 respectively. All nimls were scrificed 24 h fter the dministrtion of CCl 4. The liver functions tests were performed in ddition to their histopthologicl evlution. Results otined showed significnt dverse chnges in the levels of ll mesured prmeters in CCl 4 treted rts. However, pre-tretment with queous extrct of S. mcrocrpon prevented the dverse chnges. Our findings suggest tht S. mcrocrpon protects the liver ginst CCl 4-induced dmge. This could e ttriuted to the presence of phytochemicl compounds in the plnt. INTRODUCTION Exposure to cron tetrchloride (CCl 4 ), well-known heptotoxin, is known to induce oxidtive stress nd cuses liver injury y the formtion of free rdicls. Free rdicl-induced lipid peroxidtion is one of the mjor cuses of cell memrne dmge which leds to numer of pthologicl conditions (Slter, 1984; Oerley, 1988; Hlliwell, 1993). Therefore, there is gret need for the development of gents with potent ntioxidnt effect ginst the CC1 4 induced tissue pthology. Studies showed tht vrious plnt extrcts could hs the potentil to protect orgns ginst CCl 4 - induced oxidtive stress y ltering the levels of incresed lipid peroxidtion s well s enhncing the decresed ctivities of ntioxidnt enzymes (Rjesh nd Lth, 2004). Solnum mcrocrpon is n importnt medicinl plnt with rich source of nutritionl nd medicinl constituents. It is widely cultivted in West Afric where it * Corresponding Author Olusol Bolji Adewle, Biochemstry Unit, Deprtment of Chemicl Sciences, Afe Blol University, Ado-Ekiti, Nigeri. Emil: solustine2003@yhoo.com serves s n importnt fruit nd lef vegetle. The leves re considered very nutritious nd re used in prepring soups nd stews. The leves were known to e rich in protein, ft, crude fier, clcium nd zinc (Ooh et l., 2005). Bukeny-Zir nd Bonsu reported tht the leves hve vriety of medicinl uses such s in Sierr Leone for the tretment of throt prolems; in Keny, for the tretment of stomch prolems (Bukeny-Zir nd Bonsu, 2004). The fruit or the lefy prt of the plnt ws reported to e used for the tretment of constiption, ulcers, tooth che nd the leves s snke ite remedy (Oldirn, 1989). The lefy prt of Solnum mcrocrpon ws effective for tretment of skin disese, infections nd sores when pplied to the infected res (Edijl et l., 2005). Generlly, the plnt hs een used s indigenous medicine for the tretment of severl ilments such s sthm, llergic rhinitis, nsl ctrrh, skin infections, rheumtic disese nd swollen joint pins, gstro-esophgel reflux disese, constiption, dyspepsi nd lso in weight reduction (Dlziel, 1937). The queous fruit extrct of the plnt ws reported to exhiit lipid lowering ctivities s well s renl nd heptoproptective effects in diet-induced hypercholesterolemic rts (Sodipo et l., 2009,; Sodipo et l., 2009c, 2011) Olusol Bolji Adewle et l. This is n open ccess rticle distriuted under the terms of the Cretive Commons Attriution License -NonCommercil- ShreAlikeUnported License (

2 082 Adewle et l. / Journl of Applied Phrmceuticl Science 5 (Suppl 2); 2015: The plnt ws lso shown to improve hemtologicl prmeters in hypercholesterolemic nd triton-induced hyperlipidemic rts (Sodipo et l., 2011). The leves of S. mcrocrpon hve lso een reveled to contin high phenolic nd flvonoid content, thus possessing potent ntioxidnt ctivity which cn offer good protection ginst oxidtive dmge to some ody tissues (Adewle et l., 2014). The im of this study ws to evlute the protective potentil of queous extrct of the leves of Solnum mcrocrpon ginst CCl 4 -induced liver dmge in rts. To the est of our knowledge, this study provides first line of informtion tht queous extrct of the leves of S. mcrocrpon t different doses could e effective in preventing heptic insufficiency occsioned y CCl 4 -intoxiction. This is prticulrly importnt since trditionl consumption of Solnum mcrocrpon is usully y queous medium. MATERIALS AND METHODS Plnt collection, Identifiction nd Extrction The leves of Solnum mcrocrpon were otined from Bisi mrket in Ado-Ekiti, Ekiti Stte, nd were uthenticted t the Deprtment of Plnt Science, Ekiti Stte University, Ado-Ekiti, Nigeri. The voucher specimen of the plnt is ville nd smple of the plnt lef ws deposited t the Deprtmentl Herrium for future reference. The leves were ir-dried, lended nd soked in distilled wter for 24 h. It ws then filtered using Whtmn filter pper no. 1 nd the filtrte ws concentrted t 50ºC using the rotry evportor, following which it ws dried y mens of freeze dryer. The extrct ws dministered orlly using gvge ccording to the required doses of 250, 500 nd 750 mg/kg ody weight for 14 dys. Chemicls All chemicls nd regents used were of nlyticl grde while the wter ws glss distilled. Experimentl nimls Twenty-four femle lino rts of Wistr strin weighing etween g purchsed from the centrl niml house of Afe Blol University, Ado-Ekiti were used for the study. The nimls were housed in cges under lortory conditions in the deprtmentl niml house nd were cclimtized for 14 dys efore strting experiments. They were provided with stndrd pelleted feed nd wter d liitum. After cclimtiztion period, the nimls were divided into groups. All niml procedures were in strict ccordnce with the Guide for the Cre nd Use of Lortory Animls (8th edition, Ntionl Acdemies Press, Wshington, DC, USA, 2011). All niml experiments were pproved y the niml cre committee of Afe Blol Reserch Center, Ado-Ekiti. Grouping of nimls Six groups of four rts ech were studied; Group 1 served s norml control; Groups 2, 3 nd 4 were pretreted with queous extrct of Solnum mcrocrpon t doses of 250mg/kg, 500mg/kg nd 750 mg/kg ody weight for 14 dys respectively prior to CCl 4 dministrtion. Groups 5 nd 6 received only 750mg/kg extrct nd CCl 4 respectively. Administrtion of CCl 4 ws done fter 14 dys of Solnum mcrocrpon tretment nd following n overnight fst. Animls were scrificed 24hours fter CCl 4 dministrtion. The extrct ws dministered orlly using gvge ccording to the required doses. Administrtion of CCl 4 Where necessry, ech niml received 3 ml/kg ody weight of 1:1 preprtion of CCl 4 nd groundnut oil (in the rtio 1:1). Administrtion of CCl 4 ws y single intrperitonel injection. Administrtion ws done fter 14 dys dy tretment with S. mcrocrpon, nd following n overnight fst. Preprtion of plsm nd liver homogente The rts were scrificed 24 h fter CCl 4 dministrtion y cervicl disloction nd then dissected. Blood smples were collected from the hert using the hert puncture technique. Blood ws collected in heprinized ottles. The lood smples were susequently centrifuged t 3000 x g for 10 min using ench centrifuge to otin plsm. The plsm otined ws seprted, nd trnsferred into fresh plin smple ottles nd used for the susequent iochemicl nlyses. The liver of ech niml ws excised immeditely fter scrifice. They were rinsed in ice-cold 1.15% potssium chloride, lotted with filter pper nd weighed. Weighed portions were minced with scissors in 4ml of ice-cold 0.1M phosphte uffer, ph 7.4 nd homogenized in Potter- Elvehjem homogenizer. The homogentes were lter centrifuged using refrigerted centrifuge t 12,000 x g for 15 min t 4 o C to otin cler superntnt, which ws used for susequent iochemicl nlyses. Biochemicl nlyses Biochemicl nlyses crried out includes mesurement of the ctivities of plsm lnine minotrnsferse (ALT), sprtte minotrnsferse (AST), gmm-glutmyl trnsferse (γ- GT or GGT) nd lkline phosphtse (ALP); plsm totl protein nd lumin concentrtions. The determintion of the concentrtions of these iochemicl prmeters ws done using commercilly ville test kits, products of Rndox Lortories (Crumlin, United Kingdom). Antioxidnt ssys Lipid peroxidtion ws ssessed y mesuring the formtion of thiorituric (TBA) rective sustnces ccording to the method descried y Vrshney nd Kle, (1990). Ctlse (CAT) ctivity ws determined ccording to the method of Sinh, (1972). Superoxide dismutse (SOD) ctivity ws mesured s descried y Misr nd Fridovich, (1972).

3 Adewle et l. / Journl of Applied Phrmceuticl Science 5 (Suppl 2); 2015: Histopthologicl ssessment Liver sections from rts of different groups were fixed in 10% neutrl formlin solution, dehydrted in grded lcohol, nd emedded in prffin. Fine sections otined were mounted on glss slides nd counter-stined with hemtoxylin-eosin for light microscopic nlyses. To eliminte is the slides which were coded, exmined nd photogrphed y qulified histopthologist who hd no knowledge of the tretment groups. Sttisticl nlysis Sttisticl nlysis ws done y one-wy nlysis of vrince (ANOVA) using SPSS 16 for windows softwre pckge. Post hoc testing ws performed for inter-group comprisons using the Lest Significnt Difference (LSD) test ccording to the method descried y Zr, (1984). In ll instnces p vlues < 0.05 were considered sttisticlly significnt. RESULTS Administrtion of CCl 4 produced significnt toxic effects on the liver, s shown y the dt otined from the prmeters investigted (Figures 1 to 3). Mrker enzymes Figure 1 showed the effect of queous extrct of the leves of Solnum mcrocrpon on CCl 4 - induced chnges in some mrker enzymes. When compred with the control, CCl 4 tretment gve rise to significnt increse (p < 0.05) in the mrker enzymes such s lnine tnsminse (ALT), sprtte trnsminse (AST), gmm-glutmyl trnsferse (GGT) nd lkline phosphtse (ALP). However, pretretment of rts with queous extrct of S. mcrocrpon (AESM) t 250 mg/kg, 500 mg/kg nd 750 mg/kg ody weight produced significnt decrese in the ctivities of these enzymes when compred with CCl 4 group. As regrds the different pretretment doses of the extrct, there ws significnt difference in the ctivities of ALT, GGT nd ALP when compred with 250 mg/kg.w. dose s shown in figure 1. Tretment with AESM t 750 mg/kg.w. produced comprle result with tht of the control. Liver function prmeters Figure 2 showed the effect of queous extrct of the leves of Solnum mcrocrpon on CCl 4 - induced chnges in plsm totl protein nd lumin levels. A significnt decrese (p<0.05) in the levels of these prmeters ws oserved following single intrperitonel dministrtion of CCl 4 when compred with the control group. Pretretment of rts with queous extrct of C. ruens leves t 250 mg/kg, 500 mg/kg nd 750 mg/kg ody weight produced significnt increse (p<0.05) in the levels of totl protein nd lumin when compred with CCl 4 group. There ws significnt difference in the level of lumin in the pretretment group t 250 mg/kg.w. when compred with oth 500 mg/kg nd 750 mg/kg.w. s shown in figure 2. Antioxidnt enzymes nd lipid peroxidtion As shown in figure 3, intrperitonl dministrtion of CCl 4 resulted in mrked heptic injury s reveled y significnt decrese (p<0.05) in the ctivities of ntioxidnt enzymes (SOD nd ctlse) nd significnt increse (p<0.05) in the level of MDA respectively when compred with the control group. Pretretment with the leves extrct of S. mcrocrpon t ll the three dose levels (250 mg/kg, 500 mg/kg nd 750 mg/kg.w.) resulted in significnt increse (p<0.05) in the ctivities of these enzymes nd prevented the oserved peroxidtion when compred with the toxicnt group. A significnt difference ws oserved in these prmeters during the pretretment with the lower dose when compred with the higher doses s shown in figure 3. Tretment of rts with 750 mg/kg.w. extrct produced non significnt difference in these prmeters s compred with the control group U/L AST ALT GGT(*10) ALP Control AESM 1 + CCl4 AESM 2 + CCl4 AESM 3+ CCl4 AESM 3 only CCl4 only Fig. 1: Effect of queous extrct of Solnum mcrocrpon on CCl 4-induced chnges in the plsm in ALT, AST, GGT nd ALP. AESM 1, AESM 2 nd AESM 3 re the pretretment doses of queous extrct of Solnum mcrocrpon t 250mg/kg, 500mg/kg nd 1000mg/kg ody weight respectively. Vlues re expressed s Men ± SEM (n=4) p< 0.05 when compred with Control group; p<0.05 when compred with CCl 4 group; c p< 0.05 comprison mong the pretretment groups.

4 084 Adewle et l. / Journl of Applied Phrmceuticl Science 5 (Suppl 2); 2015: Control Concentrtion (g/dl) AESM 1 + CCl4 AESM 2 + CCl4 AESM 3+ CCl4 AESM 3 only CCl4 only 5 0 Totl protein Alumin Fig. 2: Effect of queous extrct of the fruits of Solnum mcrocrpon on CCl 4 - induced chnges in plsm totl protein nd lumin levels. AESM 1, AESM 2 nd AESM 3 re the pretretment doses of queous extrct of Solnum mcrocrpon t 250 mg/kg, 500 mg/kg nd 1000 mg/kg ody weight., Vlues re expressed s Men ± SEM (n=4)., p< 0.05 when compred with Control group; p<0.05 when compred with CCl 4 group; c p< 0.05 comprison mong the pretretment groups Unit SOD/g liver wt c Fig. 3: Effect of queous extrct of Solnum mcrocrpon on cron tetrchloride (CCl 4) induced chnges in liver superoxide dismutse (SOD) ctivity, ctlse (CAT) ctivity nd mlondildehyde (MDA) level. AESM 1, AESM 2 nd AESM 3 re the pretretment doses of queous extrct of Solnum mcrocrpon t 250 mg/kg, 500 mg/kg nd 1000 mg/kg ody weight Vlues re expressed s Men ± SEM (n=4) p< 0.05 when compred with Control group; p<0.05 when compred with CCl 4 group; c p< 0.05 comprison mong the pretretment groups. CAT (mmol/min/g liver wt) μm MDA ctivity/g liver wt c Control AESM 1 + CCl4 AESM 2 + CCl4 AESM 3+ CCl4 AESM 3 only CCl4 only Histopthology of the Liver Histopthologicl exmintions s presented in plte 1 reveled tht liver section from norml rts showed mild lymphocytic infiltrtion nd no significnt lesions (plte 1 ()). The liver of rts pretreted with 250mg/kg AESM (queous extrct of Solnum mcrocrpon) showed periportl congestion, mild lymphocytic prenchym infiltrtion nd frgmenttion of the heptocytes with progressive occlusion of the sinusoid (plte 1 ()). Rts pretreted with 500 mg/kg (plte 1 (c)) nd 750 mg/kg (plte 1 (d)) AESM, lymphocytic infiltrtion with the degenertion of the heptocytes were oserved respectively. However, rts treted with 750 mg/kg dose of the extrct showed mild lymphocytic infiltrtion nd no significnt lesions (plte 1 (e)). However, evidence of cellulr degenertion in the heptocytes nd multiple foci of heptocellulr were seen on sections of rts treted with CCl 4 only (plte 1 (f)).

5 Adewle et l. / Journl of Applied Phrmceuticl Science 5 (Suppl 2); 2015: Plte 1: Photomicrogrph of rt liver sections (Mg. x 400): (). Norml control; (). 250 mg/kg AESM + CCl 4; (c). 500 mg/kg AESM + CCl 4; (d). 750 mg/kg AESM + CCL 4; (e). 750 mg/kg AESM only; (f). CCl 4 only. DISCUSSION Heptotoxicity, n injury to the liver is ssocited with impired liver function cused y free rdicls derived from oxygen on exposure to drugs, chemicl nd non-infectious gents (Nvrro nd Senior, 2006). Vrious report confirmed tht CCl 4 induces heptic injury y producing free rdicls (Tirkey et l., 2005; Yng et l., 2008; Lvny et l., 2009). Also, the onset nd progression of CCl 4 -induced toxicity is tightly linked to the genertion of rective oxygen species (Rechngel et l., 1989). Cron tetrchloride is now known to e metolized to highly rective intermedite, trichloromethyl rdicl (CCl 3 * ) (Fdhel nd Amrn, 2002). Trichloromethyl rdicl nd trichloromethylperoxyl rdicl derived from CCl 4 re known to e involved in numer of deleterious interctions with iologicl molecules, which includes proteins, lipids nd DNA (Pcker et l., 1978). This is elieved to e prt of the criticl chemicl process in the etiology of CCl 4 - induced tissue dmge. Increse in the levels of the liver mrker enzymes (AST, ALT nd GGT) following CCl 4 dministrtion my hve resulted from the lekge of these enzymes into the circultion, which my e ttriuted to the dmged structurl integrity of the liver, ecuse these enzymes re locted in the cytoplsm (Bilgin et l., 2011). Plsm levels of ALT nd AST hve een shown to e importnt prmeters in the dignosis of liver dmge (Willimson et l., 1996; Renugdevi nd Pru, 2010). Liver cells re prticulrly rich in the trnsminses (ALT nd AST), s well s lkline phosphtse nd -glutmyltrnsferse. Incresed ctivities of plsm ALP my e due to its incresed synthesis in the presence of incresing iliry pressure. Plsm lkline phosphtse is known to increse s result of iliry ostruction s seen in cholesttic disese of the liver. GGT is memrne-ound enzyme nd incresed plsm level is n indictor of tissue dmge (Vsudh et l., 2006). Cron tetrchloride negtively interferes with protein metolism proly y inhiiting the synthesis of proteins such s lumin (Inighe et l., 2008) which my e ttriuted to the decresed levels of totl protein nd lumin oserved in this study. The susceptiility of the liver cell to oxidtive insult occsioned y CCl 4 cn e linked to the filure of the ntioxidnt mechnism to prevent free rdicl dmge therey leding to lipid peroxidtion nd ultimtely tissue dmge (Morkinyo et l., 2012). Lipid peroxidtion is mrker of oxidtive stress. Evlution of heptic ntioxidnt sttus in the present study reveled significntly elevted MDA levels, nd concomitnt decrese in the ctivities of the ntioxidnt enzymes (SOD nd ctlse). Thus CCl 4 -medited dmge to the liver ws secondry to the estlishment of oxidtive stress. The ility of the queous extrct of S. mcrocrpon leves to significntly prevent ll the oserved iochemicl lesions is worthy of note. We therefore speculte tht the ction of the plnt extrct my revolve round the possiility tht the extrct effectively down-regulte the mount of CCl 4 or its toxic metolites reching the liver. It my lso e possile tht S. mcrocrpon my ctully ct s free rdicl scvenger or quencher, thus preventing the oxidtive dmge to the cell. Bsed on the findings from this study, it cn e suggested tht queous extrct of the leves of S. mcrocrpon in dose dependent mnner holds gret hope in preventing liver dmge occsioned y CCl 4 toxicity.

6 086 Adewle et l. / Journl of Applied Phrmceuticl Science 5 (Suppl 2); 2015: CONCLUSION It is confirmed sed on the results of this experiment tht free rdicls re importnt in the pthogenesis if CCl 4 -induced heptotoxicity. Therefore, doses up to 750 mg/kg ody weight of queous extrct of the leves of Solnum mcrocrpon hve een le to prevent the injuries ssocited with the dverse effect of CCl 4. ACKNOWLEDGEMENT We pprecite Afe Blol University for the encourgement given in terms of fcilities nd other support. REFERENCES Adewle OB, Onsny A, Fdk OA, Iwere H, Andozie SO, Osukoy AO, Olyide II. In vitro ntioxidnt effect of queous extrct of Solnum mcrocrpon leves in rt liver nd rin. Oxid Antioxid Med Sci, 2014; 3(3): Bilgin HM, Atmc M, Oy BD, Ozekinci S, Tsdemir E, Ketni A. Protective effects of coumrin nd coumrin derivtives ginst cron tetrchloride-induced cute heptotoxicity in rts. Exp Toxicol Pth, 2011; 63: Bukeny-Zir R, Bonsu KO Solnum mcrocrpon L. In: Gruen GJH, Denton OA (eds). 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Protective effects of Pycnogenol on cron tetrchloride-induced heptotoxicity in Sprgue-Dwley rts. Food Chemicl Toxicol, 2008; 46: Zr JH Biosttisticl Anlysis. 5th edition, Prentice-Hll, Englewood Cliffs, NJ. pp How to cite this rticle: Olusol Bolji Adewle, Omotde Iidun Oloyede, Amos Onsny, Isrel Idowu Olyide, Scholstic Onyeuchi Andozie, Adewle Oluwseun Fdk. Heptoprotective Effect of Aqueous Extrct of Solnum mcrocrpon Leves ginst Cron tetrchloride-induced Liver Dmge in Rts. J App Phrm Sci, 2015; 5 (Suppl 2):