<?xml version="1.0" encoding="UTF-8"?><!DOCTYPE article  PUBLIC "-//NLM//DTD Journal Publishing DTD v3.0 20080202//EN" "http://dtd.nlm.nih.gov/publishing/3.0/journalpublishing3.dtd"><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" dtd-version="3.0" xml:lang="en" article-type="research article"><front><journal-meta><journal-id journal-id-type="publisher-id">PP</journal-id><journal-title-group><journal-title>Pharmacology &amp; Pharmacy</journal-title></journal-title-group><issn pub-type="epub">2157-9423</issn><publisher><publisher-name>Scientific Research Publishing</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.4236/pp.2023.144009</article-id><article-id pub-id-type="publisher-id">PP-124401</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Chemistry&amp;Materials Science</subject><subject> Medicine&amp;Healthcare</subject></subj-group></article-categories><title-group><article-title>
 
 
  Effects of &lt;i&gt;Sarcocephalus latifolius&lt;/i&gt; Fruits Extract on Paracetamol-Induced Liver Damage in Wistar Rats
 
</article-title></title-group><contrib-group><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Filkpièrè</surname><given-names>Léonard Da</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Basile</surname><given-names>Tindano</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Géneviève</surname><given-names>Zabre</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Karim</surname><given-names>Sakira</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Balé</surname><given-names>Bayala</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Raymond</surname><given-names>G. Belemtougri</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author" xlink:type="simple"><name name-style="western"><surname>Philippe</surname><given-names>Horlait</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib></contrib-group><aff id="aff4"><addr-line>Université Joseph KI-ZERBO, Laboratoire de Toxicologie, Environnement et Santé, Ouagadougou, Burkina Faso</addr-line></aff><aff id="aff2"><addr-line>Université Joseph KI-ZERBO, Laboratoire de Physiologie Animale, Ouagadougou, Burkina Faso</addr-line></aff><aff id="aff1"><addr-line>Université Norbert ZONGO, Laboratoire Sciences de la Vie et de la Terre, Koudougou, Burkina Faso</addr-line></aff><aff id="aff5"><addr-line>Health Officer and Animal Welfare, Animaleries Université Libre de Bruxelles, Brussels, Belgium</addr-line></aff><aff id="aff3"><addr-line>Ecole Normale Supérieure, Koudougou, Burkina Faso</addr-line></aff><pub-date pub-type="epub"><day>17</day><month>04</month><year>2023</year></pub-date><volume>14</volume><issue>04</issue><fpage>112</fpage><lpage>122</lpage><history><date date-type="received"><day>1,</day>	<month>March</month>	<year>2023</year></date><date date-type="rev-recd"><day>18,</day>	<month>April</month>	<year>2023</year>	</date><date date-type="accepted"><day>21,</day>	<month>April</month>	<year>2023</year></date></history><permissions><copyright-statement>&#169; Copyright  2014 by authors and Scientific Research Publishing Inc. </copyright-statement><copyright-year>2014</copyright-year><license><license-p>This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/</license-p></license></permissions><abstract><p>
 
 
  <b>Background and Aim: </b>
  Sarcocephalus latifolius is a medicinal plant commonly used in traditional medicine to treat various diseases.
  <b> </b>The aim of the present study is to evaluate the hepatoprotective activity of 
  Sarcocephalus latifolius fruits aqueous extract against paracetamol-induced liver damage in rats. 
  <b>Material and Methods:</b> Aqueous extract of 
  Sarcocephalus latifolius fruits at doses of 100, 250 and 500 mg/kg were administered orally to rats with paracetamol-induced hepatotoxicity (1 g/kg). The treatment with the extract and paracetamol lasted 7 days. 
  Silymarin (50 mg/kg) was given as reference control. All tested drugs were administered orally. 
  <b>Results:</b> Our results show that the 
  Sarcocephalus latifolius fruits extract induced a significant reduction (p &lt; 0.05) of serum enzymes alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (PAL) and total bilirubin (TB). Then, the extract at the dose of 500 mg/kg showed a better protection (p &lt; 0.001) of hepatocytes with a percentage of protection of 43.59% &#177; 2.03%; 59.43% &#177; 4.12%; 73.29% &#177; 5.72% and 62.55% &#177; 7.48% for ALAT, ASAT, PAL and TB, respectively. The histology of livers exposed to paracetamol shows an inflammation of the hepatocytes. In addition, there was a significant alteration of the liver parenchyma. The 500 mg/kg extract showed a resorption of the inflammation. Histopathological examination showed that the extract regenerated paracetamol-induced liver damage. 
  <b>Conclusion:</b> Aqueous extract of 
  Sarcocephalus latifolius fruits has hepatoprotective activity against paracetamol-induced hepatotoxicity in rats. But it would be important to evaluate the activity of aqueous extract of 
  Sarcocephalus latifolius fruits on oxidative stress parameters 
  in vivo in rats. 
  
 
</p></abstract><kwd-group><kwd>Rats</kwd><kwd> Paracetamol</kwd><kwd> Hepatotoxicity</kwd><kwd> &lt;i&gt;Sarcocephalus latifolius&lt;/i&gt;</kwd><kwd> &lt;i&gt;Silymarin&lt;/i&gt;</kwd></kwd-group></article-meta></front><body><sec id="s1"><title>1. Introduction</title><p>The liver is an auxiliary organ of the digestive tract. It fulfills many functions that are essential to life. It participates in the process of digestion through biliary secretion. All substances introduced into the body reach the bloodstream to be transformed before being excreted. Thus, the liver is exposed to various aggressions which sometimes have serious damages on the organism. It has been estimated in recent reports that 10% of world population is affected with liver diseases including hepatitis. Morbidity and mortality resulting from liver diseases is a major public health problem worldwide [<xref ref-type="bibr" rid="scirp.124401-ref1">1</xref>] .</p><p>Drug-induced hepatitis is manifested by inflammatory processes. These data show that liver disease is a public health problem in the world. It is important that some to improve the prevention and treatment of liver disease through scientific research. The availability of a varied plants repertoire with hepatotropic action in the traditional medicine of Burkina Faso [<xref ref-type="bibr" rid="scirp.124401-ref2">2</xref>] and the hepatic damage linked to Paracetamol exposure motivated this study. Sarcocephalus latifolius is a medicinal plant whose different parts are used to treat various diseases in Burkina Faso. The fruits are edible and remain an excellent source of nutrients in vitamins, minerals as well as carbohydrates [<xref ref-type="bibr" rid="scirp.124401-ref3">3</xref>] . Likewise, fruit of Sarcocephalus latifolius is used in traditional medicine for the treatment of many diseases [<xref ref-type="bibr" rid="scirp.124401-ref4">4</xref>] . These roots and fruits are used to treat liver disease and jaundice [<xref ref-type="bibr" rid="scirp.124401-ref5">5</xref>] . The objective of the study was to evaluate the hepatoprotective activity of the aqueous extract of the fruits of Sarcocephalus latifolius on paracetamol-induced hepatotoxicity in rats.</p></sec><sec id="s2"><title>2. Materiel and Methods</title><sec id="s2_1"><title>2.1. Plant Collection</title><p>The fruits of the Sarcocephalus latifolius plant were collected in the South West region of Burkina Faso. A specimen (18,028) was deposited in the Herbarium of the D&#233;partement de Botanique de l’Universit&#233; Joseph KI ZERBO, Ouagadougou (Burkina Faso). The collected fruits were washed with water, cut into small parts and dried in the shade without dust for a week and pulverized.</p></sec><sec id="s2_2"><title>2.2. Plant Extraction</title><p>These dried fruits were pulverized and 400 g of this powder were macerated in 1000 ml of distilled water for 24 hours. The filtrate was centrifuged at 2000 rpm for 10 min. The supernatant was frozen at −23˚C and lyophilized. Aqueous extract of Sarcocephalus latifolius fruits (EASL) obtained, was stored at −4˚C. The extraction yield was 24.23%.</p></sec><sec id="s2_3"><title>2.3. Experimental Animals</title><p>Thirty male Wistar rats weighing between 150 and 200 g were randomized into six groups of five rats. Rats were maintained under standard laboratory conditions (temperature: 22˚C &#177; 3˚C, relative humidity: 50% &#177; 10% and light/dark cycle: 12/24h). Food pellets and water were provided ad libitum. The animals were used in accordance with the local ethic committee of Universit&#233; Joseph KI-ZERBO.</p></sec><sec id="s2_4"><title>2.4. Paracetamol-Induced Hepatotoxicity in Rat</title><p>Rats were randomized into six groups of rats including five rats for each group. The treatments were achieved according to the experiment design described by [<xref ref-type="bibr" rid="scirp.124401-ref6">6</xref>] [<xref ref-type="bibr" rid="scirp.124401-ref7">7</xref>] :</p><p>Group I (Vehicle): Rats received 0.9% NaCl solution at 0.5 mL/rat with normal diet.</p><p>Group II (Negative control): Rats received paracetamol at 1 g/kg bw (p.o.)</p><p>Group III (Positive control): Rats received Silymarin at 50 mg/kg bw (p.o.)</p><p>Group IV: Rats received paracetamol 1 g/kg bw, (p.o.) and aqueous extract of Sarcocephalus latifolius fruit 100 mg/kg bw (p.o.)</p><p>Group V: Rats received paracetamol 1 g/kg bw, (p.o.) and aqueous extract of Sarcocephalus latifolius fruit 250 mg/kg bw (p.o.)</p><p>Group VI: Rats received paracetamol 1 g/kg bw, (p.o.) and aqueous extract of Sarcocephalus latifolius fruit 500 mg/kg bw (p.o.)</p></sec><sec id="s2_5"><title>2.5. Biochemical and Histopathology Studies</title><p>On day 8, rats were anesthetized with ether, sacrificed, and blood was collected centrifuged at 3000 rpm during 15 minutes for serum separation. Serum was stored at −20˚C until biochemical studies. The change in aspartate amino transferase (ASAT), alanine amino transferase (ALAT), alkaline phosphatase (PAL), and total bilirubin (TB) levels were measured for biochemical investigations. Atlas diagnostic product kits were used for these investigations.</p><p>Then animals were sacrified and livers were removed weighed. The liver samples were washed with saline, fixed in 70% ethanol and were processed for paraffin embedding following the microtome technique. The sections were taken at 5 μm thickness processed in alcohol-xylene series and were stained with alum-haematoxylin and eosin. The sections were examined microscopically for the evaluation of histopathological changes.</p></sec><sec id="s2_6"><title>2.6. Statistical Analysis</title><p>Results were expressed as Mean &#177; SEM, (n = 5). Statistical analyses were performed with one-way analysis of variance (ANOVA I) followed by Tukey’s multiple comparison test by using Graph Pad Prism Software. P &lt; 0.05 was considered to be statistically significant.</p></sec></sec><sec id="s3"><title>3. Results and Discussion</title><sec id="s3_1"><title>3.1. Results</title><sec id="s3_1_1"><title>3.1.1. Effect of Aqueous Extract of Sarcocephalus latifolius Fruit on the Body Weight Gain and Liver Weight in Paracetamol-Induced Hepatotoxicity in Rats</title><p>Extract caused a non-significant (p &gt; 0.05) weight gain in the rats compared to the negative control. The extract did not cause a significant (p &gt; 0.05) change in liver weight compared to the control (<xref ref-type="fig" rid="fig1">Figure 1</xref>).</p></sec><sec id="s3_1_2"><title>3.1.2. Effect of Aqueous Extract of Sarcocephalus latifolius Fruit on Transaminases Levels in Paracetamol-Induced Hepatotoxicity in Rats</title><p>The extract at all doses significantly (p &lt; 0.05) decreased ALAT level compared to the negative control. Extract at the dose of 500 mg/kg had the best percentage protection against paracetamol-induced hepatotoxicity. It was about 44% (<xref ref-type="fig" rid="fig2">Figure 2</xref>).</p><p>Paracetamol induced a significant (p &lt; 0.05) increase in ASAT levels compared to neutral control. Extract at all doses induced a significant decrease in the level of this enzyme compared to the negative control. Extract 500 mg/kg showed a better percentage of hepatocyte protection (<xref ref-type="fig" rid="fig3">Figure 3</xref>).</p></sec><sec id="s3_1_3"><title>3.1.3. Effect of Aqueous Extract of Sarcocephalus latifolius Fruit on Total Bilirubin Level in Paracetamol-Induced Hepatotoxicity in Rats</title><p>Paracetamol induced a significant (p &lt; 0.001) increase in total bilirubin levels compared to the neutral control. Extract at all doses induced a significant (p &lt; 0.001) decrease in bilirubin level compared to the negative control. The extract protected liver cells at 45%; 40% and 63% for the doses of 100, 250 and 500 mg/kg, respectively (<xref ref-type="fig" rid="fig4">Figure 4</xref>).</p></sec><sec id="s3_1_4"><title>3.1.4. Effect of Aqueous Extract of Sarcocephalus latifolius Fruit on Alkaline Phosphatase Level in Paracetamol-Induced Hepatotoxicity in Rats</title><p>Paracetamol induced a significant (p &lt; 0.001) increase in alkaline phosphatase levels compared to the neutral control. Extract at all doses induced a significant (p &lt; 0.001) decrease in alkaline phosphatase level compared to the negative control. The extract protected liver cells at 66%, 70% and 73% for the doses of 100, 250 and 500 mg/kg, respectively (<xref ref-type="fig" rid="fig5">Figure 5</xref>).</p></sec><sec id="s3_1_5"><title>3.1.5. Histopathological Evaluation of the Effect of Sarcocephalus latifolius and Vehicles Groups in Paracetamol-Induced Hepatic Injury in Rats</title><p>Histopathological profiles showed a hepatoprotective activity of the aqueous extract of Sarcocephalus latifolius fruits at all doses. However, animals only treated with paracetamol showed hepatocellular and centrilobular necrosis. This necrosis was accompanied by leukocyte infiltration in the liver. There were also</p><p>vascular congestion leading to destruction of the sinusoidal canaliculi and hepatic arteries. The inflammation of the hepatocytes was less severe or even reduced in the groups treated with the 500 mg/kg extract, as well as in the groups treated with Silymarin 50 mg/kg (<xref ref-type="fig" rid="fig6">Figure 6</xref>).</p></sec></sec><sec id="s3_2"><title>3.2. Discussion</title><p>Paracetamol is sometimes used as an analgesic and antipyretic. When taken in overdose (at least 200 mg/kg), Paracetamol can produce significant hepatotoxic effects [<xref ref-type="bibr" rid="scirp.124401-ref8">8</xref>] . In the liver, there is a protective mechanism involving glutathione in the regression of cellular damage [<xref ref-type="bibr" rid="scirp.124401-ref9">9</xref>] . But when paracetamol is used in high doses, the glutathione level is not sufficient to conjugate N-acetyl-p-benzoquinoneimine (NAPQI). Therefore, NAPQI alkylates the proteins present in the biomembranes of microsomes and mitochondria, producing hepatic necrosis [<xref ref-type="bibr" rid="scirp.124401-ref10">10</xref>] [<xref ref-type="bibr" rid="scirp.124401-ref11">11</xref>] [<xref ref-type="bibr" rid="scirp.124401-ref12">12</xref>] . Therefore, macromolecules such as enzymes will pass from the damaged tissues into the bloodstream [<xref ref-type="bibr" rid="scirp.124401-ref13">13</xref>] and the study of the activity of these enzymes in plasma is very important for the assessment of liver injury [<xref ref-type="bibr" rid="scirp.124401-ref14">14</xref>] . Increased ASAT and ALAT level indicates cellular damage and loss of functional integrity of hepatocytes [<xref ref-type="bibr" rid="scirp.124401-ref15">15</xref>] .</p><p>Increased PAL in liver disease reflects pathological alteration of bile flow [<xref ref-type="bibr" rid="scirp.124401-ref16">16</xref>] .</p><p>The abnormally high serum level of ALAT, ASAT, PAL and total bilirubin observed in the negative control group is a consequence of paracetamol-induced liver dysfunction and indicates liver cell damage. The extract at doses of 100,250, and 500 mg/kg significantly (p &lt; 0.01) decreased the activity of ASAT and ALAT compared with the negative control. The increase in serum PAL could be due to its high synthesis following high bile pressure. The extract at all doses showed a highly significant reduction in PAL and bilirubin levels in the test groups. These results were comparable to those of the standard drug, Silymarin. The extract appears to offer protection and maintain liver cell function. Extract of Sarcocephalus latifolius fruits possesses flavonoids and tannins recognized for their hepatoprotective action. Saponins, alkaloids, flavonoids, phytates and triterpenoids are phytochemical constituents of Sarcocephalus latifolius with antioxidant, free radical scavenging and peroxidant inhibition capacity and inhibition of lipid peroxidation. These results are comparable to those of [<xref ref-type="bibr" rid="scirp.124401-ref7">7</xref>] [<xref ref-type="bibr" rid="scirp.124401-ref17">17</xref>] [<xref ref-type="bibr" rid="scirp.124401-ref18">18</xref>] [<xref ref-type="bibr" rid="scirp.124401-ref19">19</xref>] . Silymarin isolated from Silybum marianum has a protective effect on the plasma membrane of hepatocytes and has multiple inhibitory effects against different hepatotoxic agents. The antioxidant effects and the regenerative functions of Silymarin cells involve protein synthesis, which has been considered as the most important actions of Silymarin. The hepatoprotective activity observed in the present study may be due to the protective effect of Sarcocephalus latifolius on the plasma membrane of hepatocytes or cells regeneration function similar to that of Silymarin. These results are comparable to those [<xref ref-type="bibr" rid="scirp.124401-ref7">7</xref>] [<xref ref-type="bibr" rid="scirp.124401-ref20">20</xref>] .</p><p>The histopathological results showed that Sarcocephalus latifolius extract exhibited good protection on the architecture of the liver. Paracetamol could have an inflammatory effect by inducing the release and action of endogenous pro-inflammatory mediators responsible for the development of inflammation. The aqueous extract of Sarcocephalus latifolius fruits could show an anti-inflammatory effect by preventing the release of endogenous pro-inflammatory mediators responsible for inflammation [<xref ref-type="bibr" rid="scirp.124401-ref21">21</xref>] . The extract of Sarcocephalus latifolius fruits could block the degradation of arachidonic acid by the cyclooxygenase or lipo-oxygenase pathway. It would thus oppose the production of prostaglandins, thromboxane A<sub>2</sub> and also leukotrienes [<xref ref-type="bibr" rid="scirp.124401-ref22">22</xref>] . This protection was almost to the liver of rats treated with Silymarin. These results validate the hepatoprotective effect of the aqueous extract of Sarcocephalus latifolius fruits on paracetamol-induiced hepatotoxicity.</p></sec></sec><sec id="s4"><title>4. Conclusion</title><p>These results validate the hepatoprotective effect of the aqueous extract of Sarcocephalus latifolius fruits on paracetamol-induced hepatotoxicity. By applying the appropriate dose and orally, the aqueous extract of Sarcocephalus latifolius fruits constitutes a good hepatoprotective drugs. But it would be important to evaluate the activity of aqueous extract of Sarcocephalus latifolius fruits on oxidative stress parameters in vivo in rats. Also it would be interesting to isolate the bioactive compounds found in the fruits of Sarcocephalus latifolius to confirm its use in traditional medicine.</p></sec><sec id="s5"><title>Conflicts of Interest</title><p>The authors declare no conflicts of interest regarding the publication of this paper.</p></sec><sec id="s6"><title>Cite this paper</title><p>Da, F.L., Tindano, B., Zabre, G., Sakira, K., Bayala, B., Belemtougri, R.G. and Horlait, P. (2023) Effects of Sarcocephalus latifolius Fruits Extract on Paracetamol-Induced Liver Damage in Wistar Rats. Pharmacology &amp; Pharmacy, 14, 112-122. https://doi.org/10.4236/pp.2023.144009</p></sec></body><back><ref-list><title>References</title><ref id="scirp.124401-ref1"><label>1</label><mixed-citation publication-type="other" xlink:type="simple">Zhang, A., Sun, H. and Wang, X. (2013) Recent Advances in Natural Products from Plants for the Treatment of Liver Diseases. European Journal of Medicinal Chemistry, 63, 570-577. https://doi.org/10.1016/j.ejmech.2012.12.062</mixed-citation></ref><ref id="scirp.124401-ref2"><label>2</label><mixed-citation publication-type="other" xlink:type="simple">Nacoulma/Ouédraogo, O.G. (1996) Plantes médicinales et Pratiques médicales Traditionnelles au Burkina Faso: Cas du plateau central T1 &amp; T2. Thèse de l’université Ouaga I Pr Joseph KI-ZERBO, 91-92.</mixed-citation></ref><ref id="scirp.124401-ref3"><label>3</label><mixed-citation publication-type="other" xlink:type="simple">Plassart, L. (2015) Sarcocephalus latifolius (Sm.) Bruce: études botanique, chimique et pharmacologique. Sciences Pharmaceutiques.</mixed-citation></ref><ref id="scirp.124401-ref4"><label>4</label><mixed-citation publication-type="other" xlink:type="simple">Eze, S.O. and Obinwa, E. (2014) Phytochemical and Nutrient Evaluations of the Leaves and Fruits of Nauclea latifolia (Uvuru-ilu). Communications in Applied Sciences, 2, 8-24.</mixed-citation></ref><ref id="scirp.124401-ref5"><label>5</label><mixed-citation publication-type="other" xlink:type="simple">Malgras, D. (1992) Arbres et arbustes guérisseurs des savanes maliennes. Ed Karthala, Paris.</mixed-citation></ref><ref id="scirp.124401-ref6"><label>6</label><mixed-citation publication-type="other" xlink:type="simple">Hafez, E.M., Paulis, M.G., Ahmed, M.A., et al. (2015) Protective and Anti-Oxidant Activity of the Euryops arabicus against Paracetamol Induced Hepatorenal Toxicity in Rats. Journal of Clinical Toxicology, 5, 227.  
https://doi.org/10.4172/2161-0495.1000227</mixed-citation></ref><ref id="scirp.124401-ref7"><label>7</label><mixed-citation publication-type="other" xlink:type="simple">Ur Rehman, J., Akhtar, N., Khan, M.Y., et al. (2015). Phytochemical Screening and Hepatoprotective Effect of Alhagi maurorum Boiss (Leguminosae) against Paracetamol-Induced Hepatotoxicity in Rabbits. Tropical Journal of Pharmaceutical Research, 14, 1029-1034. https://doi.org/10.4314/tjpr.v14i6.13</mixed-citation></ref><ref id="scirp.124401-ref8"><label>8</label><mixed-citation publication-type="other" xlink:type="simple">Parmar, S.R., Vashrambhai, P.H. and Kalia, K. (2010) Hepatoprotective Activity of Some Plants Extract against Paracetamol Induced Hepatotoxicity in Rats. Journal of Herbal Medicine and Toxicology, 4, 101-106.</mixed-citation></ref><ref id="scirp.124401-ref9"><label>9</label><mixed-citation publication-type="other" xlink:type="simple">Potter, W.Z., Thorgeirsson, S.S., Jollow D.J. and Mitchell, J.R. (1974) Acetaminophen-Induced Hepatic Necrosis V. Correlation of Hepatic Necrosis, Covalent Binding and Glutathione Depletion in Hamsters. Pharmacology, 12, 129-143.  
https://doi.org/10.1159/000136531</mixed-citation></ref><ref id="scirp.124401-ref10"><label>10</label><mixed-citation publication-type="other" xlink:type="simple">Aldridge, W.N. (1981) Mechanism of Toxicity: New Concepts Are Required in Toxicology. Trends in Pharmacological Sciences, 2, 228-231.  
https://doi.org/10.1016/0165-6147(81)90321-7</mixed-citation></ref><ref id="scirp.124401-ref11"><label>11</label><mixed-citation publication-type="other" xlink:type="simple">Tirmenstein, M.A. and Nelson, S.P. (1989) Sub Cellular Binding and Effects on Calcium Homeostasis Produced by Acetaminophen and a Non-Hepatotoxic Regioisomer 3-Hydroxyacetanilide in Mouse Liver. Journal of Biological Chemistry, 264, 9814-9819. https://doi.org/10.1016/S0021-9258(18)81731-8</mixed-citation></ref><ref id="scirp.124401-ref12"><label>12</label><mixed-citation publication-type="other" xlink:type="simple">Vermeulen, N.P.E., Bessems, J.G.M., Van, D.E. and Straat, R. (1992) Molecular Aspects of Paracetamol-Induced Hepatotoxicity and Its Mechanism Based Prevention. Drug Metabolism Reviews, 24, 367-407.  
https://doi.org/10.3109/03602539208996298</mixed-citation></ref><ref id="scirp.124401-ref13"><label>13</label><mixed-citation publication-type="book" xlink:type="simple">Hearse, D.J. (1979) Cellular Damage during Myocardial Ischaemia: Metabolic Changes Leading to Enzyme Leakage. In: Hearse, D.J., De Leiris, J. and Loisance, D., Eds., Enzymes in Cardiology, John Wiley and Sons Ltd., New York, 1-21.</mixed-citation></ref><ref id="scirp.124401-ref14"><label>14</label><mixed-citation publication-type="book" xlink:type="simple">Plaa, G.L. and Zimmerman, H.J. (1997) Evaluation of Hepatotoxicity: Physiological and Biochemical Measures of Hepatic Function. In: McCuskey, R.S. and Earnest, D.L., Eds., Comprehensive Toxicology, Vol. 9, Cambridge University Press, Cambridge, 97-109.</mixed-citation></ref><ref id="scirp.124401-ref15"><label>15</label><mixed-citation publication-type="other" xlink:type="simple">Drotman, R.B. and Lowhorn, G.T. (1978) Serum Enzymes as Indicators of Chemical Induced Liver Damage. Drug and Chemical Toxicology, 1, 163-171.  
https://doi.org/10.3109/01480547809034433</mixed-citation></ref><ref id="scirp.124401-ref16"><label>16</label><mixed-citation publication-type="book" xlink:type="simple">Plaa, G.L. and Hewitt, W.R. (1989) Detection and Evaluation of Chemically Induced Liver Injury. In: Wallace Hayes, A, Ed., Principles and Methods of Toxicology, 2nd Edition, Raven Press, New York, 399-428.</mixed-citation></ref><ref id="scirp.124401-ref17"><label>17</label><mixed-citation publication-type="other" xlink:type="simple">Faure, M., Lissi, E., Torres, R. and Vidella, L.A. (1990) Antioxidant Activity of Liginin and Flavonoids. Phytochem, 29, 3773-3775.  
https://doi.org/10.1016/0031-9422(90)85329-E</mixed-citation></ref><ref id="scirp.124401-ref18"><label>18</label><mixed-citation publication-type="other" xlink:type="simple">Jin, X., Qian, J. and Lu, Y. (2011) The Role of Hepatoprotective Effect of a Flavonoid-Rich Extract of Salvia plebeia R.Br. on Carbon Tetrachloride Induced Acute Hepatic Injury in Mice. Journal of Medicinal Plants Research, 5, 1558-1563.</mixed-citation></ref><ref id="scirp.124401-ref19"><label>19</label><mixed-citation publication-type="other" xlink:type="simple">Badiaga, M. (2011) Etude ethnobotanique, phytochimique et activités biologiques de Nauclea latifolia Smith une plante medecinale recolté au Mali. Ph.D. Sciences, Université de Bamako, Bamako.</mixed-citation></ref><ref id="scirp.124401-ref20"><label>20</label><mixed-citation publication-type="other" xlink:type="simple">Bagban, I.M., Roy, S.P., Chaudhary, A., Das, S.K., Gohil, K.J. and Bhandari, K.K. (2012) Hepatoprotective Activity of the Methanolic Extract of Fagonia indica Burm in Carbon Tetra Chloride Induced Hepatotoxicity in Albino Rats. Asian Pacific Journal of Tropical Biomedicine, 2, S1457-S1460.  
https://doi.org/10.1016/S2221-1691(12)60437-7</mixed-citation></ref><ref id="scirp.124401-ref21"><label>21</label><mixed-citation publication-type="other" xlink:type="simple">Gobiannand, K., Vivekanandan, P., Pradeep, C.V., Mohan, R. and Karthikeyan, S. (2010) Anti-Inflammatory and Antipyretic Activities of Indian Medicinal Plant Cassia fistula Linn. (Golden Shower) in Albino Wistar Rats. Journal of Pharmacology, 6, 719-725. https://doi.org/10.3923/ijp.2010.719.725</mixed-citation></ref><ref id="scirp.124401-ref22"><label>22</label><mixed-citation publication-type="other" xlink:type="simple">Khalil, N.M., Sperotto, J.S. and Manfron, M.P. (2006) Anti-Inflammatory Activity and Acute Toxicity of Dodonea viscose. Fitoterapia, 77, 478-480.  
https://doi.org/10.1016/j.fitote.2006.06.002</mixed-citation></ref></ref-list></back></article>