Paracetamol (acetaminophen) is commonly used in relieving fever, headache, and other minor aches and pains and has an excellent safety record when taken at therapeutic doses 1. The main problem with this medication is misuse through intentional or unintentional ingestion of supratherapeutic dosages, which usually lead to liver damage in both humans and experimental animals 2. Paracetamol hepatotoxicity is by far the most common cause of acute liver failure in the western world 3. Paracetamol overdose, single doses above 10 g, is the leading cause for calls to Poison Control Centers (>1 00 000/year) and accounts for more than 56000 emergency visits, 2600 hospitalizations, and an estimated 458 deaths each year in the USA 4.
Paracetamol is primarily metabolized by the liver into several chemical compounds, most of which are inactive, nontoxic, and eventually excreted by the kidneys. Cases of hepatotoxicity have been reported near the recommended maximum doses (4 g/day) 5. An overdose of paracetamol can cause liver injury through a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). The hepatic levels of glutathione (GSH), required for inactivation of NAPQI, the toxic metabolite of paracetamol, is reduced with an overdose of paracetamol 6. Therefore, at overdose, the essential routes become saturated and the production of NAPQI exceeds the capacity to detoxify it. The excess NAPQI then causes liver damage associated with generation of free radicals and oxidative stress 7.
The Food and Drug Administration (FDA) advisory committee recommended that new restrictions be placed to protect people from the potential toxic effects of paracetamol 8.
Recently, the use of herbal natural products has gained interest in the world population. Many of the herbs have been developed into herbal supplements, which are claimed to assist in a healthy lifestyle. Among these herbs is curcumin, which is extracted from the roots of the Curcuma longa plant (turmeric), with high potential medicinal value, and is pharmacologically safe for humans and animals 9. It has been shown to possess a wide spectrum of biological actions. These include its anti-inflammatory, antioxidant, anticarcinogenic, anticoagulant, and antidiabetic activities 10,11. There is a global trend toward the use of traditional herbal preparations for the treatment of liver diseases. The list of hepatoprotective biologically active compounds in the scientific literature is quite long, but only some of them have enough strong effects to combat different types of liver damage. Some of them such as silymarin and curcumin have attracted the attention of the scientific community 12. One of the most prominent features of curcumin is its extremely good tolerance and its very low toxicity and side effects as no studies in either animals 13 or humans 14 have found any toxicity associated with the consumption of curcumin.
Unfortunately, the number of studies on curcumin in liver diseases is still very low and investigations in this area must be encouraged because hepatic disorders constitute one of the main causes of worldwide mortality. Therefore, the aim of this study was to investigate the potential protective effects of curcumin on liver damage in rabbits caused by paracetamol. This study included biochemical, hematological, and histological investigations.
Materials and methods
Paracetamol tablets were obtained from El-Nasr Pharmaceutical Chemicals Co. (Cairo, Egypt). The tablets (each one, 500 mg) were crushed, dissolved in distilled water, and given orally through a gastric tube at a dose of 500 mg/kg/day for 15 days 15. Curcumin was purchased from Sigma Chemical Company in the form of powder (St Louis, Missouri, USA), dissolved in corn oil, and given orally through a gastric tube at doses of 50 and 100 mg/kg/day 16.
Thirty healthy adult male rabbits, weighing 1.0–1.5 kg, were used in this study. The animals were housed in clean, properly ventilated cages and had free access to food and water for at least 10 days before the experiment. Rabbits were randomly divided into five equal groups of six animals each and received treatments as described in Table 1.
The duration of the experiment was 15 days. One day after the last dose, the animals were sacrificed.
Blood samples were collected into clean, dry tubes, allowed to clot, and centrifuged for 10 min to obtain serum. The serum activity of aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) as markers of liver functions was determined. Stored plasma samples were analyzed for total protein and albumin concentrations. The serum enzyme activities and total protein and albumin were assayed spectrophotometrically with an autoanalyzer according to standard procedures, using commercially available diagnostic kits.
Blood samples were collected from the sacrificed animals and placed immediately on ice. Heparin was used as an anticoagulant and noncoagulated blood was tested, shortly after collection, for white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (Hb), hematocrit value, and platelet count.
Liver tissue was removed immediately upon the animal’s sacrifice, sliced, and immediately fixed in 10% formol saline. Sections were prepared and stained with conventional H&E and Masson’s trichrome stains 17. Examination of sections from all groups under a light microscope and assessment of various groups were performed.
For transmission electron microscopic examination, immediately after sacrificing the animals, small pieces from the liver of all groups were fixed in 2.5% gluteraldehyde for 24 h. The specimens were then washed in 3–4 changes of cacodylate buffer (pH 7.2) for 20 min each and postfixed in cold 1% osmium tetroxide for 2 h. They were then washed in four changes of cacodylate buffer for 20 min each. Dehydration was carried out by using ascending grades of alcohol (70, 90, 95, and absolute alcohol), each for 2 h, followed by clearing in propylene oxide. Specimens were embedded in Epon 812 using gelatin capsules. For polymerization, the embedded samples were kept in an incubator at 35°C for 1 day, at 45°C for another day, and at 60°C for 3 days.
Ultrathin sections (500–800 Å) from selected areas of trimmed blocks were collected on copper grids. The ultrathin sections were then contrasted in uranyl acetate for 10 min and in lead acetate for 5 min, and examined with an electron microscope Jeol JEM 1010 (Jeol, Tokyo, Japan) in the Electron Microscopic Unit of the Faculty of Science, Alexandria University 18.
Data were expressed as mean±SD and were analyzed with SPSS (version 12.0; SPSS Inc., Chicago, Illinois, USA) software. Mean differences between groups were calculated with one-way analysis of variance. Differences were considered statistically significant when P values were less than 0.05.
Table 2 shows the activities of serum ALT, AST, ALP, total protein, and albumin in control and experimental rabbits. The results showed that there were no statistical differences in any parameter between the control group (group I) and rabbits treated with curcumin only (group II). Paracetamol administration (group III) significantly increased the activities of ALT, AST, and ALP. These enzymes decreased significantly to normal value in group IV and group V, which received 50 and 100 mg/kg of curcumin besides paracetamol, compared with group III, which received paracetamol alone (P<0.001) (Histograms 1 and 2). Also, the levels of total protein and albumin were significantly reduced in paracetamol-treated rabbits (group III) when compared with groups I and II. These results returned to control values (group I) in rabbits treated with curcumin besides paracetamol (groups IV and V) (Histogram 3).
The results reported in Table 3 showed the counts of WBCs, RBCs, and platelets in control and experimental rabbits, as well as Hb and hematocrit values. There was no significant difference between WBC counts in group III (treated with paracetamol) compared with other groups (P>0.05). RBC counts decreased only in paracetamol-treated rabbits (group III) (P<0.001). Similarly, the decrease in Hb and hematocrit values was found to be significant in group III (P<0.001). Further, rabbits treated with a combination of paracetamol with 50 and 100 mg/kg of curcumin (groups IV and V, respectively) showed a normal range of WBC, RBC, Hb, and hematocrit values (no difference from group I) (Histograms 4 and 5).
Platelet counts were significantly decreased in rabbits treated with paracetamol (group III) compared with the control group (group I) (P<0.001). Treatment of paracetamol-administered rabbits with 50 and 100 mg/kg of curcumin (groups IV and V, respectively) restored the platelet counts to normal values, which was statistically different from those of group III (P>0.05) (Histogram 6).
Histological examination of the liver
Light microscopic results
In H&E-stained sections, the liver sections of both the control group (group I) and the curcumin-treated group (group II) showed a normal hepatic structure. The hepatocytes were arranged in the form of plates radiating from the central vein. The hepatocytes were polyhedral with acidophilic granular cytoplasm. They had large rounded central vesicular nuclei with prominent nucleoli. Binucleated cells were common. Hepatic sinusoids appeared as narrow spaces between the hepatic plates (Figs 1 and 2).
In group III rabbits, the liver sections stained with H&E showed swollen hepatocytes with cytoplasmic vacuolations. The nuclei were shrunken and deeply stained. The hepatic sinusoids were slightly dilated. Areas of cellular infiltration were also observed (Figs 3 and 4).
Restoration of liver structure was observed with administration of curcumin with paracetamol in both groups IV and V (nearly the same results in both groups). The liver restored the normal architecture and hepatocytes appeared normal but some cells still revealed dark nuclei. The blood sinusoids were still dilated (Fig. 5).
Using Masson’s trichrome stain, the normal distribution of collagen fibers around the portal areas and central veins was observed in the liver of the control group (Fig. 6).
In group III, excessive deposition of collagen fibers was observed in Masson’s trichrome-stained section (Fig. 7), whereas normal distribution of collagen fibers around the portal areas and central veins was observed in groups VI and V (Fig. 8).
Electron microscopic results
The hepatocytes of groups I and II had oval euchromatic nuclei, and some of them appeared binucleated (Fig. 9). Their cytoplasm contained numerous mitochondria with packed cristae, rough endoplasmic reticulum (RER), smooth endoplasmic reticulum (SER), numerous glycogen granules, and lipid droplets. Von Kupffer cells were seen lining the blood sinusoids, and bile canaliculi were observed between the adjacent hepatocytes (Figs 9 and 10).
In group III rabbits, some of the hepatocytes appeared with darkly stained irregular nuclei (Fig. 11). The mitochondria were numerous with distorted cristae and some of them had electron-dense matrix as well as dense granules. Large or giant mitochondria were observed; some mitochondria showed rupture of the membrane (Figs 11–13). The cytoplasm showed proliferated SER, destructed RER (Fig. 12), and numerous vacuoles (Fig. 13). Darkly stained nuclei of Von Kupffer cells were seen (Fig. 14).
As regards groups IV and V, most of the hepatocytes appeared normal with large oval euchromatic nuclei and prominent nucleolus. The cytoplasm appeared with normal mitochondria, RER, and SER (Fig. 15). However, a few hepatocytes appeared with electron-dense nuclei and slight cytoplasmic vacuolation. Von Kupffer cells appeared normal (Figs 16 and 17).
Metabolism of chemicals takes place largely in the liver, which accounts for the organ’s susceptibility to metabolism-dependent drug-induced injury. Drug-induced liver injuries are widespread and account for approximately one-half of the cases of acute liver failure and mimic all forms of acute and chronic liver disease 19.
Paracetamol toxicity is one of the most widespread drug-induced side effects worldwide and damage to the liver is a major complication of paracetamol. Liver enzymes ALT, AST, and ALP are often used as markers of hepatic function and their increase in blood indicates liver damage 20. In this study, there was a significant increase in ALT, AST, and ALP as well as a decrease in total plasma proteins and albumin in paracetamol-treated animals. ALT and AST are sensitive indicators of necrotic lesions within the liver 21. Hence, the marked release of transaminases into the circulation is indicative of severe damage to hepatic tissue membranes during paracetamol intoxication 22. This was consistent with the results of previous investigators who studied the effect of chronic paracetamol ingestion (using the protocol of 1000 mg every 6 h for 14 days) on liver damage as measured by elevation of serum ALT. ALT elevations of up to eight times the upper limit of normal were found in 8% of participants, and three times the upper limit of normal were found in 39% of participants 23.
In the present study, histological investigations of tissue damage induced by paracetamol in the liver confirmed previous findings as there was hepatocellular necrosis as manifested by swelling of the hepatocytes with cytoplasmic vacuolations and dark nuclei. There was also an increase in collagen fibers around the central veins and portal tracts. This is in agreement with the results of some researchers who reported that overdose of paracetamol produces a centrilobular hepatic necrosis that can be fatal 24.
Using electron microscopy, the liver of group III animals treated with paracetamol showed some hepatocytes with dark irregular nuclei and distorted mitochondria; some of them showed electron-dense matrix and others appeared with rupture of the membrane. Histochemical and ultrastructural studies have shown that the late stages of liver necrosis are associated with structural damage to subcellular components including the mitochondria 25. They added that paracetamol elicits a direct and early change in the membrane potential of the mitochondria, which is followed by ATP depletion and cell death. Acetaminophen administration selectively depletes (within 2 h) mitochondrial GSH and produces local toxicity by altering membrane permeability and decreasing the efficiency of oxidative phosphorylation. This renders mitochondria more susceptible to oxidative damage, especially during increased free radical production 26.
The hepatic necrosis is mediated by opening of the mitochondrial membrane permeability transition pore, which triggers the collapse of the membrane potential and cessation of ATP formation. The resulting mitochondrial swelling leads to the rupture of the outer mitochondrial membrane with the release of intermembrane proteins and subsequent nuclear DNA fragmentation 27.
Large mitochondria, proliferated SER, and destructed RER were observed in this study. This is in agreement with the results of previous investigators who stated that the paracetamol toxicity induced disorderly distributions of cytoplasmic organelles, enlargement of mitochondria, mild dilatation of RER and SER, and cytoplasmic myeloid bodies 28.
Paracetamol causes liver injury through a toxic metabolite, NAPQI, which is detoxified by hepatic GSH to form a paracetamol–GSH conjugate 6,29. During paracetamol overdose, total hepatic GSH is depleted and NAPQI is dramatically increased in the liver, which interacts with a range of cellular proteins, disrupting their function and causing damage to cells, finally resulting in organ failure 30. Excess of NAPQI causes oxidative stress and binds covalently to liver proteins 31. The precise molecular mechanism of paracetamol-induced hepatotoxicity is still not well understood but it is believed that mitochondria may play an important role in paracetamol-induced liver cell death 32.
In this study, it has been shown that the increase in ALT, AST, and ALP was reduced by administration of curcumin 1 h after paracetamol. Both 50 and 100 mg/kg of curcumin completely prevented the increase in these enzymes in the blood stream. There was no statistical difference between the levels of ALT, AST, and ALP in these experimental groups and the control group. These results were in agreement with the results of other researchers 33 who stated that curcumin showed significant hepatoprotective activity by lowering the levels of serum marker enzymes following aflatoxicosis in rats.
The liver is the major source of most serum proteins 34. The observed decease in serum proteins and albumin may be attributed to damage of liver cells by paracetamol. These decreasing values were returned to normal levels after concomitant administration of curcumin with paracetamol.
The hepatoprotective effect of curcumin at both doses (50 and 100 mg/kg) was also confirmed from the histological appearance of the liver of animals treated with curcumin and paracetamol (groups IV and V) as the liver restored its normal architecture, hepatocytes appeared with normal arrangement, and mitochondria appeared normal with closely packed cristae.
Also, this study demonstrated that paracetamol caused a decrease in total RBC, Hb, and hematocrit values. These results were consistent with the results of some researchers who reported that the damaged liver cells are unable to produce erythropoietin hormone, which is responsible for the formation of RBCs 35. In addition, decreased circulating RBCs led to a reduction in Hb content and hematocrit value. Marked improvement in all of the above parameters was observed after addition of curcumin. Curcumin might exert its protective action possibly by enhancing erythropoiesis and preventing oxidative damage to various blood cells 36.
In this study, decreased platelet count was observed in paracetamol-treated animals, which markedly improved with addition of curcumin. This is in agreement with a previous study that found that paracetamol causes platelet inhibition and thus increases the risk of surgical bleeding 37. Improvement in platelet counts was observed after the addition of curcumin. This was attributed to the antioxidative activity of curcumin in the protection of human blood platelets 38.
The results obtained in the present study demonstrated that curcumin offered significant protection of liver damaged by paracetamol. This was clearly evident in the histological examination of the liver and was demonstrated by the decrease in plasma transaminases and ALP, paralleled with a simultaneous increase in total plasma protein and albumin as well as increased RBC and platelet counts. The preventive effects of curcumin in acetaminophen toxicity are based on its antioxidant activity 39. This coincides with the results of another author 33 who reported that curcumin worked as an antioxidant and increased the levels of nonenzymatic antioxidant GSH. Also, other investigators 40 have considered that the beneficial effects of curcumin are mediated by its antioxidant defense ability and the scavenging of free radicals; furthermore, they stated that curcumin is 10 times more active as an antioxidant compared with vitamin E as it has potent anti-inflammatory property. In addition, curcumin can inhibit nuclear factor κB-mediated transcription of inflammatory cytokines 41. Accordingly, the amelioration of paracetamol-induced liver damage by curcumin as demonstrated in the present results is suggested to be due to its antioxidant and anti-inflammatory properties as it neutralizes free radicals, which are highly unstable molecules that can damage cellular structures through abnormal oxidative reactions.
The results of the present study show that curcumin at low and high doses ameliorates hepatotoxicity induced by a high dose of paracetamol.
Conflicts of interest
There are no conflicts of interest.
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