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Hepatoprotective Effects of Apricot against Acetaminophen-Induced Acute Hepatotoxicity in Rats

İsmet YILMAZ*, Aslı ÇETİN, Yılmaz BİLGİÇ

Department of Pharmacology, Faculty of Pharmacy, Inonu University, 44280 Malatya, Turkey

Abstract: This study was to investigate the hepatoprotective effects of sun-dried organic apricot (SDOA) supplementation to chow against acetaminophen(APAP)-induced acute hepatotoxicity in rats. In this study, 24 female rats were randomized into four groups (n=6/groups). Blood and liver tissue samples were subjected to biochemical and histological examinations. SDOA consumption have strongly hepatoprotective effects againist APAP- induced acute hepatotoxicity in rats. The SDOA supplementation over a 45-day feeding period showed a beneficial effect against APAP-induced acute hepatotoxicity in rats, as reflects by histologycal and biochemical findings. Therefore, for humans in case of overdose APAP administration or chronic APAP treatments apricot consumption may be recommended.

Keywords: acetaminophene, hepatotoxicity, apricot, rat

Received April 13, 2015; Revised April 27, 2015; Accepted April 29, 2015

Citation: İsmet YILMAZ, Aslı ÇETİN, Yılmaz BİLGİÇ, Hepatoprotective Effects of Apricot against Acetaminophen-Induced Acute Hepatotoxicity in Rats. American Journal of Pharmacological Sciences, 3 (2). 44-48. January 2015. doi:10.12691/ajps-3-2-3

1. Introduction

The liver is a primary organ which is responsible for many important vital functions such as drug metabolism/detoxification, and also protein, lipid and glucose metabolism [1]. Many different mechanisms of hepatotoxicity and its importance in clinical research have been reported by authors [2,3,4]. In this context, APAP-induced hepatic damage is the second leading cause of liver transplantation and accounts for considerable levels of morbidity and mortality [4]. APAP is a widely used safe drug at therapeutic doses due to its analgesic and antipyretic properties. But, in case of overdoses or chronic use, it can cause hepatic necrosis, nephrotoxicity, extra hepatic lesions, and even death in humans and animals [4,5,6,7]. It is reported that, APAP is rapidly absorbed from the stomach and small intestine and metabolized to non-toxic agents in the liver, but in acute overdose the normal metabolism becomes saturated and it is metabolism exceeded over a prolonged period. During excess conditions, APAP is oxidatively metabolizes to a toxic metabolite as N-acetyl-P-benzoquinoneimine (NAPQI), it has an extremely short half-life and is rapidly conjugated with glutathione, and reduced hepatocellular glutathione store. Subsequently, this toxic metabolite is covalently binds to vital proteins and the lipid bilayer of hepatocyte membranes, and the result is hepatocellular death and centrilobular liver necrosis [8].

In different kind of drug therapies including APAP, hepatocellular, cholestatic or cytolytic injuries of liver concludes with marked elevations of serum total bilirubin (TB), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. In addition, against to hepatotoxicity, adults are more susceptible than children, and women are more commonly affected than men were reported by authors [2]. Drug-induced (APAP) liver disease is a worldwide problem [3], and some alternative research results such as Phyllanthus acidus (L.) Skeels leaf extracts [7], leaf extracts of Boerhaavia diffusa L. [8] Ambrosia maritima extract [9], potential protective effect of honey [10] have been reported elsevier.

Our main goal is not only examine inward mechanisms of hepatotoxicity but also provide other alternatives to treat or prevention of drug-induced (APAP) hepatotoxicity. Our previous studies about effects of SDOA supplemented diet consumption on some serum mineral levels, serum liver enzymes and liver regeneration after partial hepatectomy in rats have been published [11,12,13]. Moreover other reports about hepatoprotective and beneficial effects of apricot against ethanol-induced hepatotoxicity [14], carbon tetrachloride [15], myocardial ischemia-reperfusion injuries [16] and methotrexate-induced intestinal oxidative damages [17]. We have not found any information about hepatoprotective effects of SDOA consumption against APAP-induced acute hepatotoxicity. Therefore, the present study was aimed to evaluate the effects of 10% SDOA consumption against APAP-induced acute hepatotoxicity in rats.

2. Materials and Methods

The protocol of present experiment was approved by Ethics Committee of Inonu University (2013/A-72) and, 24 female Sprague-Dawley rats were used. Animals were provided from our Experimental Animal Research and Production Center. Guidelines the Care and Use of Laboratory Animals were considered. At the beginning of the study, their average body weight was 194±20 g. The animals were randomly divided into four groups (n=6/groups); group 1 (control), group 2 (APAP), group 3 (APAP+SDOA) and group 4 (SDOA). Rats within group 1 and 2 were fed normal rat chow and tap water ad libitum and they were humanely killed on 3th days of study. At the beginnining of the study, single 835 mg/kg dose APAP were administered by orally to group 2 and 3. Rats within group 3 and 4 were fed with 10% SDOA-supplemented chow from beginning to the end of the study (45 days trial). On 45th of the study, all rats were anesthetized by intraperitoneal injection of ketamine+xylazine and approximately 10-mL blood samples were taken from all rats by intracardiac puncture to measurement of serum liver enzymes. Blood samples were centrifuged at 3000g for 10 minutes, and obtained serum samples were stored at -45C until analysis. These samples were used for measurement of serum ALT, AST, ALP and TB levels. For histological examinations, taken liver tissue samples were processed by routine tissue techniques and embedded in paraffin from all rats.

In the present study, standard rat chow (Elazığ, Turkey) and the Kabaaşı variety of SDOA which was provided from a local market in Malatya (having organic certificate) were used. No pelleted 9 kg rat chow and 1 kg SDOA (10%) were mixed homogenously in a clean container by hand. The mixture was wetted and pelleted by a simple machine before during within 5-6 days at room temperature and feeding to the rats. Nutrient and mineral contents of SDOA and rat chow have been shown in Yilmaz et al [11]. In the present study, experimental design, duration and group numbers of rats were determined according to other experiments [13,14,15,16,17].

3. Results

In the present study serum AST, ALT, ALP and TB levels were measured using Abbott clinical autoanalyser (Architect c16000) with Abbott kits (Abbott Diagnostics, Abbott Park, Ill, United States).

The statistical differences between groups of parameters was evaluated by Kruskal-Wallis test. In multiple comparisons, a Bonferroni correction of Mann-Whitney U test was used. Data as summarized as median with (min-max), and p <0.05 was considered statistically significant. Among serum AST, ALT, ALP and TB parameters, although ALP value of group 4 very near to group 3, only in group 3 of the ALP value was shown statistically significant difference (p = 0.032), and no significant differences were observed between groups in the other parameters. The results of statistical analyses were summarized in Table 1.

Table 1. Serum biochemical parameters. (n=6/groups)

For light microscopic evaluation, liver samples were fixed in 10% formalin and embedded in paraffin blocks. Paraffin blocks were cut into 5 µm thick sections, mounted on slides and stained with Hematoxylen-Eosin (H-E). Sections were examined using a Leica DFC280 light microscope and a Leica Q Win Image Analysis system (Leica Micros Imaging Solutions Ltd., Cambridge, UK).

Figure 1. Control group (A) and 10% SDOA (B) groups. We showed normal histological appearence in control and 10% SDOA groups. VC: Vena centralis. H-E;X40

In control (Figure 1A) and 10% SDOA (Figure 1B) groups; liver showed normal histological appearence. In APAP treated rats showed some histopathological changes. These changes were necrosis (Figure 2A), hemorrhage (Figure 2A, D), disruption of radial arrangement of hepatocytes from central vein, eosinophilic stained and pyknotic nuclei cells (Figure 2A, B), vascular congestion (Figure 2C), mononuclear cell infiltration (Figure 2C, E) and cellular swelling (Figure 2F). On the other hand, in APAP and 10% SDOA group, histopathological findings were not as extensive as in the APAP group. Histopathological changes were significantly decreased in APAP + 10% SDOA group.

Figure 2. APAP group: (A) necrosis (arrows), (A,D) hemorrhage, disruption of radial arrangement of hepatocytes from central vein, (A,B) eosinophilic stained and pyknotic nuclei cells, (C) vascular congestion (white arrow), (C,E) mononuclear cell infiltration (black arrows), and (F) cellular swelling. A,B,C,E,F: H-E; x20, D: H-E; x40

Figure 3. APAP + 10% SDOA: Histopathological changes were significantly decreased in APAP + 10% SDOA compared with APAP group. A: H-E;x20, B: H-E;x40

Statistical analysis of histological results were made with SPSS 13 and MedCalc programme. All groups were compared by the nonparametric Kruskal- Wallis test. Exact p values were given where available, and p< 0,0001 was accepted as statistically significant. All results were expressed as means ± Standard deviation (SD). The microscopic damage score for each group was determined in the histological section, and results were given in Table 2. The mean differences the values bearing different superscript letters within the same column are statistically significant (p≤0,0001).

Table 2. Comparisons of the effect of 10% SDOA on microscopic damage caused by APAP in liver. (n=6/groups)

4. Discussion

There is an alarming increase in the incidence of alcohol- and drug-related liver damage in the world [1,6]. At therapeutic doses, APAP is considered as safe, on the other hand at higher doses it produces a centrilobular hepatic necrosis that can be fatal, and also APAP poisoning accounts for approximately one-half of all cases of acute liver failure in the United States and Great Britain today. Annual costs of APAP overdose and correlation of acetaminophen-induced hepatotoxicity are reported extensively [18]. In this context, APAP-induced liver injury has reported in several mechanisms. APAP metabolise to glucuronide and sulfate conjugates, which are excreted in the urine. In normal conditions, only a small proportion (about 5%) of APAP is oxidized to NAPQI and that is detoxified by hepatic GSH, in case of excessive doses of APAP (>7.5 g/day in adult, >150 mg/kg in children) the saturation of glucuronic acid and/or sulfate pathways. Binds of thiol groups by NAPQI is leading to transition of mitochondrial permeability, and this resulting in the ensuing mitochondrial dysfunction and also facilitates peroxynitrate formation. These events culminate in GSH reserves are depleted and the hepatorenal toxicity occurs [19].

It is reported that, hepatocellular damage due to various reasons causes increase in plasma levels of ALT and AST, and normalization of these is accepted as an indicator of the improvement of liver functions. Besides, a major portion of serum ALP (about 80%) originates from hepatobiliary and/or bone tissues and serum ALP levels are used as an indicator of either liver function or bone metabolism. Osteoblastic activity is at its minimum levels in adults (animals of present study), so the contribution of bone isoenzyme to total ALP activity during this period is minimal [12]. In the present study, statistically significant increase have determined in serum ALP levels of 3 (p<0.05) (and ALP levels of group 4 is very neer to group 3). Similarly an increase in serum ALP levels of female rats were reported by Yilmaz et al [12]. Therefore, again it can say that, 10% SDOA consumption during 45 days have an increasing effect in serum ALP levels and this increasing effect in ALP levels of female rats may be due to rich carbohydrate and mineral (as K, Mg and P) contents of apricot [11].

AST values of the present study were very near to APAP + CS group, and among our ALP values only gruop 2 was near groups 3, 4 and ALP values of us were lower than APAP + CS group of Ozcelik et al study [4]. On the other hand, AST, ALT and ALP values of the present study were significantly lower than Yang et al., and our AST and ALT values were significantly lower than Galal et al [10,20]. AST and ALT values of the present study are high than Ramadoss et al's study, except APAP group of them. ALP value of control group of the present study are near to them of control group, and their APAP group of ALP was very high than us, but their ALP values of groups 3 and 4 are near our control and APAP groups. But their ALP value of APAP group is very high than our APAP group. TB values of the present study are same with them study of all 4 groups, except group 2 of them (Table 1). Our AST values were very lower, and ALT values were significantly lower than Werawatganon et al's study (Table 1), [19]. This important changes can be originated from used dosage, animal number and species/sex, analytical methods and equipment or route of administration/duration, and also according to the structures of hepatotoxic chemicals (as APAP, CCl₄, Thioacetamide).

Considering the histopatologycal findings; in control (Figure 1A) and 10% SDOA (Figure 1B) groups, liver showed normal histological appearence. In APAP treated rats showed some histopathological changes as necrosis (Figure 2A), hemorrhage (Figure 2A, D), disruption of radial arrangement of hepatocytes from central vein, eosinophilic stained and pyknotic nuclei cells (Figure 2A, B), vascular congestion (Figure 2C), mononuclear cell infiltration (Figure 2C, E) and cellular swelling (Figure 2F). On the other hand, in APAP and 10% SDOA group, histopathological findings were not as extensive as in the APAP group.

Histopathological changes were significantly decreased in APAP + 10% SDOA group. (Figure 3A, B). Comparisons of the effect of 10% SDOA on microscopic damage caused by APAP in liver have been summarized in Table 2. This results were very similar with Galal et al somewhat similar with Wang et al and near similar with Werawatganon et al, although different animal species even used in third study [10,19,21].

In summary; it should be emphasized that above histopathological changes were significantly decreased in APAP+10% SDOA group than the others, and also this is supporting by serum biomarkers and histopathologycal findings (Table 1, Table 2 and Figure 1, Figure 2, Figure 3). Therefore, based on above histopathological changes daily SDOA consumption were significantly hepatoprotective in case of APAP therapy.

5. Conclusion

This study was demonstrated that SDOA consumption have strongly hepatoprotective effects againist acute APAP overdose induced liver histopathology in rats. For humans, in case of overdose APAP administration or chronic APAP treatments with SDOA consumption may be recommended.

Conflict of Interest

No conflict of interest was declared by the authors.

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