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Abstract

Aim: The aim of the present study was to investigate the therapeutic and preventive effects of N-acetyl cysteine and erdosteine on renal injury associated with paracetamol (acetaminophen) intoxication. Materials and methods: Female albino Wistar rats were divided into six groups: control; paracetamol (1 g/kg, oral); paracetamol (1 g/kg, oral) + erdosteine (150 mg/kg/day, oral); paracetamol (1 g/kg, oral) + N-acetyl cysteine (140 mg/kg bolus, followed by 70 mg/kg, oral); N-acetyl cysteine control (140 mg/kg bolus, followed by 70 mg/kg, oral); and erdosteine control (150 mg/kg/day, oral). Potential renal injury was assessed using biochemical analyses, radionuclide imaging, and histopathological parameters. Results: In the paracetamol group, blood urea nitrogen and creatinine levels were significantly increased compared with controls. Histopathological examination showed tubular vacuolization, tubular necrosis, and remarkable interstitial inflammation. The excretion function was observed to be insufficient on radionuclide imaging. However, in the groups treated with erdosteine or N-acetyl cysteine after paracetamol, biochemical analyses, radionuclide imaging, and histopathological parameters showed significantly less evidence of renal toxicity than that observed in the group receiving paracetamol alone. Less renal toxicity was detected in rats receiving N-acetyl cysteine than in those receiving erdosteine. Conclusion: Renal injury may develop after paracetamol overdose. Erdosteine and N-acetyl cysteine are both effective in the prevention of renal injury when given in the early phase of paracetamol nephrotoxicity. N-acetyl cysteine is more protective than erdosteine.

Keywords

paracetamol erdosteine renal toxicity radionuclide imaging

Introduction

Paracetamol (acetaminophen, N-acetyl-p-aminophenol, APAP) is one of the most commonly used analgesic and antipyretic drugs worldwide. It is safe when used in appropriate doses and amounts. The toxic dose of paracetamol is >7.5 g or >150 mg/kg.^1-3 The drug may produce toxic effects when taken long-term at doses of more than 4 g/day.³ Toxic doses of paracetamol can cause hepatic necrosis and acute tubular necrosis.^4,5 Acute renal failure secondary to paracetamol intoxication may be seen either alone or together with hepatic necrosis.^5-9 Hepatic encephalopathy accompanies renal failure, and dialysis may be needed in cases of severe intoxication.⁴

The reason for acute renal failure after ingestion of toxic amounts of paracetamol has not been conclusively determined. However, animal studies show that tubular injury is caused by the oxidation of paracetamol by the cytochrome P450 system when the kidneys are exposed to large amounts of paracetamol.^4-10

N-Acetyl cysteine (NAC) is used as an antidote in the treatment of paracetamol intoxication. NAC, which is also used as a mucolytic, is a cysteine precursor drug and has an antioxidant effect.^11-14 NAC prevents N-acetyl-p-benzo-quinone imine (NAPQI) from binding to hepatic macromolecules in the early phase of paracetamol intoxication (<8 h). It may exert its effect by acting as a glutathione precursor or alternatively as a sulfate precursor. NAC decreases neutrophil infiltration by increasing blood flow in the microcirculation and oxygen transport to the tissues in the late phase of paracetamol intoxication (>24 h).¹

Erdosteine, like NAC, is a mucolytic agent used in the treatment of pulmonary diseases. The erdosteine molecule contains two blocked thiol groups in its structure. Active erdosteine metabolites have antioxidant activity through the action of their sulfhydryl groups, which are formed by degradation of erdosteine in the liver.^14-17 Several studies have been published regarding the use of erdosteine in paracetamol intoxication,^9,14 but no direct comparison between erdosteine and NAC in paracetamol intoxication has been published previously.

The aim of the present study was to investigate the therapeutic and preventive effects of NAC and erdosteine on renal injury associated with paracetamol intoxication.

Methods

Animals and experimental procedures

This study, performed at the Duzce University Experimental Animals Laboratory in 2010, used 42 adult female albino Wistar rats weighing 200–230 g and selected from the same breed. The Ethics Committee of Duzce University (DU Ethics Committee Number: 2010-02) approved the study. The rats were cared for in accordance with the Guide for the Care and Use of Laboratory Animals. The rats were provided with standard rat feed and tap water in rhythmically lighted (12 h light/12 h dark) rooms at a temperature of 22 ± 2°C.

The animals were divided into six groups of seven rats each, as follows:

Group 1, control group;

Group 2, paracetamol group: Paracetamol (1 g/kg) given orally;

Group 3, erdosteine-treatment group: erdosteine given at an initial oral dose of 150 mg/kg 2 h after oral paracetamol (1 g/kg), followed by a single daily dose of 150 mg/kg erdosteine for 3 days;

Group 4, NAC treatment group: NAC given at an initial dose of 140 mg/kg 2 h after oral paracetamol (1 g/kg), followed by a maintenance dose of 70 mg/kg NAC given 17 times, 4 h apart;

Group 5, NAC control group: NAC given at an initial dose 140 mg/kg, followed by a maintenance dose of 70 mg/kg NAC given 17 times, 4 h apart; and

Group 6, erdosteine control group: Erdosteine given as a single oral dose of 150 mg/kg daily for 3 days.

Paracetamol, NAC, and erdosteine solutions were prepared with distilled water and given orally via nasogastric tube. At the end of 3 days of treatment, all rats were anesthetized by intramuscular injection of 50 mg/kg ketamine hydrochloride (Ketalar; Parke Davis, Eczacibasi, Istanbul, Turkey) and 3 mg/kg xylazine hydrochloride (Rompun; Bayer AG, Leverkusen, Germany). Additional doses were applied as needed during radionuclide imaging and surgery. Intravenous access was achieved through the tail after appropriate anesthesia was applied. Radionuclide imaging was performed prior to surgery.

For the surgical procedure, the animals were placed in the supine position, and the anterior abdominal wall was shaved and disinfected using 10% povidone-iodine solution. Laparotomy was performed through a midline incision, and renal tissue samples and blood samples were taken. The animals were then sacrificed by intraperitoneally administering a lethal dose of ketamine hydrochloride.

Biochemical analysis

Blood urea nitrogen (BUN) and creatinine levels were studied as measures of renal injury. Assessment was performed using commercially available kits in an Abbott Architect C-8000 Autoanalyzer (Abbott Laboratories, Chicago, Illinois, USA).

Histopathological examination

For histopathological examination, renal tissues were dissected, and tissue samples were fixed in Zenker solution for 24 h, processed through a graded ethanol series, and embedded in paraffin. The paraffin sections were cut into 5-μm-thick slices and stained with hematoxylin and eosin dye for light microscopic examination. The sections were viewed and photographed using an Olympus light microscope (Olympus BX51; Olympus Optical Co. Ltd., Tokyo, Japan) with an attached camera (Olympus E-330; Olympus Optical Co. Ltd., Japan). Ten slides were prepared from each kidney. All sections were evaluated for the degree of tubular vacuolization, tubular necrosis, and interstitial inflammation. The severity of the changes observed was scored using a scale of none (−), mild (+), moderate (++), and severe (+++) damage. Histopathological analysis was performed by an experienced pathologist.

Radionuclide imaging

Seven rats per group were imaged using a gamma camera (low energy, general purpose collimator, Siemens e.CAM, USA). To ensure adequate hydration, saline solution (5 mL) was given 15 min prior to the administration of the radiopharmaceutical. A bolus of 37 MBq (1 mCi) of Tc-99m MAG-3 (Technescan® MAG-3, Mallinckrodt Inc., Nepha, Ankara, Turkey) was injected intravenously through the tail vein of each rat lying supine under the gamma camera. Dynamic images were acquired at 1-min intervals during a period of 25 min on a 64 × 64 matrix. Regions of interest (ROIs) were drawn over each kidney. Radioactivity-versus-time curves were generated for the ROI. The percentage renal radioactivity uptake for each minute was calculated using the maximum uptake as the reference point, and then the mean percentage activity-versus-time curve, with standard errors, was drawn using Microsoft Excel. All groups were compared with controls via the mean percentage activity-versus-time curve. The images were also visually interpreted during the scanning procedure.

Statistical analysis

All measured information was uploaded to and assessed in SPSS v.11.5 (SPSS, Inc., Chicago, Illinois, USA). To show the normal distribution of groups, the one-sample Kolmogorov-Smirnov test (Lilliefors significance correction) was used. As all groups showed a normal distribution, parametric statistical methods were used to analyze the data. One-way ANOVA was performed, and post-hoc multiple comparisons were performed with the Bonferroni correction. The chi-square (Fisher’s exact) test was used for analysis of categorical data. Correlation analysis was performed using Kendall's tau-b test. The results are presented as means ± SEM. A p value <0.05 indicated statistical significance.

Results

Biochemical analysis

Statistically significant increases in serum BUN and creatinine levels were detected in the rats given paracetamol (group 2) compared with the rats in the other groups (p < 0.001 for each; Figure 1a and b). However, compared with the group receiving paracetamol alone (group 2), the groups administered erdosteine (group 3) and NAC (group 4) after receiving paracetamol showed significantly lower BUN and creatinine levels (p < 0.001 for each). The decreases in the BUN and creatinine levels did not differ significantly between the erdosteine (group 3) and NAC (group 4) groups (p > 0.05), although the levels tended to be lower in the NAC group (group 4). Furthermore, the BUN and creatinine levels after treatment (groups 3 and 4) did not differ significantly from the control levels.

Figure 1.

a, Comparison of blood urea nitrogen (BUN) levels in study groups. b, Comparison of creatinine in study groups.

There were statistically significant positive correlations of the BUN and creatinine levels, respectively, with tubular vacuolization (r = 0.547, p < 0.0001, and r = 0.677, p < 0.0001), necrosis (r = 0.428, p = 0.004, and r = 0.573, p < 0.0001), and interstitial inflammation (r = 0.565, p < 0.0001, and r = 0.650, p < 0.0001). The BUN and creatinine levels were negatively correlated (r = –0.518, p < 0.0001 and r = –0.668, p < 0.0001) with groups (from group 2 to group 6).

Histopathological examination results

Light microscopic examination of the kidneys revealed obvious tubular vacuolization, tubular necrosis, and interstitial inflammation in the paracetamol group (group 2) compared with the control group (Figure 2a). Tubular cellular necrosis was distinct (Figure 2b). As in the paracetamol group (group 2), tubular vacuolization, tubular necrosis, and interstitial inflammation were present in the erdosteine treatment group (group 3), but they were significantly decreased (p < 0.001), and the glomerular morphological appearance was better than in the paracetamol group (Figure 2c). In the NAC group (group 4), cellular desquamation injury was similar to that in the control group (Figure 2d) and was significantly less than that in the paracetamol group (group 2; p < 0.0001). The NAC control (group 5) and erdosteine control (group 6) groups showed good renal parenchymal morphology with well-defined glomeruli and tubules (Figure 2e and f). Table 1 presents data on the severity of the changes.

Figure 2.

Normal appearance tubular and interstitial area in the rat kidney of the group 1 (hematoxylin and eosin [HE], ×200; A). This microphotograph shows the severe tubular necrosis and vacuolization in the kidney of the paracetamol group, group 2 (HE, ×200; B). Moderate tubular necrosis and vacuolization in the group 3 (HE ×200; C). Mild tubular vacuolization in the NAC+ Para group, group 4 tubular necrosis was minimal or absent (HE, ×200; D). Normal appearance tubular and interstitial area in the rat kidney of the group 5 (HE, ×200; E). Normal appearance tubular and interstitial area in the rat kidney of the group 6 (HE, ×200; F).

Table 1.

Histopathological examination results

Parameter	Degree	Groups						p ^a
Parameter	Degree	Group 1	Group 2^a	Group 3	Group 4	Group 5	Group 6	p ^a
Tubular vacuolization^b	None	7	0	0	0	7	7	<0.0001
	Mild	0	0	5	7	0	0
	Moderate	0	4	2	0	0	0
	Severe	0	3	0	0	0	0
Tubular necrosis^b	None	7	0	1	3	7	7	<0.0001
	Mild	0	0	6	4	0	0
	Severe	0	7	0	0	0	0
Interstitial inflammatory^c	None	7	0	0	5	7	7	<0.0001
Interstitial inflammatory^c	Mild	0	7	7	2	0	0	<0.0001
Total	None	7	7	7	7	7	42

^a Comparison of group 2 vs other groups; statistically significant difference in tubular vacuolization and necrosis, and interstitial inflammation (p < 0.0001).

^b Comparison of group 3 vs group 4; no statistically significant difference in tubular vacuolization and necrosis (p > 0.05).

^c Comparison of group 3 vs group 4; statistically significant difference in interstitial inflammation (p < 0.005).

Radionuclide imaging

The renograms were interpreted visually using time-curve parameters for images of both the left and right kidneys from all 42 rats. Sufficient concentration function was achieved in all kidneys. A comparison of the mean percentage activities revealed that the excretion function was poor in the paracetamol group (group 2). The excretion function in both the paracetamol group treated with erdosteine and the paracetamol group treated with NAC (groups 3 and 4) was well preserved and similar to that in the control group ( 3), although relatively better function was seen in the paracetamol group treated with NAC (group 4).

Figure 3.

Mean percentage activity-time curve with standard error. The excretion functions were poor in paracetamol group compared to controls (upper right). The functions were preserved in group 3 (paracetamol group treated with erdosteine) and group 4 (paracetamol group treated with N-acetyl cysteine (NAC; middle left). NAC (middle right) and erdosteine (bottom) have not any unfavorable effects on excretion functions, individually. 209 × 208 mm (300 × 300 DPI).

Discussion

Paracetamol is metabolized 20%–46% by sulfation and 40%–67% by glucuronidation in the liver. Less than 5% is eliminated directly through the kidneys. A small amount is metabolized through oxidation by cytochrome P450 to produce NAPQI, a toxic reactive metabolite. The NAPQI is eliminated from the body as acetaminophen mercapturate, which is a non-toxic metabolite formed after detoxification of NAPQI by glutathione in the liver.^1,2,14

In the body, cytochrome P450 enzymes normally metabolize 4%–5% of paracetamol to NAPQI. However, this percentage increases when the glucuronidation and sulfation mechanisms are saturated, as when an overdose of paracetamol is taken. The majority of paracetamol may be metabolized by cytochrome P450, leading to the depletion of glutathione stores. Paracetamol-induced renal injury is thought to result from the reactive paracetamol metabolite NAPQI.^18,19 NAPQI interacts directly with glutathione and could thereby decrease the cellular glutathione level. There are two significant consequences of a decreased amount of glutathione. First, there is decreased inactivation of reactive metabolites and increased covalent binding of macromolecules. Second, low levels of glutathione cause seriously harmful effects on cellular balance and may increase the toxic effects of reactive metabolites.⁵

Although the exact renoprotective mechanisms of erdosteine and NAC are not clearly known, their antioxidant effect is thought to be a potential mechanism for decreasing the amount of reactive metabolites produced, thus preserving renal function. NAC is also known to replenish decreased glutathione stores.^1-3 The standard treatment for paracetamol overdose is NAC, which can be given orally or intravenously. After the first bolus dose of 140 mg/kg, 17 doses of 70 mg/kg are given 4 h apart.¹ Studies investigating the effects of NAC treatment in cases of renal failure caused by toxic compounds such as gentamycin²⁰ and ifosfamide²¹ have been published. Recently, erdosteine has been used to prevent injury caused by toxic compounds such as gentamycin,²² doxorubicin,²³ and cisplatin²⁴ in experimental animal models. It has been shown to prevent renal injury caused by paracetamol intoxication in a single experimental study.⁹ Erdosteine has been used at different dosages in different studies,^9,14,25 with dosages of up to 1000 mg/kg in animal studies.^9,24 In the present study, NAC was used as a 140 mg/kg bolus dose given orally, followed by a total of 17 doses of 70 mg/kg given orally every 4 h. Erdosteine was used at a dose of 150 mg/kg/day for a period of 3 days.

The direct nephrotoxic effects of paracetamol in large doses have been proven in animal studies.^4,9,26 In our study, increases in serum BUN and creatinine levels; evidence of tubular vacuolization, tubular necrosis, and interstitial inflammation on histopathological examination; and failure of the excretion function in renal scintigraphy were findings that indicated renal injury. Measurement of serum BUN and creatinine levels is one of the accepted methods for evaluating renal injury. In studies performed with nephrotoxic agents such as paracetamol, gentamycin, and ifosfamide, BUN and creatinine levels increased in the presence of renal injury.^9,20,21,26 The present study showed significant increases in levels of BUN and creatinine after exposure to high doses of paracetamol. However, these increases could be reversed by the administration of erdosteine or NAC. This finding is important, because it shows that both erdosteine and NAC were effective in the prevention of renal injury. The therapeutic efficacies of both agents were similar, resulting in BUN and creatinine levels close to those of the control group. Isik and colleagues⁹ used erdosteine at 150 mg/kg and 300 mg/kg dosages to prevent renal injury in paracetamol intoxication and found that the protective effect was comparable at both dosages (p > 0.05). Therefore, we used erdosteine at a dosage of 150 mg/kg in our study.

Renal structural changes have been shown in rats given paracetamol at dosages of 600 mg/kg/day and 1000 mg/kg/day.^9,27 To produce renal injury in the present study, paracetamol was given at a dosage of 1000 mg/kg/day, which caused tubular vacuolization, tubular necrosis, and interstitial inflammation. Our study supports the hypothesis that the main injury caused by paracetamol intoxication is tubular necrosis. Another significant finding is that renal intoxication was prevented to a greater extent with NAC. Tubular necrosis was also significantly less in the NAC-treated rats. Beneficial effects of erdosteine in the treatment of paracetamol intoxication were shown in a study performed by Isik and colleagues.⁹ Confirming those results, we further showed that both erdosteine and NAC can prevent histopathological renal injury induced by paracetamol intoxication.

Radionuclide imaging may also be used to demonstrate renal damage. Using radiopharmaceuticals to study nephrotoxicity caused by drugs in animal models provides certain advantages over histopathological examination and biochemical measurements of BUN and creatinine. Radionuclide imaging has been used effectively as an alternative toxicological method for studying the nephrotoxicity of drugs,^28,29 and 99mTc MAG-3, which is concentrated by the whole renal parenchyma, can show early biochemical or physiological dysfunction before anatomical alterations develop. Furthermore, both local and systemic information regarding kidney dysfunction can be obtained. The procedure is generally simple, easily repeatable, and adaptable to chronological study in the same animals.^29,30 Using radionuclide imaging, we showed that the excretion function was insufficient in the paracetamol group but was preserved in rats treated with either erdosteine or NAC following paracetamol treatment, with slightly better function in the paracetamol group treated with NAC. We also demonstrated that neither NAC nor erdosteine administered alone had any unfavorable effects on kidney function. We concluded that paracetamol impairs tubular functions and may cause acute tubular necrosis.

The risk for development of renal injury is decreased when NAC or erdosteine treatment is given in the early phase of paracetamol overdose. However, it is not known whether these treatments are effective after the development of renal injury. Although there was no statistically significant difference between the erdosteine and NAC treatment groups, less renal injury developed in the NAC group, suggesting that NAC is more effective in the treatment of paracetamol-induced renal injury. According to the results of the present study, NAC should be preferred, rather than erdosteine, as a protective agent against paracetamol-induced acute tubular necrosis.

The limitations of this study include the short study period and lack of screening for oxidant and antioxidant variables.

In conclusion, renal injury may develop in paracetamol overdose. When given in the early phase of paracetamol nephrotoxicity, erdosteine and NAC are both effective in the prevention of renal injury. However, NAC produced superior results in terms of histological renoprotection.

Footnotes

We received no financial support for the research and/or authorship of this article.

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Comparison of the effects of N -acetyl cysteine and erdosteine in rats with renal injury caused by paracetamol intoxication

Abstract

Keywords

Introduction

Methods

Animals and experimental procedures

Biochemical analysis

Histopathological examination

Radionuclide imaging

Statistical analysis

Results

Biochemical analysis

Histopathological examination results

Radionuclide imaging

Discussion

Footnotes

References